* 608537

VON HIPPEL-LINDAU TUMOR SUPPRESSOR; VHL


HGNC Approved Gene Symbol: VHL

Cytogenetic location: 3p25.3     Genomic coordinates (GRCh38): 3:10,141,778-10,153,667 (from NCBI)


Gene-Phenotype Relationships
Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
3p25.3 Erythrocytosis, familial, 2 263400 AR 3
Hemangioblastoma, cerebellar, somatic 3
Pheochromocytoma 171300 AD 3
Renal cell carcinoma, somatic 144700 3
von Hippel-Lindau syndrome 193300 AD 3

TEXT

Description

The protein products of the VHL gene play a role in the oxygen-sensing pathway, in microtubule stability and orientation, tumor suppression, cilia formation, regulation of senescence, cytokine signaling, collagen IV (see 120130) regulation, and assembly of a normal extracellular fibronectin matrix (summary by Nordstrom-O'Brien et al., 2010).


Cloning and Expression

By positional cloning, Latif et al. (1993) identified the VHL tumor suppressor gene. The gene encodes a 213-amino acid protein with a predicted acidic repeat domain found in the procyclic surface membrane glycoprotein of Trypanosoma brucei. The authors identified 2 widely expressed mRNA transcripts of approximately 6 and 6.5 kb.

Iliopoulos et al. (1995) demonstrated that the VHL protein has a molecular mass of approximately 30-kD.

By screening a rat liver cDNA library, Duan et al. (1995) isolated the rat VHL gene, which is predicted to encode a 185-amino acid protein. The rat protein is 88% identical to the aligned 213-amino acid human VHL gene product. The human and rat proteins had molecular masses of 28 and 21 kD, respectively.

Richards et al. (1996) used in situ hybridization to investigate the principal sites of VHL expression during embryogenesis. They also analyzed a variety of fetal tissues for levels of 2 VHL isoforms, isoform 1, which contains all 3 exons, and isoform 2, which contains only exons 1 and 3. Although VHL expression was found to be ubiquitous, particularly high levels of expression were detected in the urogenital system, brain, spinal cord, sensory ganglia, eyes, and bronchial epithelium. Richards et al. (1996) noted that this expression pattern correlated to some extent with the pattern of organ involvement in VHL syndrome but that there were significant differences. Both isoforms of VHL were detected in all tissues, and the ratio of isoforms was similar between tissues.

Schoenfeld et al. (1998) identified a second native VHL gene product. They showed that this 18-kD protein is initiated from the second translation start site at codon 54, which contains a more conserved Kozak consensus sequence and thus may serve as a second, internal, translation initiation site. The significance of a second translation start site is underscored by the lack of mutations found between the first and second methionine codons of the VHL gene in both sporadic and VHL-associated renal carcinomas. This observation suggested that mutation in this region may not lead to VHL inactivation if translation could be initiated at the second methionine codon, producing a functional VHL protein. Furthermore, both the rat and mouse contain only 19 of the 53 amino acids present in this region in the human VHL ORF. Schoenfeld et al. (1998) concluded that the 18-kD protein contains the biologic activity of the VHL gene.

Iliopoulos et al. (1998) also demonstrated that in addition to the 213-amino acid VHL protein with an apparent molecular mass of 30 kD (VHL30), a second VHL protein (VHL19) resulted from internal translation from the second methionine within the VHL ORF. VHL30 resides primarily in the cytosol, with lower amounts found in the nucleus or associated with cell membranes. In contrast, VHL19 is equally distributed between the nucleus and cytosol and is not found in association with membranes. VHL19, like VHL30, can bind to elongin B (ELOB; 600787), elongin C (ELOC; 600788), and Hs-Cul2 in coimmunoprecipitation assays and can inhibit the production of hypoxia-inducing proteins such as VEGF (192240) and GLUT1 (138140) when reintroduced into renal carcinoma cells that lack a wildtype VHL allele. Thus, cells contain 2 biologically active VHL gene products.

The commonly described VHL transcript contains all 3 exons that encode a 213-residue protein (termed VHL213 or VHL30). A smaller isoform, VHL160 or VHL19, is initiated from an in-frame internal translation start site in exon 1. VHL isoform VHL172 lacks exon 2. Lenglet et al. (2018) identified a cryptic exon deep in intron 1 of the VHL gene, termed E1-prime, which is naturally expressed in many tissues. Isoforms containing E1-prime with VHL exons produce a protein termed X1. Isoforms containing exon 1 spliced with E1-prime theoretically encode a protein of 193 amino acids (114 encoded by exon 1, and 79 encoded by E1-prime) (summary by Lenglet et al., 2018).


Gene Structure

Latif et al. (1993) determined that the VHL gene contains at least 3 exons.

Zatyka et al. (2002) analyzed the promoter region of the VHL gene and found 4 regions of conservation between human, primate, and rodent sequences. In silico analysis identified binding sites for numerous transcription factors within the conserved regions, and deletion analysis of the promoter in a reporter assay in 293 and HeLa cells identified 1 negative and 2 positive regulatory elements. The promoter contains a functional SP1 (189906) site and overlapping SP1/AP2 (107580) sites.

Lenglet et al. (2018) identified a cryptic exon, termed E1-prime, deep in intron 1 of the VHl gene.


Gene Function

Role in Tumor Suppression

Maher et al. (1990) compared age incidence curves for sporadic cerebellar hemangioblastoma and sporadic renal cell carcinoma to those for familial forms of these tumors that occur as part of von Hippel-Lindau syndrome (193300). The curves for tumors in VHL syndrome were compatible with a single mutation model, whereas the age incidence curves for sporadic tumors suggested a 2-stage mutation process. On the whole, the findings suggested that the VHL gene functions as a recessive tumor suppressor gene.

Crossey et al. (1994) presented convincing evidence that the VHL syndrome gene functions as a recessive tumor suppressor gene and that inactivation of both alleles of the VHL gene is a critical event in the pathogenesis of VHL neoplasms. Studies of loss of heterozygosity (LOH) showed that in 7 tumors from 7 familial cases in which the parental origin of the 3p26-p25 allele loss could be determined, the allele had been lost from the chromosome inherited from the unaffected parent. In 4 VHL tumors, LOH on other chromosomes (5q21, 13q, 17q) was found, indicating that homozygous VHL gene mutations may be required but not sufficient for tumorigenesis in von Hippel-Lindau syndrome.

When expressed in COS-7 cells, Duan et al. (1995) found that both the human and the rat VHL proteins showed predominant nuclear, nuclear and cytosolic, or predominant cytosolic VHL staining by immunofluorescence. A complicated pattern of cellular proteins was seen that could be specifically coimmunoprecipitated with the introduced VHL protein. A complex containing VHL and proteins with apparent molecular masses of 16 and 9 kD was the most consistently observed. Certain naturally occurring VHL missense mutations demonstrated either complete or partial loss of the p16-p9 complex. Duan et al. (1995) concluded that the VHL tumor suppressor gene product is a nuclear protein, perhaps capable of specifically translocating between the nucleus and the cytosol. They suggested that VHL may execute its function via formation of specific multiprotein complexes.

Vogelstein (1995) referred to the VHL gene as a gatekeeper gene for cancers such as those of the kidney. Rubenstein and Yaari (1994) suggested that the VHL gene may serve that role in relation to astrocytoma. They presented the pedigree of a Puerto Rican family in which at least 9 members had von Hippel-Lindau syndrome and 2 of these had astrocytoma.

To elucidate the biochemical mechanisms underlying tumor suppression by the VHL protein, Duan et al. (1995) and Kibel et al. (1995) searched for cellular proteins that bind to wildtype VHL protein but not to tumor-derived VHL protein mutants. They found that 2 transcriptional elongation factors, elongin B (600787) and elongin C (600788), bind in vitro and in vivo to a short, colinear region of the VHL protein that is frequently mutated in human tumors. Kibel et al. (1995) showed that a peptide replica of this region inhibited binding of VHL protein to elongin B and elongin C, whereas a point-mutant derivative, corresponding to a naturally occurring VHL missense mutation, had no effect. Duan et al. (1995) showed that recombinant VHL competes with elongin A (ELOA; 600786) for elongin B and C binding in vitro. The results were interpreted as indicating that the normal tumor suppression function of VHL protein involves the inhibition of transcription elongation by its binding to elongin B and elongin C.

In a review article, Tyers and Willems (1999) stated that the VHL protein is part of a complex that includes elongin B, elongin C, and cullin-2 (CUL2; 603135), proteins that are associated with transcriptional elongation and ubiquitination. Components of the VCB (VHL/elongin C/elongin B) complex share sequence similarities with the E3 ubiquitin ligase complexes SCF (SKP1, (601434); CUL1, (603134); F-box protein) and APC (anaphase promoting complex; see 603462). Thus, elongin B is ubiquitin-like, and elongin C and CUL2 are similar to the SKP1 and CUL1 components of SCF, respectively. Substrate recognition by E3 enzymes such as SCF and APC is crucial because protein degradation must be highly selective. Both SCF and APC interact with a set of adaptor proteins that recruit different binding partners through specific protein-protein interaction domains. SOCS-box-containing proteins (see 603597) may act as adaptors for the VCB complex.

Feldman et al. (1999) demonstrated that the folding and assembly of VHL into a complex with its partner proteins, elongin B and elongin C, is directly mediated by the chaperonin TRiC, also called CCT (see 600114). Association of VHL with TRiC is required for formation of the VHL-ELOB-ELOC complex. A 55-amino acid domain of VHL (amino acids 100 to 155) is both necessary and sufficient for binding to TRiC. Mutation or deletion of this domain is associated with VHL syndrome, and 2 mutations that disrupt the normal interaction with TRiC and impair VHL folding were identified. These results defined a novel role for TRiC in mediating oligomerization and suggested that inactivating mutations can impair polypeptide function by interfering with chaperone-mediated folding.

Lee et al. (1996) demonstrated that there is a tightly regulated, cell-density-dependent transport of the VHL protein into and/or out of the nucleus. In densely grown cells, it is predominantly in the cytoplasm, whereas in sparse cultures, most of the protein can be detected in the nucleus. They identified a putative nuclear localization signal in the first 60 and first 28 amino acids of the human and rat VHL protein, respectively. Sequences in the C-terminal region of VHL protein may also be required for localization to the cytosol. The findings indicated a novel cell-density-dependent pathway responsible for the regulation of VHL cellular localization.

Iliopoulos et al. (1995) showed that the renal cell carcinoma cell line 786-O, which is known to harbor a VHL mutation, fails to produce a wildtype VHL protein. Reintroduction of wildtype, but not mutant, VHL into these cells had no demonstrable effect on their growth in vitro but inhibited their ability to form tumors in nude mice. Like many cancer cells, the 786-0 RCC fails to exit the cell cycle upon serum withdrawal. Pause et al. (1998) showed that reintroduction of the wildtype VHL gene restores the ability of VHL-negative RCC cells to exit the cell cycle and enter G0/quiescence in low serum. The cyclin-dependent kinase inhibitor p27 (CDKN1B; 600778) accumulates upon serum withdrawal, only in the presence of VHL, as a result of an increase in protein stability. Pause et al. (1998) proposed that loss of the wildtype VHL gene results in a specific cellular defect in serum-dependent growth control, which may initiate tumor formation. Thus, VHL appears to be the first tumor suppressor involved in the regulation of cell cycle exit, which is consistent with its gatekeeper function in the kidney.

To discover genes involved in VHL-mediated carcinogenesis, Ivanov et al. (1998) used renal cell carcinoma cell lines stably transfected with wildtype VHL-expressing transgenes. Large-scale RNA differential display technology applied to these cell lines identified several differentially expressed genes, including an alpha carbonic anhydrase gene, termed CA12 (603263). The deduced protein sequence was classified as a one-pass transmembrane carbonic anhydrase possessing an apparently intact catalytic domain in the extracellular CA module. Reintroduced wildtype VHL strongly inhibited the overexpression of the CA12 gene in the parental renal cell carcinoma cell lines. Similar results were obtained with CA9 (603179) which encodes another transmembrane carbonic anhydrase with an intact catalytic domain. Although both domains of the VHL protein contributed to regulation of CA12 expression, the elongin binding domain alone could effectively regulate CA9 expression. By fluorescence in situ hybridization, Ivanov et al. (1998) mapped CA12 and CA9 to chromosome bands 15q22 and 17q21.2, respectively, regions prone to amplification in some human cancers. Ivanov et al. (1998) stated that additional experiments were necessary to define the role of CA IX and CA XII enzymes in the regulation of pH in the extracellular microenvironment and its potential impact on cancer cell growth.

Roe et al. (2006) found that VHL directly associated with and stabilized p53 (TP53; 191170) by suppressing MDM2 (164785)-mediated ubiquitination and nuclear export of p53. Moreover, upon genotoxic stress, VHL invoked an interaction between p53 and p300 (EP300; 602700) and the acetylation of p53, which led to an increase in p53 transcriptional activity and cell cycle arrest and apoptosis. Roe et al. (2006) concluded that VHL has a function in upregulating p53.

Yang et al. (2007) noted that VHL-defective renal carcinoma cells exhibit increased NF-kappa-B (see 164011) activity, which can promote resistance to chemotherapy or cytokines. They showed that VHL downregulates NF-kappa-B activity by acting as an adaptor to promote casein kinase-2 (see 115440)-mediated inhibitory phosphorylation of CARD9 (607212), an NF-kappa-B agonist.

Using in situ hybridization, analysis of RNA sequencing data, and quantitative RT-PCR, Zhu et al. (2017) found that DAAM2 (606627) was more highly expressed in human low-grade glioma and glioblastoma multiforme (GBM; see 137800) than in normal brain tissue. DAAM2 was also highly expressed in xenograft tumors generated from primary human GBM cell lines and in tumors generated in a mouse model of GBM. Overexpression of DAAM2 in human GBM cell lines resulted in accelerated rates of cell growth and colony formation, whereas knockdown of DAAM2 via short hairpin RNA inhibited growth of these cell lines. Overexpression of Daam2 in 2 mouse models of malignant glioma also resulted in accelerated tumorigenesis. Protein screening and bioinformatic analysis revealed an inverse correlation of DAAM2 and VHL expression across a broad spectrum of cancers. Similarly, Vhl protein expression was reduced in Daam2 gain-of-function mouse tumors and increased in Daam2 loss-of-function mouse tumors. Gene expression analysis showed altered Vhl signaling in Daam2-expressing mouse gliomas. Biochemical analyses revealed that DAAM2 and VHL physically interacted and that DAAM2 overexpression resulted in decreased VHL protein levels and increased VHL ubiquitination levels, suggesting that DAAM2 facilitates ubiquitin-driven protein degradation of VHL. Zhu et al. (2017) concluded that DAAM2 is part of an upstream mechanism regulating VHL suppression in cancer.

Role in Oxygen-Related Gene Expression

The highly vascular tumors associated with von Hippel-Lindau syndrome overproduce angiogenic peptides such as vascular endothelial growth factor/vascular permeability factor (VEGF/VPF; 192240). Iliopoulos et al. (1996) found that renal carcinoma cells lacking wildtype VHL protein produce mRNAs encoding VEGF/VPF, the glucose transporter GLUT1 (SLC2A1; 138140), and the platelet-derived growth factor B chain (190040) under both normoxic and hypoxic conditions. Reintroduction of wildtype, but not mutant, VHL protein into these cells specifically inhibited production of these mRNAs under normoxic conditions, thus restoring their previously described hypoxia-inducible profile. Iliopoulos et al. (1996) concluded that the VHL protein appears to play a critical role in the transduction of signals generated by changes in ambient oxygen tension.

VEGF mRNA is upregulated in von Hippel-Lindau syndrome-associated tumors. Mukhopadhyay et al. (1997) assessed the effect of the VHL gene product on VEGF expression. Using a VEGF promoter-luciferase construct for cotransfection with a wildtype VHL vector in embryonic kidney and renal cell carcinoma cell lines, they showed that wildtype VHL protein inhibited VEGF promoter activity in a dose-dependent manner up to 5- to 10-fold. Deletion analysis defined a 144-bp region of the VEGF promoter necessary for VHL repression. This VHL-responsive element is GC rich and specifically bound the transcription factor Sp1 (189906) in crude nuclear extracts. They further demonstrated that VHL and Sp1 directly interact with an inhibitory effect on Sp1, suggesting that loss of Sp1 inhibition may be important in the pathogenesis of von Hippel-Lindau syndrome and renal cell carcinoma.

Maxwell et al. (1999) studied the involvement of VHL in oxygen-regulated gene expression using ribonuclease protection analysis of 2 VHL-deficient renal carcinoma cell lines, RCC4 and 786-O. Eleven genes encoding products involved in glucose transport, glycolysis, high energy phosphate metabolism, and angiogenesis were examined; 9 were induced by hypoxia in other mammalian cells and 2 were repressed by hypoxia. None of these responses were seen in the VHL-defective cell lines. Responses to hypoxia were restored by stable transfection of a wildtype VHL gene, with effects ranging from a modest action of hypoxia to substantial regulation. These results indicated that the previously described upregulation of hypoxia-inducible mRNAs in VHL-defective cells extend to a broad range of oxygen-regulated genes and involves a constitutive 'hypoxia pattern' for both positively and negatively regulated genes.

Hypoxia-inducible factor-1 (HIF1; 603348) has a key role in cellular response to hypoxia, including the regulation of genes involved in energy metabolism, angiogenesis, and apoptosis. The alpha subunits of HIF are rapidly degraded by the proteasome under normal conditions but are stabilized by hypoxia. Cobaltous ions or iron chelators mimic hypoxia, indicating that the stimuli may interact through effects on a ferroprotein oxygen sensor. Maxwell et al. (1999) demonstrated a critical role for the von Hippel-Lindau tumor suppressor gene product VHL in HIF1 regulation. In VHL-defective cells, HIF-alpha subunits were constitutively stabilized and HIF1 was activated. Reexpression of VHL restored oxygen-dependent instability. VHL and HIF-alpha subunits coimmunoprecipitated, and VHL was present in the hypoxic HIF1 DNA-binding complex. In cells exposed to iron chelation or cobaltous ions, HIF1 is dissociated from VHL. These findings indicated that the interaction between HIF1 and VHL is iron dependent and that it is necessary for the oxygen-dependent degradation of HIF-alpha subunits. Maxwell et al. (1999) suggested that constitutive HIF1 activation may underlie the angiogenic phenotype of VHL-associated tumors.

In the presence of oxygen, HIF is targeted for destruction by an E3 ubiquitin ligase containing the VHL tumor suppressor protein. Ivan et al. (2001) found that human VHL protein binds to a short HIF-derived peptide when a conserved proline residue at the core of this peptide is hydroxylated. Because proline hydroxylation requires molecular oxygen and iron, this protein modification may play a key role in mammalian oxygen sensing. Jaakkola et al. (2001) also demonstrated that the interaction between VHL protein and a specific domain of the HIF1-alpha subunit is regulated through hydroxylation of a proline residue (HIF1-alpha P564) by an enzyme which they termed HIF-alpha prolyl-hydroxylase (HIF-PH). An absolute requirement for dioxygen as a cosubstrate and iron as a cofactor suggests that HIF-PH functions directly as a cellular oxygen sensor.

Mahon et al. (2001) showed that the N-terminal 155 residues of VHL interact with HIF1AN (606615). They found that VHL functions as a transcriptional corepressor inhibiting HIF1A transactivation by recruiting HDAC1 (601241), HDAC2 (605164), and HDAC3 (605166). Epstein et al. (2001) defined a conserved HIF-VHL-prolyl hydroxylase pathway in C. elegans and identified Egl9 as a dioxygenase that regulates HIF by prolyl hydroxylation. In mammalian cells, they showed that the HIF-prolyl hydroxylases are represented by 3 proteins, PHD1 (606424), PHD2 (606425), and PHD3 (606426), with a conserved 2-histidine-1-carboxylate iron coordination motif at the catalytic site. Direct modulation of recombinant enzyme activity by graded hypoxia, iron chelation, and cobaltous ions mirrored the characteristics of HIF induction in vivo, fulfilling requirements for these enzymes being oxygen sensors that regulate HIF.

Hoffman et al. (2001) reported that the products of 4 different type 2C VHL alleles retain the ability to downregulate HIF but are defective for promotion of fibronectin (135600) matrix assembly. Furthermore, leu188 to val (L188V; 608537.0014), a well-studied type 2C mutation, retained the ability to suppress renal carcinoma growth in vivo.

Clifford et al. (2001) investigated in detail the effect of 13 naturally occurring VHL mutations (11 missense), representing each phenotypic subclass, on HIF-alpha subunit regulation. Mutations associated with the PHE-only phenotype (type 2C) promoted HIF-alpha ubiquitylation in vitro and demonstrated wildtype binding patterns with VHL interacting proteins, suggesting that loss of other VHL functions are necessary for PHE susceptibility. Mutations causing HAB susceptibility (types 1, 2A, and 2B) demonstrated variable effects on HIF-alpha subunit and elongin binding, but all resulted in defective HIF-alpha regulation and loss of fibronectin binding. All RCC-associated mutations caused complete HIF-alpha dysregulation and loss of fibronectin binding. These studies strengthened the notion that HIF deregulation plays a causal role in hemangioblastoma and renal carcinoma, and raised the possibility that abnormal fibronectin matrix assembly contributes to pheochromocytoma pathogenesis in the setting of VHL syndrome.

Hemangioblastomas of the central nervous system and retina in VHL patients overexpress vascular endothelial growth factor, which represents a potential target for anti-angiogenic drugs. In 3 VHL patients with CNS or retinal hemangioblastomas treated by the anti-VEGF receptor SU5416, Richard et al. (2002) observed, after 3 to 4 months of treatment, a secondary paradoxical polycythemia. Hematocrit was normal before the beginning of the trial, and no progression of hemangioblastomas was observed. Polycythemia had never been reported in SU5416 trials for advanced malignancies. In the studies of Richard et al. (2002), the polycythemia may have represented a specific action on red blood cell precursors occurring only in the absence of a functional VHL gene.

Staller et al. (2003) demonstrated that the VHL tumor suppressor protein negatively regulates CXCR4 (162643) expression owing to its capacity to target HIF1A (603348) for degradation under normoxic conditions. This process is suppressed under hypoxic conditions, resulting in HIF-dependent CXCR4 activation. An analysis of clear cell renal carcinoma that manifests mutations in the VHL gene in most cases revealed an association of strong CXCR4 expression with poor tumor-specific survival. Staller et al. (2003) concluded that their results suggest a mechanism for CXCR4 activation during tumor cell evolution and imply that VHL inactivation acquired by incipient tumor cells early in tumorigenesis confers not only a selective survival advantage but also the tendency to home to selected organs.

Corn et al. (2003) established that the VHL protein binds to Tat-binding protein-1 (TBP1; 186852). TBP1 associates with the beta-domain of VHL and complexes with VHL and HIF1A in vivo. Overexpression of TBP1 promotes degradation of HIF1A in a VHL-dependent manner that requires the ATPase domain of TBP1. Several distinct mutations in exon 2 of the VHL gene disrupt binding of VHL to TBP1. A VHL protein mutant containing an exon 2 missense substitution coimmunoprecipitated with HIF1A, but not TBP1, and did not promote degradation of HIF1A. Thus, the ability of the VHL protein to degrade HIF1A depends in part on its interaction with TBP1 and suggests a new mechanism for HIF1A stabilization in some VHL-deficient tumors.

To identify novel target genes of the VHL protein, Zatyka et al. (2002) investigated the effect of wildtype VHL protein on the expression of 588 cancer-related genes in 2 VHL-defective renal cell carcinoma cell lines. Expression array analysis identified 9 genes that demonstrated a greater than 2-fold decrease in expression in both RCC cell lines after restoration of wildtype VHL protein. Three of the 9 genes, VEGF, PAI1 (173360), and LRP1 (107770), had previously been reported as targets of the VHL protein and are hypoxia-inducible. In addition, 6 novel targets were detected, including cyclin D1 (CCND1; 168461). No evidence was found that CCND1 expression was influenced by hypoxia, suggesting that VHL protein downregulates these targets by an HIF-independent mechanism.

Using yeast 2-hybrid and pull-down assays, Li et al. (2003) showed that the KRAB-A domain of human VHLAK (618359) interacted with VHL. Immunoprecipitation and expression analyses in HEK293 and A498 cells showed that VHL repressed transactivation of HIF1-alpha and HIF1-alpha-induced expression of VEGF by recruiting VHLAK to HIF1-alpha.

Homozygous disruption of the Vhl gene in mice results in embryonic lethality from lack of placental vasculogenesis (Gnarra et al., 1997). To investigate Vhl function in the adult, Haase et al. (2001) generated a conditional Vhl-null allele (2-lox allele) and a null allele (1-lox allele) by Cre-mediated recombination in embryonic stem cells. They showed that mice heterozygous for the 1-lox allele developed cavernous hemangiomas of the liver, a rare manifestation in the human disease. Histologically, these tumors were associated with hepatocellular steatosis and focal proliferations of small vessels. To study the cellular origin of these lesions, Haase et al. (2001) inactivated VHL tissue specifically in hepatocytes. Deletion of VHL in the liver resulted in severe steatosis, many blood-filled vascular cavities, and foci of increased vascularization within the hepatic parenchyma. These histopathologic changes were similar to those seen in livers from mice heterozygous for the 1-lox allele. Hypoxia-inducible mRNAs encoding vascular endothelial growth factor, glucose transporter-1, and erythropoietin (EPO; 133170) were upregulated. Thus, targeted inactivation of mouse Vhl replicated clinical features of the human disease and underscored the importance of the VHL gene product in the regulation of hypoxia-responsive genes in vivo.

Wang et al. (2007) showed that mice overexpressing Hif1a in osteoblasts through selective deletion of Vhl expressed high levels of Vegf (192240) and developed extremely dense, heavily vascularized long bones. In contrast, mice lacking Hif1a in osteoblasts had long bones that were significantly thinner and less vascularized than those of controls. Loss of Vhl in osteoblasts increased endothelial sprouting from the embryonic metatarsals in vitro but had little effect on osteoblast function in the absence of blood vessels. Wang et al. (2007) concluded that activation of the HIF1A pathway in osteoblasts during bone development couples angiogenesis to osteogenesis.

Endocytosis plays a major role in the deactivation of receptors localized to the plasma membrane, and early endocytic events require the small GTPase RAB5 (179512) and its effector rabaptin-5 (RABEP1; 603616). Wang et al. (2009) found that hypoxia, via the VHL-HIF2A (603349) signaling pathway, downregulated rabaptin-5 expression, leading to decelerated endocytosis and prolonged activation of ligand-bound EGFR (131550). Primary kidney and breast tumors with strong hypoxic signatures showed significantly lower expression of rabaptin-5 RNA and protein. Wang et al. (2009) identified a conserved hypoxia-responsive element (HRE) in the rabaptin-5 promoter that bound in vitro-translated HIF1A and HIF2A, leading to displacement of RNA polymerase II and attenuating rabaptin-5 transcription.

Mehta et al. (2009) reported that in C. elegans the loss of VHL1 significantly increased life span and enhanced resistance to polyglutamine and beta-amyloid toxicity. Deletion of HIF1 (603348) was epistatic to VHL1, indicating that HIF1 acts downstream of VHL1 to modulate aging and proteotoxicity. VHL1 and HIF1 control longevity by a mechanism distinct from both dietary restriction and insulin-like signaling. Mehta et al. (2009) concluded that their findings define VHL1 and the hypoxic response as an alternative longevity and protein homeostasis pathway.

Russell et al. (2011) demonstrated that VHL binds to SOCS1 (603597) and promotes degradation of phosphorylated JAK2 (147796) via ubiquitin-mediated destruction.

Guo et al. (2016) explored a possible link between hypoxia and AKT (608537) activity. They found that AKT was prolyl-hydroxylated by the oxygen-dependent hydroxylase EGLN1 (606425). The VHL protein bound directly to hydroxylated AKT and inhibited AKT activity. In cells lacking oxygen or functional VHL, AKT was activated to promote cell survival and tumorigenesis. Guo et al. (2016) also identified cancer-associated AKT mutations that impair AKT hydroxylation and subsequent recognition by VHL, thus leading to AKT hyperactivation. Guo et al. (2016) concluded that microenvironmental changes, such as hypoxia, can affect tumor behaviors by altering AKT activation, which has a critical role in tumor growth and therapeutic resistance.

Role in Protein Assembly

Ohh et al. (1998) showed that fibronectin coimmunoprecipitated with normal VHL protein but not tumor-derived VHL mutants. Immunofluorescence and biochemical fractionation experiments showed that fibronectin colocalized with a fraction of VHL associated with the endoplasmic reticulum, and cold competition experiments suggested that complexes between fibronectin and VHL protein exist in intact cells. Assembly of an extracellular fibronectin matrix by VHL -/- renal carcinoma cells, as determined by immunofluorescence and ELISA assays, was grossly defective compared with VHL +/+ renal carcinoma cells. Reintroduction of wildtype, but not mutant, VHL protein into VHL -/- renal carcinoma cells partially corrected this defect. Extracellular fibronectin matrix assembly by VHL -/- mouse embryos and mouse embryo fibroblasts, unlike their VHL +/+ counterparts, was grossly impaired. Ohh et al. (1998) concluded that VHL protein is important in fibronectin matrix assembly.

Hergovich et al. (2003) found that VHL is a microtubule-associated protein that can protect microtubules from depolymerization in several cell lines. Both the microtubule binding and stabilization functions depended on amino acids 95-123, a hotspot for mutations in VHL syndrome. They found that the syndrome-associated mutations Y98H (608537.0009) and Y112H (608537.0012) disrupted the microtubule-stabilizing function of the protein.

Role in Ciliary Maintenance

Using immunofluorescence and confocal microscopy, Lolkema et al. (2008) showed that Vhl localized to cilia extending from basal bodies stained with gamma-tubulin (TUBG1; 191135) in primary mouse kidney cells. Cilia were absent in renal cell carcinoma cells derived from a VHL patient, but reintroduction of VHL into these cells resulted in rapid cilia assembly. The cilia function of VHL required residues 1 to 53, which constitute an acidic domain, and residues 95 to 123, which were previously implicated in microtubule binding and tumor suppression.

Role in Central Nervous System Development

Kanno et al. (2000) investigated the role of the VHL gene in CNS development using rodent CNS progenitor cells. They showed that expression of the VHL protein is correlated with neuronal differentiation but not with glial differentiation in CNS progenitor cells, and also that VHL gene transduction induces neuronal differentiation. Furthermore, a VHL mRNA antisense oligonucleotide inhibited differentiation of CNS progenitor cells and upregulated their cell cycle.


Biochemical Features

Crystal Structure

The ubiquitination of HIF by VHL plays a central role in the cellular response to changes in oxygen availability. VHL protein binds to HIF only when a conserved proline in HIF is hydroxylated, a modification that is oxygen-dependent. Min et al. (2002) determined the 1.85-angstrom structure of a 20-residue HIF1A-VHL protein-elongin B-elongin C complex that shows that HIF1A binds to VHL protein in an extended beta strand-like conformation. The hydroxyproline inserts into a gap in the VHL hydrophobic core, at a site that is a hotspot for tumorigenic mutations, with its 4-hydroxyl group recognized by buried serine and histidine residues. Although the beta sheet-like interactions contribute to the stability of the complex, the hydroxyproline contacts are central to the strict specificity characteristic of signaling.

Hon et al. (2002) determined the crystal structure of a hydroxylated HIF1A peptide bound to the VHL protein, elongin C, and elongin B and performed solution binding assays, which revealed a single, conserved hydroxyproline-binding pocket in the VHL protein. They found that optimized hydrogen bonding to the buried hydroxyprolyl group confers precise discrimination between hydroxylated and unmodified prolyl residues. Hon et al. (2002) concluded that this mechanism provides a new focus for development of therapeutic agents to modulate cellular responses to hypoxia.


Molecular Genetics

Nordstrom-O'Brien et al. (2010) provided a review of the molecular genetics of the VHL gene, including the mutational spectrum and associated phenotypes.

Von Hippel-Lindau Syndrome, Autosomal Dominant

Using restriction fragment analysis, Latif et al. (1993) identified rearrangements of the VHL gene in 28 of 221 kindreds with von Hippel-Lindau syndrome (VHLS; 193300). Eighteen of these rearrangements were due to deletion in the candidate gene. Using pulsed field gel electrophoresis and cosmid mapping, Latif et al. (1993) established a physical map of the VHL gene region and identified 3 large nonoverlapping constitutional deletions in 3 unrelated VHL patients; one of these was an in-frame 3-nucleotide deletion at nucleotide 434, predicted to remove ile146 in the gene product (608537.0001).

Using single-strand conformation polymorphism and heteroduplex analysis to investigate 94 VHLS patients without large deletions, Crossey et al. (1994) identified 40 different mutations in the VHL gene in 55 unrelated kindreds: 19 missense mutations, 6 nonsense mutations, 12 frameshift deletions or insertions, 2 in-frame deletions, and 1 splice donor site mutation. The 2 most frequent mutations were arg238-to-gln (608537.0005) and arg238-to-trp (608537.0003), which were detected in 5 and 4 unrelated kindreds, respectively.

Olschwang et al. (1998) screened 92 unrelated patients with VHL syndrome for point mutations and found 61 DNA variants. In addition, a search for EcoRI rearrangements revealed germline anomalies in 5 patients. The 61 variants could be subdivided into 20 mutations predicted to alter the open reading frame and 43 DNA sequence variants that on a priori grounds were of unknown biologic consequence. The 3-prime end of the coding sequence of the VHL gene, which encodes the elongin (see 600787)-binding domain, was the site of 5 of 20 truncating mutations (25%) and 18 of 41 DNA variants (44%) of uncertain functional significance. A similar screening in 18 patients with sporadic hemangioblastoma revealed 2 missense DNA variants.

Wait et al. (2004) performed genetic analysis of 5 CNS hemangioblastomas excised from 3 related VHL patients with the same germline VHL gene deletion. All of the tumors showed distinct 'second-hit' point mutations on the wildtype allele, even those tumors originating in the same patient. Moreover, the same types of tumors from the same locations also showed different point mutations. Wait et al. (2004) concluded that the somatic mutations were random, and that there is a unique mechanism underlying tumorigenesis in patients with germline deletion mutations.

Using markers specific for chromosome 3, Glasker et al. (2006) mapped the deletion size of the 'second-hit' in 16 tumor tissue specimens from a single patient with VHL syndrome who had a germline heterozygous partial deletion in the VHL gene. The tumors consisted of 3 central nervous system hemangioblastomas, 7 renal cell carcinomas, 3 cystic renal structures, 2 pancreatic tumors, and 1 pancreatic cyst. Deletion size was highly variable, ranging from short deletions around the VHL gene to complete deletion of chromosome 3. However, there was no correlation between deletion size and site of the germline mutation, affected organ, or type or biological behavior of the tumor. Glasker et al. (2006) concluded that loss of VHL gene function alone is not immediately causative for neoplastic growth and suggested that further molecular events may be required for tumor formation.

In 6 patients from a family (F8) with von Hippel-Lindau syndrome, Lenglet et al. (2018) identified heterozygosity for an in cis complex mutation in the cryptic exon 1-prime of the VHL gene (608537.0032). The mutations, which were found by a combination of microsatellite analysis and gene sequencing, segregated with the disorder in the family. The mutations were predicted to result in leu128-to-val (L128V) and leu138-to-pro (L138P) substitutions in the newly identified X1 VHL protein isoform. Analysis of patient cells and tumor tissue showed upregulation of isoforms containing exon 1 and exon 1-prime, predicted to result in premature termination that would likely be degraded by nonsense-mediated mRNA. There was also lower expression of other wildtype VHL isoforms. Minigene assays in various cell lines showed a synergistic effect of the 2 mutations on abnormal splicing; the expression of exon 1-prime-containing isoforms was higher for mutations associated with cancer than with erythrocytosis. The authors postulated downreguation of VHL isoforms as a pathogenic mechanism. Sequencing of tumor tissue from these patients did not identify VHL loss of heterozygosity, indicating that somatic VHL deletion may not be a prerequisite for developing cancer in patients with this genotype.

For a discussion of genotype/phenotype correlations in VHL syndrome, see 193300.

Cancer

The Knudson model predicts that sporadic cancers should be associated with mutations in the same locus affected in the corresponding hereditary cancer. Using SSCP and RT-PCR techniques, Latif et al. (1993) identified aberrant patterns in the VHL gene in 5 renal cell carcinoma (RCC) lines. In 4 of them, the pattern was due to small, 1- to 10-nucleotide deletions that created frameshift mutations and, presumably, truncated proteins. In the fifth RCC line, the change was a nonsense mutation, resulting from a 761C-A transversion.

Eng et al. (1995) identified mutations in the VHL gene in 4 of 48 sporadic pheochromocytomas (171300). Two mutations were somatic and 2 were germline. In a mother and 2 sons with pheochromocytoma, Crossey et al. (1995) identified a VHL mutation (R238W; 608537.0003) mutation. None of them had evidence of VHL syndrome.

In 30 (11%) of 271 unrelated patients with sporadic pheochromocytoma, Neumann et al. (2002) identified 22 different germline mutations in the VHL gene (see, e.g., 608537.0014 and 608537.0026).

Zhuang et al. (1996) analyzed VHL gene alterations in sporadic human colon carcinomas and adenomas using techniques that allowed for procurement and analysis of selected subpopulations of cells from paraffin embedded and frozen human tumor specimens. Allelic loss of the VHL gene was detected in 7 of 11 (64%) of informative patients with sporadic colon carcinoma. No allelic loss was shown in colon adenomas from 8 informative patients. The authors suggested that VHL gene loss may represent a relatively late event in colonic neoplasia progression.

Oberstrass et al. (1996) found abnormalities of the VHL gene in 10 of 20 capillary hemangioblastomas of the CNS. Seven tumors had a frameshift mutation due either to deletion of 1 or more basepairs (6 cases) or to insertion of 1 basepair (1 case). The remaining 3 tumors had either point mutations with intron splice site sequences (2 cases) or a point mutation resulting in an amino acid substitution (1 case). Evidence for germline alterations of the VHL gene was found in 2 patients who showed identical mutations in both tumors and corresponding leukocyte DNA. Oberstrass et al. (1996) noted that it is significant that one of the 2 tumors with a germline mutation was in an 18-year-old male, and the other in a 40-year-old female. The non-germline mutations included tumors from individuals 70, 62, 60, 55, and 52 years old.

Kenck et al. (1996) investigated 91 different parenchymal tumors of the kidney for mutation in the VHL gene by SSCP and/or heteroduplex techniques. Evidence of mutation of the VHL gene was associated exclusively with nonpapillary renal cell carcinoma.

Fearon (1997) reviewed more than 20 different hereditary cancer syndromes that had been defined and attributed to specific germline mutations in various inherited cancer genes. In a useful diagram, he illustrated the roles of allelic variation ('1 gene - different syndromes') and genetic heterogeneity ('different genes - 1 syndrome') in inherited cancer syndromes. VHL mutations were used as an example of the former: inactivating mutations, such as nonsense mutations or deletions, predisposed to clear-cell renal carcinoma, retinal angioma, and cerebellar and spinal hemangioblastoma; missense mutations, e.g., in codon 167, predisposed to these tumors and pheochromocytoma in addition.

Van der Harst et al. (1998) screened the VHL gene for germline mutations in 68 patients who were operated on for pheochromocytoma. This was undertaken to follow up on the work of Neumann et al. (1993), who reported that, according to clinical criteria, approximately 23% of the apparently sporadic pheochromocytomas may in fact be related to a familial disorder; these disorders are, in addition to von Hippel-Lindau syndrome, neurofibromatosis-1 (NF1; 162200) and multiple endocrine neoplasia types IIA (MEN2A; 171400) and IIB (MEN2B; 162300). They found mutations in the VHL gene in 8 patients; 2 patients were an uncle and nephew who had the same missense mutation, R64P (608537.0015). In 4 other patients, missense mutations, P25L, L63P (608537.0016), G144Q, and I147T, were identified. Three of these mutations (P25L, L63P, and R64P) were located closer to the N terminus of the VHL protein than any previously reported VHL mutation. In 2 other cases, the mutations were located not in the coding region but in the intronic sequence (but not within splice sites), adjacent to the exon, so that they were probably not related to the syndrome. The results suggested that 8.8% of patients (6 of 68) with apparently sporadic pheochromocytomas may carry germline mutations in the VHL gene. This is a relatively high proportion, although not as high as the 23% reported earlier.

Gallou et al. (1999) investigated the nature of somatic VHL mutations in 173 primary sporadic human renal cell carcinomas using PCR and SSCP analysis. They detected an abnormal SSCP pattern in 73 samples. After sequencing, they identified microdeletions in 58% of cases, microinsertions in 17%, nonsense mutations in 8%, and missense mutations in 17%. VHL mutations were found only in the nonpapillary renal cell carcinoma subtype, as previously reported. To compare somatic and germline mutations, they used the VHL database, which included 507 mutations. The study of mutational events revealed a significant difference between somatic and germline mutations. Mutations leading to truncated proteins were observed in 78% of somatic mutations but in only 37% of germline mutations (P less than 0.001). The authors postulated that a specific pattern of VHL mutations is associated with sporadic RCC. This pattern corresponds to mutations leading to truncated proteins, with few specific missense mutations.

Bender et al. (2000) studied 36 VHL-related pheochromocytomas for somatic VHL and RET gene alterations and LOH of markers on chromosome arms 1p, 3p, and 22q. For comparison, they performed the same analyses in 17 sporadic pheochromocytomas. They found significantly different LOH frequencies at 3 loci between sporadic and VHL tumors; the more than 91% LOH of markers on 3p and the relatively low frequencies of LOH at 1p and 22q (15% and 21%, respectively) in VHL pheochromocytomas argue for the importance of VHL gene dysregulation and dysfunction in the pathogenesis of almost all VHL pheochromocytomas. In contrast, the relatively low frequency of 3p LOH (24%) and the lack of intragenic VHL alterations compared with the high frequency of 1p LOH (71%) and the moderate frequency of 22q LOH (53%) in sporadic pheochromocytomas argue for genes other than VHL, especially on 1p, that are significant for sporadic tumorigenesis and suggest that the genetic pathways involved in sporadic versus VHL pheochromocytoma genesis are distinct.

Renal cell carcinomas occur frequently in patients treated with long-term dialysis, especially in cases of end-stage renal disease (ESRD)/acquired cystic disease of the kidney (ACDK). In patients receiving dialysis, Yoshida et al. (2002) examined 14 RCCs (7 clear-cell and 7 papillary carcinomas) for somatic mutations of the VHL gene as well as of the tyrosine kinase domain of the MET oncogene (164860) to address the molecular pathogenesis of ESRD/ACDK-associated RCCs. They found that 3 tumors had VHL frameshifts; 1 showed additional LOH at the VHL gene locus. All 3 tumors were clear-cell RCCs occurring in ESRD with 55, 106, and 156 months of dialysis, respectively. No mutations were found in the tyrosine kinase domain of the MET oncogene, where mutations had previously been found in cases of papillary RCCs.

Maranchie et al. (2004) observed a paradoxically lower prevalence of RCC in patients with complete germline deletion of VHL. They retrospectively evaluated 123 patients from 55 families with large germline VHL deletions, including 42 intragenic partial deletions and 13 complete VHL deletions. An age-adjusted comparison demonstrated a higher prevalence of RCC in patients with partial germline VHL deletions relative to complete deletions (48.9% vs 22.6%, p = 0.007). This striking phenotypic dichotomy was not seen for cystic renal lesions or for CNS (p = 0.22), pancreas (p = 0.72), or pheochromocytoma (p = 0.34). Deletion mapping demonstrated that development of RCC had an even greater correlation with retention of HSPC300 (C3ORF10; 611183), located within the 30-kb region of 3p, immediately telomeric to VHL (52.3% vs 18.9%, p less than 0.001), suggesting the presence of a neighboring gene or genes critical to the development and maintenance of RCC.

Gallou et al. (2004) studied the renal phenotype in 274 individuals from 126 unrelated VHL families in whom 92 different VHL mutations were identified. The incidence of renal involvement was increased in families with mutations leading to protein truncation or large rearrangement, as compared to families with missense mutations (81% vs 63%, respectively; p = 0.03). In the group with missense mutations, Gallou et al. (2004) identified 2 mutation cluster regions (MCRs) associated with a high risk of harboring renal lesions: MCR-1 (codons 74-90) and MCR-2 (codons 130-136). In addition, the incidence of RCCs was higher in families with mutations leading to protein truncation than in families with missense mutations (75% vs 57%, respectively; p = 0.04). Furthermore, missense mutations within MCR-1, but not MCR-2, conferred genetic susceptibility to RCC.

Chuvash Polycythemia

Chuvash polycythemia (see ECYT2, 263400) is an autosomal recessive disorder of erythrocytosis that is endemic to the mid-Volga River region. Ang et al. (2002) studied 5 multiplex Chuvash families and confirmed that polycythemia was associated with significant elevations of serum erythropoietin levels and ruled out a location of the gene on chromosome 11 that had previously been reported by Vasserman et al. (1999). They also ruled out mutation in the HIF1A gene, which is located on 14q. Using a genomewide screen, they identified a region on 3p with a lod score greater than 2 and identified a homozygous c.598C-T transition in the VHL gene, resulting in an arg200-to-trp mutation (R200W; 608537.0019) in all cases. Ang et al. (2002) concluded that the R200W substitution impairs the interaction of VHL with HIF1-alpha, reducing the rate of degradation of HIF1-alpha and resulting in increased expression of downstream target genes including EPO, SLC2A1 (138140), transferrin (TF; 190000), transferrin receptor (TFRC; 190010), and vascular endothelial growth factor (VEGF; 192240). Mutations in VHL had been associated with pheochromocytoma, hemangioblastoma, and renal cell carcinoma, none of which were observed in individuals with Chuvash polycythemia or obligate carriers of the R200W mutation. Ang et al. (2002) stated that more than 700 mutations had been reported in VHL (Beroud et al., 1998), but that no individual had been found to be homozygous or compound heterozygous for germline mutations.

Familial Erythrocytosis 2

Inheritance of germline mutations on both VHL alleles was found by Ang et al. (2002) and by others (Pastore et al., 2003; Percy et al., 2002) as the cause of autosomal recessive familial erythrocytosis (ECYT2; 263400; see, e.g., 608537.0019). The VHL protein plays an important role in hypoxia sensing. It binds to hydroxylated HIF1-alpha and serves as a recognition component of an E3 ubiquitin ligase complex. In hypoxia or secondary to a mutated VHL gene, the nondegraded HIF1-alpha forms a heterodimer with HIF1-beta and leads to increased transcription of hypoxia-inducible genes, including EPO. Pastore et al. (2003) reported 7 erythrocytosis patients with VHL mutations on both alleles (608537.0021-608537.0024). Two Danish sibs and an American boy were homozygous for the R200W mutation (608537.0019). Three unrelated white Americans were compound heterozygous for R200W and another VHL mutation: L188V (608537.0014) in 2 and P192A (608537.0023) in the third. Additionally, a Croatian boy was homozygous for an H191D mutation (608537.0024). Pastore et al. (2003) stated that they had not observed VHL syndrome-associated tumors in subjects with erythrocytosis or their heterozygous relatives. They found that up to half of the consecutive patients with apparent congenital erythrocytosis and increased serum EPO whom they had examined had mutations of both VHL alleles. They concluded that VHL mutations are the most frequent cause of recessive congenital erythrocytosis and define a class of disorders due to augmented hypoxia sensing.

In an 8-year-old boy with ECYT2, Bond et al. (2011) identified compound heterozygous missense mutations in the VHL gene (D126N, 608537.0028 and S183L, 608537.0029). The mutations were found by direct gene sequencing. Transfection of the mutations into renal carcinoma cells showed decreased protein levels consistent with instability of the mutant proteins, suggesting a loss-of-function effect. Transfected cells also showed decreased pH, decreased glucose, and increased lactate, consistent with upregulation of glycolysis. These changes were associated with increased expression of HIF1A, PHD3 (606426), and GLUT1 (138140), suggesting impaired ability of mutant VHL to regulate HIF. The patient presented at 2 months of age with right ventricular dysfunction and hypertrophy, pulmonary hypertension, increased hematocrit and hemoglobin, and significantly increased EPO. He was managed successfully by phlebotomy.

Sarangi et al. (2014) identified homozygosity for the D126N mutation in the VHL gene in a 2-year-old boy, born of consanguineous Bangladeshi parents, with fatal ECYT2. In vitro studies showed that patient erythroid progenitors were not hypersensitive to EPO and did not overexpress NFE2 (601490) or RUNX1 (151385) transcripts, which are associated with EPO hypersensitivity. This demonstrated a different pathogenic mechanism from patients with Chuvash polycythemia due to the R200W mutation (608537.0019). The patient reported by Sarangi et al. (2014) presented in infancy with failure to thrive, polycythemia, elevated EPO, pulmonary hypertension, and a thrombotic state. Neither parent had polycythemia or evidence of VHL-associated tumors.

Tomasic et al. (2013) reported a 5-year-old Croatian girl with early-onset ECYT2 due to a homozygous H191D mutation (608537.0024). Family history revealed that she was related to the Croatian patient reported by Pastore et al. (2003). Patient erythroid precursors showed normal growth and were not hypersensitive to EPO in vitro; these findings differed from those observed in Chuvash polycythemia in which the erythroid precursors are intrinsically hyperproliferative and also show hypersensitivity to EPO. Tomasic et al. (2013) concluded that the polycythemia in patients with the H191D mutation is solely driven by increased circulating EPO. Patient cells showed changes in gene expression, including increased expression of several HIF1A-related genes (TFRC, 190010; VEGF, 192240; and HK1, 142600), and decreased expression of other genes (BNIP3L, 605368 and ADM, 103275).

In a 15-year-old girl of Asian Indian descent with ECYT2, Lanikova et al. (2013) identified a homozygous missense mutation in the VHL gene (P138L; 608537.0035). The mutation, which was found by direct sequencing of the VHL gene, segregated with the disorder in the family.

In 10 patients from 9 unrelated families with familial ECYT2, Lenglet et al. (2018) identified compound heterozygous mutations in the VHL gene. All patients carried heterozygous mutations in the newly identified cryptic exon 1-prime (E1-prime) (see, e.g., 608537.0030 and 608537.0031) deep in intron 1, resulting in a splicing alteration. Prior to the study of Lenglet et al. (2018), several of these patients were thought to carry only 1 VHL mutation (e.g., R200W, consistent with Chuvash polycythemia; the patient from F2 had previously been reported by Cario et al., 2005). The mutations, which were found by a combination of whole-genome and Sanger sequencing, segregated with the disorder in the families. RT-PCR analysis from lymphocytes derived from these patients showed decreased mRNA levels, increased amounts of E1/E3 transcripts suggesting that the mutations resulted in the skipping of exon 2, and severe decreases in the wildtype VHL mRNA and protein isoforms compared to controls. The findings by Lenglet et al. (2018) confirmed that ECYT2 is an autosomal recessive disorder, and the authors postulated that the splice site mutations in these patients caused a global defect in VHL protein expression with downregulation of VHL, rather than reduced HIF1A binding.

In a 22-year-old man, born of consanguineous Italian parents, with ECYT2, Perrotta et al. (2020) identified a homozygous c.222C-A transversion in exon 1 of the VHL gene, predicted to result in a synonymous val75-to-val (V75V; 608537.0034) substitution. The mutation, which was found by direct sequencing, segregated with the disorder in the family. Analysis of patient cells showed that it created an alternative splice donor site, resulting in a frameshift and premature termination. Patient and paternal cells showed 80% and 40% lower levels of wildtype mRNA, respectively, compared to controls. Patient cells showed decreased amounts of the 3 main VHL protein isoforms (213, 160, and 172) as well as increased HIF1A, suggesting a loss of VHL function. Patient cells also showed increased levels of BNIP3L (605368) and MXI1 (600020) compared to controls.


Animal Model

Gemmill et al. (2002) isolated the Drosophila homolog of TRC8 (603046) and studied its function by genetic manipulations and a yeast 2-hybrid screen. Human and Drosophila TRC8 proteins localize to the endoplasmic reticulum. Loss of either Drosophila Trc8 or Vhl resulted in an identical ventral midline defect. Direct interaction between Trc8 and Vhl in Drosophila was confirmed by GST-pull-down and coimmunoprecipitation experiments. Gemmill et al. (2002) found that in Drosophila, overexpression of Trc8 inhibited growth consistent with its presumed role as a tumor suppressor gene. Human JAB1 (604850) localization was dependent on VHL mutant status. Thus, the VHL, TRC8, and JAB1 proteins appear to be linked both physically and functionally, and all 3 may participate in the development of kidney cancer.

Ding et al. (2006) used the Cre-loxP system to delete the Vhl gene from podocytes in the glomerular basement membrane of mice. At about 4 weeks of age, the mice developed rapidly progressive renal disease with hematuria, proteinuria, and renal failure with crescentic glomerulonephritis with prominent segmental fibrin deposition and fibrinoid necrosis. No immune deposits were present; the phenotype was similar to human 'pauci-immune' rapidly progressive glomerulonephritis (RPGN). Gene expression profiling showed increased expression of the HIF target gene Cxcr4 (162643) in glomeruli from both mice and humans with RPGN. Treatment of the mice with a Cxcr4 antibody resulted in clinical improvement, and isolated overexpression of Cxcr4 was sufficient to cause glomerular disease. Ding et al. (2006) hypothesized that upregulation of Cxcr4 allowed terminally differentiated podocytes to reenter the cell cycle, proliferate, and form cellular crescents.

Hickey et al. (2007) found that mice homozygous for the Chuvash polycythemia-associated VHL mutation (R200W; 608537.0019) developed polycythemia similar to the human disease. Although bone marrow cellularity and morphology was similar to controls, spleens from the mutant mice showed increased numbers of erythroid progenitors and megakaryocytes, as well as erythroid differentiation of splenic cells in vitro. Further analysis showed upregulation of HIF2A (603349) and of key target genes, including EPO, VEGF (192240), GLUT1 (138140), and PAI1 (173360), that contribute to polycythemia.

Using immunofluorescence microscopy, Zehetner et al. (2008) found that Vhl was expressed in mouse insulin-producing pancreatic beta cells. Conditional inactivation of Vhl in beta cells promoted a diversion of glucose away from mitochondria into lactate production, causing cells to produce high levels of glycolytically derived ATP and to secrete elevated levels of insulin at low glucose concentrations. Vhl-deficient mice exhibited diminished glucose-stimulated changes in cytoplasmic Ca(2+) concentration, electrical activity, and insulin secretion, which culminated in impaired systemic glucose tolerance. Vhl deletion was associated with upregulation of Hif1a and the glucose transporter Glut1, an Hif1a target gene. Combined deletion of Vhl and Hif1a rescued the defects due to Vhl deletion alone, implying that they resulted from Hif1a activation.

Lee et al. (2009) generated transgenic mouse embryonic stem cells with the homozygous VHL type 2B mutation R167Q (608537.0005). Mutant cells had preserved regulation of both HIF-alpha factors with slightly greater normotoxic dysregulation of HIF2-alpha. R167Q-derived teratomas had a growth advantage and showed hemangioma formation. Homozygous mice were embryonic lethal due to placental failure, and heterozygous mice developed renal cysts and were predisposed to the carcinogen-promoted renal carcinoma.


ALLELIC VARIANTS ( 35 Selected Examples):

.0001 VON HIPPEL-LINDAU SYNDROME

VHL, 3-BP DEL, ILE75DEL
  
RCV000002298

Following the revised codon numbering system of Kuzmin et al. (1995), the ILE146DEL mutation has been renumbered as ILE75DEL.

In a patient with von Hippel-Lindau syndrome (VHLS; 193300), Latif et al. (1993) identified an in-frame 3-nucleotide deletion at nucleotide 434 of the VHL gene, predicted to remove isoleucine-146 in the gene product.


.0002 RENAL CELL CARCINOMA, SOMATIC

VHL, SER183TER
  
RCV000002299...

Following the revised codon numbering system of Kuzmin et al. (1995), the SER254TER mutation has been renumbered as SER183TER (S183X).

In a cell line from a sporadic case of renal cell carcinoma (144700), Latif et al. (1993) identified a 761C-A transversion in the VHL gene, predicted to result in a ser254-to-ter (S254X) substitution.


.0003 VON HIPPEL-LINDAU SYNDROME

PHEOCHROMOCYTOMA, INCLUDED
VHL, ARG167TRP
  
RCV000002302...

Following the revised codon numbering system of Kuzmin et al. (1995), the ARG238TRP mutation has been renumbered as ARG167TRP (R167W).

In a study of 94 patients with von Hippel-Lindau syndrome (VHLS; 193300) patients without large deletions, Crossey et al. (1994) found that the 2 most frequent mutations were missense mutations at codon 238: 4 kindreds had a 712C-T transition, resulting in an arg238-to-trp (R238W) substitution, and 5 kindreds had a 713G-A transition, leading to an arg238-to-gln (R238Q; 608537.0005) substitution. Another identified mutation was a 712C-G transversion, resulting in an arg238-to-gly (R238G) substitution (608537.0004). All 3 mutations at codon 238 occurred at a CpG dinucleotide. The authors noted that although pheochromocytoma occurs in only about 7% of patients with VHL, a codon 238 mutation carried a high risk (62%) of pheochromocytoma.

The R238W mutation was found by Garcia et al. (1997) in a Spanish family in which VHLS was manifested predominantly as familial pheochromocytoma in 2 generations, consistent with VHL syndrome type 2C.

In a mother and 2 sons with pheochromocytoma (171300), consistent with VHL syndrome type 2C, Crossey et al. (1995) identified the R238W mutation.

Zbar et al. (1996) confirmed previous observations that germline codon 167 mutations of the VHL gene (R167W and R167Q, 608537.0005) convey a high risk for the development of pheochromocytoma and renal cell carcinoma. In 21 of 33 families with mutations at codon 167, pheochromocytoma occurred, compared to 15 of 223 families without a mutation at codon 167. The association between codon 167 mutations and pheochromocytoma was detected in all nationalities tested. Two of 4 Japanese VHL pheochromocytoma families had mutations at codon 167; and 3 of 10 French VHL pheochromocytoma families had mutations at codon 167.

Neumann et al. (2002) identified the R167Q substitution in the germline of a patient with sporadic pheochromocytoma (171300).

In the germlines of 6 unrelated patients with sporadic pheochromocytoma, Neumann et al. (2002) identified the R167W substitution. The mutation was not identified in 600 control chromosomes.


.0004 VON HIPPEL-LINDAU SYNDROME

VHL, ARG167GLY
  
RCV000002304...

Following the revised codon numbering system of Kuzmin et al. (1995), the ARG238GLY mutation has been renumbered as ARG167GLY (R167G).

See 608537.0003 and Crossey et al. (1994).


.0005 VON HIPPEL-LINDAU SYNDROME

VHL, ARG167GLN
  
RCV000002300...

Following the revised codon numbering system of Kuzmin et al. (1995), the ARG238GLN mutation has been renumbered as ARG167GLN (R167Q).

See 608537.0003 and Crossey et al. (1994).


.0006 VON HIPPEL-LINDAU SYNDROME

VHL, ARG161TER
  
RCV000002301...

Following the revised codon numbering system of Kuzmin et al. (1995), the ARG232TER mutation has been renumbered as ARG161TER (R161X).

In a patient with von Hippel-Lindau syndrome (VHLS; 193300), Loeb et al. (1994) identified a 694C-T transition in exon 3 of the VHL gene, resulting in an amber stop codon arg232-to-ter (R232X).

Gilcrease et al. (1995) found the identical 694C-T transition as a somatic mutation in a clear cell papillary cystadenoma of the epididymis in a patient who showed no evidence of von Hippel-Lindau syndrome and in whom somatic cells did not contain this mutation.


.0007 HEMANGIOBLASTOMA, SPORADIC CEREBELLAR, SOMATIC

VON HIPPEL-LINDAU SYNDROME, INCLUDED
VHL, TRP88SER
  
RCV000002306

Following the revised codon numbering system of Kuzmin et al. (1995), the TRP159SER mutation has been renumbered as TRP88SER (W88S).

In 13 sporadic cases of cerebellar hemangioblastoma, Kanno et al. (1994) sought somatic mutations in the VHL gene with single-strand conformation polymorphism analyses of the tumor DNAs. An abnormal SSCP pattern was detected in 7, and in 3 of these the mutation was successfully characterized by direct sequencing. The somatic mutations were 2 missense mutations and 1 deletion of a single base. One of the missense mutations was a 476G-C transversion, resulting in a trp-to-ser change. The codon number was not noted.

In a Japanese patient with von Hippel-Lindau syndrome (VHLS; 193300), the Clinical Research Group for VHL in Japan (1995) identified the 476G-C transversion, which resulted in a trp159-to-ser (W159S) substitution.


.0008 HEMANGIOBLASTOMA, SPORADIC CEREBELLAR, SOMATIC

VHL, LEU135PHE
  
RCV000002307

In a sporadic case of cerebellar hemangioblastoma, Kanno et al. (1994) identified a somatic missense mutation in exon 2 of the VHL gene: a 618A-C transversion, resulting in a leu135-to-phe substitution.


.0009 VON HIPPEL-LINDAU SYNDROME

VHL, TYR98HIS
  
RCV000002309...

Following the revised codon numbering system of Kuzmin et al. (1995), the TYR169HIS mutation has been renumbered as TYR98HIS (Y98H), resulting from a 292T-C transition.

In 14 apparently unrelated families from the Black forest region of Germany with von Hippel-Lindau syndrome (VHLS; 193300), apparently VHL type 2A, Brauch et al. (1995) found a 505T-C transition in the VHL gene, resulting in a tyr169-to-his (Y169H) substitution. Brauch et al. (1995) suggested that more than 75 VHL germline mutations had been identified in VHL patients to that date. The same mutation, associated with pheochromocytoma, had been identified by Chen et al. (1995) in 2 VHL 2A families in Pennsylvania. All affected individuals in the 16 families shared the same VHL haplotype, indicating a founder effect. In at least one of the Pennsylvania families, the Y169H mutation probably derived from their Pfalz ancestors, who were among Germans who migrated to Pennsylvania.

In a patient with the Y169H mutation as the cause of VHLS, Schimke et al. (1998) found a functioning carotid paraganglioma.

Allen et al. (2001) performed a longitudinal clinical study and DNA analysis of 24 family members, 16 of whom exhibited a 505T-C change in exon 1 of the VHL gene. Two of the 16 were asymptomatic carriers of the 505T-C mutation. Twelve of 16 (75%) of the gene carriers had 1 or more ocular angiomas. The mean number of ocular angiomas per gene carrier was 3.3. Six eyes had optic disc angiomas. Five gene carriers (31%) lost vision because of ocular angiomatosis. Four patients (25%) had cerebellar hemangioblastomas and 11 patients (69%) had pheochromocytomas. No patient had renal cell carcinoma, consistent with the clinical diagnosis of VHL syndrome type 2A. The authors stated that recognition of the VHL syndrome 2A phenotype suggested the presence of a specific mutation (505T-C) in the VHL gene. They suggested that confirmation of this genotype would increase a clinician's ability to provide favorable prognostic information to affected family members.

Bender et al. (2001) studied 125 individuals in southern Germany carrying the 505T-C mutation. Forty-seven percent had pheochromocytoma; 36% had retinal angioma; 36%, hemangioblastoma of the spine; and 16% had hemangioblastoma of the brain. Forty-seven percent of patients were symptomatic; 30% were asymptomatic despite the presence of at least 1 VHL-related tumor; and 23% of the carriers had no detectable VHL lesion. Of the 19 patients who died, 10 died of symptomatic VHL lesions. Overall penetrance by cumulative incidence was estimated at 48% by 35 years and 88% by 70 years. Bender et al. (2001) suggested that the mortality rate for those carrying this mutation was much lower than in unselected VHL mutations and was comparable to that of the general population of Germany.


.0010 MOVED TO 608537.0003


.0011 MOVED TO 608537.0003


.0012 VON HIPPEL-LINDAU SYNDROME

VHL, TYR112HIS
  
RCV000002308...

In a large family with von Hippel-Lindau syndrome (VHLS; 193300) studied by Tisherman et al. (1962, 1993), Zbar et al. (1996) identified a tyr112-to-his (Y112H) mutation in the VHL gene. Of 22 affected family members, 19 were affected with pheochromocytoma; no affected family member had renal cell carcinoma. In the original report (Tisherman et al., 1962), at least 7 persons had pheochromocytoma. One or more cafe-au-lait spots (in 22 persons), extensive hemangiomas (in 2 persons), and angiomatosis retinae (in 2 persons) were discovered in the family.


.0013 VON HIPPEL-LINDAU SYNDROME

VHL, VAL166PHE
  
RCV000002310...

In a family with von Hippel-Lindau syndrome (VHLS; 193300), Gross et al. (1996) identified a val166-to-phe (V166F) mutation in the VHL gene. Seven members had pheochromocytoma, all without renal carcinoma.


.0014 VON HIPPEL-LINDAU SYNDROME

ERYTHROCYTOSIS, FAMILIAL, 2, INCLUDED
PHEOCHROMOCYTOMA, INCLUDED
VHL, LEU188VAL
  
RCV000002311...

In a family with von Hippel-Lindau syndrome (VHLS; 193300), Neumann et al. (1995) identified a leu188-to-val (L188V) mutation in the VHL gene. Nine patients had pheochromocytoma without renal carcinoma (Zbar et al., 1996).

In 6 members of the same German family identified by Neumann et al. (1995) with von Hippel-Lindau syndrome type 2C, Weirich et al. (2002) found a P81S mutation in the VHL gene (608537.0020), which cosegregated with the L188V mutation. Weirich et al. (2002) discussed the possible impact of these mutations on protein function and phenotype.

In 2 unrelated white American children, a 15-year-old male and a 13-year-old female, who presented at 5 years of age with familial erythrocytosis (ECYT2; 263400), Pastore et al. (2003) identified a 562C-G transversion in the VHL gene, resulting in the L188V mutation. In both patients the mutation occurred in compound heterozygous state with the common R200W mutation (608537.0019).

Neumann et al. (2002) identified the L188V mutation in the germline of a patient with sporadic pheochromocytoma (171300). The mutation was not identified in 600 control chromosomes.


.0015 PHEOCHROMOCYTOMA

VHL, ARG64PRO
  
RCV000002314...

In an uncle and his nephew with apparently isolated pheochromocytoma (171300), van der Harst et al. (1998) found an arg64-to-pro (R64P) mutation in the VHL gene. This mutation was 1 of 3 missense mutations identified by van der Harst et al. (1998) that were located closer to the N terminus of the VHL protein than any previously reported VHL mutation (see also 608537.0016).


.0016 PHEOCHROMOCYTOMA

VHL, LEU63PRO
  
RCV000002315...

In a patient with apparently sporadic pheochromocytoma (171300), van der Harst et al. (1998) found a leu63-to-pro (L63P) mutation in the VHL gene. This mutation was 1 of 3 missense mutations identified by van der Harst et al. (1998) that were located closer to the N terminus of the VHL protein than any previously reported VHL mutation (see also 608537.0015).


.0017 VON HIPPEL-LINDAU SYNDROME

VHL, TYR112ASN
  
RCV000002316

In a family with von Hippel-Lindau syndrome (VHLS; 193300), Bradley et al. (1999) identified a 547T-A transversion in exon 1 of the VHL gene, resulting in a tyr112-to-asn (Y112N) substitution. Of 13 affected individuals, 7 had renal cell carcinoma and 1 had pheochromocytoma. The authors contrasted this family to 2 families reported by Chen et al. (1996) that had a mutation at the same position but causing a different amino acid change (tyr112 to his; 608537.0012). In these families, 19 of 22 affected individuals had pheochromocytoma and none had renal cell carcinoma. Bradley et al. (1999) concluded that different amino acid changes at the same position can cause very distinct clinical phenotypes.


.0018 RENAL CELL CARCINOMA WITH PARANEOPLASTIC ERYTHROCYTOSIS

VHL, LEU163PRO
  
RCV000002319...

Wiesener et al. (2002) described a 50-year-old man, admitted to hospital for acute myocardial infarction, who was found to have marked erythrocytosis. Serum erythropoietin (EPO; 133170) was increased, and ultrasonography demonstrated a mass at the upper pole of the left kidney. Following nephrectomy, which confirmed the diagnosis of renal cell carcinoma (144700), EPO serum concentration decreased within 7 days and hemoglobin levels returned to normal. The patient was well 9 months later with normal EPO serum concentration. In this patient, Wiesener et al. (2002) reported that EPO mRNA was not detectable in normal kidney tissue but markedly upregulated in the tumor. Hypoxia-inducible genes, including VEGF (192240), GLUT1 (138140), carbonic anhydrase-9 (603179), lactate dehydrogenase-A (150000), and aldolase A (103850), were also strongly induced in the tumor. Immunoblots showed significant overexpression of the HIF1A (603348) and HIF2A (603349) subunits in the tumor, and immunohistochemistry performed for HIF1A showed nuclear accumulation of the transcription factor in virtually every tumor cell. A mutation analysis of the VHL gene in tumor cells revealed a leu163-to-pro (L163P) missense mutation due to a 701T-C transition in exon 3. This mutation had previously been identified in another RCC. The mutation was not present in other tissues of the patient. In this case, there was a clear indication that the pronounced erythrocytosis was a precipitating factor in the coronary thrombosis.


.0019 POLYCYTHEMIA, CHUVASH TYPE

VHL, ARG200TRP
  
RCV000002320...

Chuvash polycythemia (see ECYT2, 263400), caused by this specific arg200-to-trp (R200W) mutation in the VHL gene, is an autosomal recessive disorder of erythrocytosis that is endemic to the mid-Volga River region. Ang et al. (2002) studied 5 multiplex Chuvash families and confirmed that polycythemia was associated with significant elevations of serum erythropoietin (EPO; 133170) levels and ruled out a location of the gene on chromosome 11 as had been reported previously by Vasserman et al. (1999). They also ruled out mutation in the HIF1A gene (603348), which is located in 14q. Using a genomewide screen, they identified a region on 3p with a lod score greater than 2 and identified a 598C-T transition in the VHL gene, resulting in an arg200-to-trp (R200W) mutation in all cases. Ang et al. (2002) concluded that the R200W substitution impairs the interaction of VHL with HIF1-alpha, reducing the rate of degradation of HIF1-alpha and resulting in increased expression of downstream target genes including EPO, SLC2A1 (138140), transferrin (TF; 190000), transferrin receptor (TFRC; 190010), and vascular endothelial growth factor (VEGF; 192240). Mutations in VHL had been associated with pheochromocytoma, hemangioblastoma, and renal cell carcinoma, none of which were observed in individuals with Chuvash polycythemia or obligate carriers of the R200W mutation. Ang et al. (2002) stated that more than 700 mutations had been reported in VHL (Beroud et al., 1998), but that no individual had been found to be homozygous or compound heterozygous for germline mutations.

Pastore et al. (2003) evaluated the role of the VHL gene in 8 children with a history of polycythemia and an elevated serum EPO level and identified 3 different germline VHL mutations in 4 of them. One child was homozygous for the R200W mutation, and another was compound heterozygous for the R200W mutation and a val130-to-leu mutation (V130L; 608537.0021). Of 2 sibs who were heterozygous for an asp126-to-tyr mutation (D126Y; 608537.0022), 1 fulfilled some criteria of VHL syndrome (193300); a pulmonary angioma was discovered at 10 years of age and treated by coil embolization without effect on the polycythemia, and at 15 years of age nephrectomy was performed for a subcapsular hemangioma.

Percy et al. (2002) observed homozygosity for the R200W mutation in 3 Bangladeshi families with Chuvash-type congenital polycythemia living in the United Kingdom.

By haplotype analysis of 101 ethnically diverse individuals with the common R200W mutation, including 72 Chuvash individuals, Liu et al. (2004) determined that the R200W mutation is due to a founder effect that originated from 14,000 to 62,000 years ago.

In a matched cohort study, Gordeuk et al. (2004) found that homozygosity for the 598C-T transition in the VHL gene was associated with vertebral hemangiomas, varicose veins, lower blood pressures, and elevated serum VEGF concentrations (p less than 0.0005), as well as premature mortality related to cerebral vascular events and peripheral thrombosis. Spinocerebellar hemangioblastomas, renal carcinomas, and pheochromocytomas typical of classic VHL syndrome were not found, suggesting that overexpression of HIF1-alpha and VEGF is not sufficient for tumorigenesis. Although hemoglobin-adjusted serum erythropoietin concentrations were approximately 10-fold higher in 598C-T homozygotes than in controls, erythropoietin response to hypoxia was identical. Gordeuk et al. (2004) concluded that Chuvash polycythemia is a distinct VHL syndrome manifested by thrombosis, vascular abnormalities, and intact hypoxic regulation despite increased basal expression of hypoxia-regulated genes.

Cario et al. (2005) reported a Turkish patient who was homozygous for the R200W mutation. Haplotype analysis showed a different haplotype than that associated with the Chuvash population, indicating that the mutation arose independently and is not geographically restricted.

Perrotta et al. (2006) found that the R200W missense mutation (598C-T) causing Chuvash polycythemia is more frequent on the island of Ischia in the Bay of Naples (0.070) than it is in Chuvashia (0.057). The haplotype of all patients in Ischia matched that identified in the Chuvash cluster, thus supporting the single founder hypothesis. Perrotta et al. (2006) also found that unaffected heterozygotes had increased HIF1-alpha activity, which might confer a biochemical advantage for mutation maintenance. They suggested that this form of familial polycythemia may be endemic in other regions of the world, a hypothesis supported by the reports of Percy et al. (2002, 2003).

Russell et al. (2011) presented evidence suggesting 2 main molecular mechanisms by which the R200W and H191D (608537.0024) VHL mutations result in polycythemia. In vitro studies showed that the R200W mutation attenuated formation of the E3 ubiquitin ligase and attenuated binding of HIF1 (603348). In patients, this would lead to overproduction of the HIF-target erythropoietin (EPO; 133170) and thus secondary polycythemia. In addition, VHL mutations result in conformational changes causing increased binding to SOCS1 (603597), which inhibits binding and degradation of phosphorylated JAK2 (147796). The resulting pJAK2 stabilization promotes hyperactivation of the JAK2-STAT5 (601511) pathway in erythroid progenitors, causing hypersensitivity to erythropoietin and thereby to primary polycythemia. Treatment of R200W/R200W transgenic mice with a JAK2 inhibitor resulted in decreased hematocrit, smaller spleen, and decreased sensitivity to EPO compared to untreated transgenic mice.

Tomasic et al. (2013) stated that Russell et al. (2011) erroneously quoted the H191D mutation as a Chuvash polycythemia variant. The data presented by Tomasic et al. (2013) showed that erythrocyte precursors from homozygous H191D patients did not exhibit intrinsic hyperproliferation or a hyperproliferative response to EPO, as observed in R200W homozygotes. Their studies indicated different functional effects of the mutations.


.0020 VON HIPPEL-LINDAU SYNDROME

VHL, PRO81SER
  
RCV000002321...

In 6 members of a German family in which the L188V mutation in the VHL gene (608537.0014) had previously been identified in association with von Hippel-Lindau syndrome type 2C (VHLS; 193300), Weirich et al. (2002) identified a 454C-T transition in exon 1 of the VHL gene, resulting in a pro81-to-ser (P81S) mutation. The concurrent P81S mutation was identified by novel screening approaches, including denaturing high-performance liquid chromatography (DHPLC) and sequencing. The 2 mutations cosegregated with the syndrome. Weirich et al. (2002) discussed the possible impact of the mutations on protein function and phenotype.


.0021 ERYTHROCYTOSIS, FAMILIAL, 2

VHL, VAL130LEU
  
RCV000002317...

.0022 ERYTHROCYTOSIS, FAMILIAL, 2

VHL, ASP126TYR
  
RCV000002318...

.0023 ERYTHROCYTOSIS, FAMILIAL, 2

VHL, PRO192SER
  
RCV000002322...

In a 10-year-old white American boy who presented at age 9 years with familial erythrocytosis-2 (ECYT2; 263400), Pastore et al. (2003) identified compound heterozygosity for a 574C-T transition in the VHL gene, resulting in a pro192-to-ser (P192S) change, and the common R200W mutation (608537.0019).


.0024 ERYTHROCYTOSIS, FAMILIAL, 2

VHL, HIS191ASP
  
RCV000002323...

In a 17-year-old Croatian boy who presented at age 1 year with familial erythrocytosis-2 (ECYT2; 263400), Pastore et al. (2003) identified homozygosity for a 571C-G transversion in the VHL gene, resulting in a his191-to-asp (H191D) change.

Russell et al. (2011) presented evidence suggesting 2 main molecular mechanisms by which the H191D and R200W (608537.0019) VHL mutations result in polycythemia. In vitro studies showed that the H191D mutation attenuated formation of the E3 ubiquitin ligase and attenuated binding of HIF1 (603348). In patients, this would lead to overproduction of the HIF-target erythropoietin (EPO; 133170) and thus secondary polycythemia. In addition, VHL mutations result in conformational changes causing increased binding to SOCS1 (603597), which inhibits binding and degradation of phosphorylated JAK2 (147796). The resulting pJAK2 stabilization promotes hyperactivation of the JAK2-STAT5 (601511) pathway in erythroid progenitors, causing hypersensitivity to erythropoietin and thereby to primary polycythemia. Treatment of R200W/R200W transgenic mice with a JAK2 inhibitor resulted in decreased hematocrit, smaller spleen, and decreased sensitivity to EPO compared to untreated transgenic mice.

Tomasic et al. (2013) stated that Russell et al. (2011) erroneously quoted the H191D mutation as a Chuvash polycythemia variant. The data presented by Tomasic et al. (2013) showed that erythrocyte precursors from homozygous H191D patients did not exhibit intrinsic hyperproliferation or a hyperproliferative response to EPO, as observed in R200W homozygotes. Their study indicated different functional effects of the mutations.

Tomasic et al. (2013) reported a 5-year-old Croatian girl with early-onset ECYT2 due to a homozygous H191D mutation. Family history revealed that she was related to the patient reported by Pastore et al. (2003). Patient erythroid precursors showed normal growth and were not hypersensitive to EPO in vitro; these findings differed from those observed in Chuvash polycythemia in which the erythroid precursors are intrinsically hyperproliferative and also show hypersensitivity to EPO. Tomasic et al. (2013) concluded that the polycythemia in patients with the H191D mutation is solely driven by increased circulating EPO. Patient cells showed changes in gene expression, including increased expression of several HIF1A-related genes (TFRC, VEGF, and HK1), and decreased expression of other genes (BNIP3L and ADM). The patient presented at age 2 years with failure to thrive, increased hematocrit and hemoglobin, low ferritin, and extremely high erythropoietin. She also had delayed psychomotor development. Heterozygous carriers in the family did not have VHL-associated tumors.


.0025 VON HIPPEL-LINDAU SYNDROME

VHL, VAL84LEU
  
RCV000002324...

Following the revised codon numbering system of Kuzmin et al. (1995), the VAL155LEU (V155L) mutation has been renumbered as V84L.

In 2 sibs from Wales with bilateral pheochromocytoma without other features of von Hippel-Lindau syndrome (VHLS; 193300), consistent with VHL type 2C, Crossey et al. (1995) identified a heterozygous 463G-T transversion in exon 1 of the VHL gene, resulting in a val155-to-leu (V155L) substitution.

Abbott et al. (2006) identified the V84L substitution in affected individuals from 3 unrelated families with early-onset isolated pheochromocytoma consistent with VHL syndrome type 2C. Although no other signs of VHL syndrome were present in 7 patients, 1 patient was suspected to have a spinal hemangioblastoma based on imaging studies.


.0026 PHEOCHROMOCYTOMA

VHL, GLY93SER
  
RCV000002325...

In the germlines of 2 unrelated patients with sporadic pheochromocytoma (171300), Neumann et al. (2002) identified a 490G-A transition in exon 1 of the VHL gene, resulting in a gly93-to-ser (G93S) substitution. The mutation was not identified in 600 control chromosomes.


.0027 VON HIPPEL-LINDAU SYNDROME

VHL, GLN164ARG
  
RCV000002326...

In a 2.5-year-old girl who presented with a pheochromocytoma but no other manifestations of von Hippel-Lindau syndrome (VHLS; 193300), Sovinz et al. (2010) identified a heterozygous 491A-G transition in exon 3 of the VHL gene, resulting in an gln164-to-arg (Q164R) substitution in a protein surface residue. Genotyping of the family indicated that she inherited the mutation from her father, in whom it occurred de novo. Although he was in good health and asymptomatic, detailed physical examination found a retinal angioma, an adrenal adenoma, and bilateral pheochromocytoma, consistent with VHL syndrome. Sovinz et al. (2010) noted that Ong et al. (2007) had identified the Q164R mutation in a family in which a patient developed pheochromocytoma at age 10 years and retinal angioma at age 23 years, suggesting that this mutation may be associated with early onset of symptoms.


.0028 ERYTHROCYTOSIS, FAMILIAL, 2

VHL, ASP126ASN
  
RCV000129380...

In an 8-year-old boy with familial erythrocytosis-2 (ECYT2; 263400), Bond et al. (2011) identified compound heterozygous missense mutations in the VHL gene: a c.376G-A transition in exon 2, resulting in an asp126-to-asn (D126N) substitution, and a c.548C-T transition in exon 3, resulting in a ser138-to-leu (S183L; 608537.0029) substitution. The mutations were found by direct gene sequencing. Transfection of the mutations into renal carcinoma cells showed decreased protein levels consistent with instability of the mutant proteins and suggesting a loss-of-function effect. Transfected cells also showed decreased pH, decreased glucose, and increased lactate, consistent with upregulation of glycolysis. These changes were associated with increased expression of HIF1A (603348), PHD3 (606426), and GLUT1 (138140), suggesting impaired ability of mutant VHL to regulate HIF. The patient presented at 2 months of age with right ventricular dysfunction and hypertrophy, pulmonary hypertension, increased hematocrit and hemoglobin, and significantly increased EPO (133170). He was managed successfully by phlebotomy.

Sarangi et al. (2014) identified a homozygous D126N mutation in the VHL gene in a 2-year-old boy, born of consanguineous Bangladeshi parents, with fatal ECYT2. In vitro studies showed that patient erythroid progenitors were not hypersensitive to EPO and did not overexpress NFE2 (601490) or RUNX1 (151385) transcripts, which are associated with EPO hypersensitivity. This demonstrated a different pathogenic mechanism from patients with Chuvash polycythemia due to the R200W mutation (608537.0019). The patient reported by Sarangi et al. (2014) presented in infancy with failure to thrive, polycythemia, elevated EPO, pulmonary hypertension, and a thrombotic state. Neither parent had polycythemia or evidence of VHL-associated tumors.


.0029 ERYTHROCYTOSIS, FAMILIAL, 2

VHL, SER183LEU
  
RCV000476376...

For discussion of the c.548C-T transition in exon 3 of the VHL gene, resulting in a ser138-to-leu (S183L) substitution, that was found in compound heterozygous state in a patient with familial erythrocytosis-2 (ECYT2; 263400) by Bond et al. (2011), see 608537.0028.


.0030 ERYTHROCYTOSIS, FAMILIAL, 2

VHL, c.340+770T-C
  
RCV001007626...

In 4 patients from 3 unrelated families (F1, F2, and F3) with familial erythrocytosis-2 (ECYT2; 263400), Lenglet et al. (2018) identified compound heterozygous mutations in the VHL gene. All 4 patients carried a T-to-C transition (c.340+770T-C) in cryptic exon 1-prime (E1-prime), resulting in a splicing alteration, on 1 allele. Three patients from F2 and F3 had previously been diagnosed with Chuvash polycythemia since they were heterozygous for the R200W mutation (608537.0019) on the other allele. Prior to the study of Lenglet et al. (2018), these patients were thought to carry only 1 VHL mutation (the patient from F2 had previously been reported by Cario et al., 2005). The mutations, which were found by a combination of whole-genome and Sanger sequencing, segregated with the disorder in the families. RT-PCR analysis of lymphoblastoid cells from 1 patient (F1) showed a decrease in the exon 1/exon 2/exon 3 isoform and an increase in an exon 1/exon 3 isoform compared to wildtype. The patient from F1 carried a synonymous c.429C-T transition (asp143-to-asp, D143D) on the other allele, which also affected splicing. Two further unrelated patients with ECYT2 (families F9 and F10) were homozygous for the c.429C-T transition in the VHL gene. RT-PCR analysis from lymphocytes derived from these patients showed decreased mRNA levels, increased amounts of the E1/E3 transcripts, and severe decreases in the wildtype VHL mRNA and protein isoform compared to controls, suggesting that the mutation resulted in the skipping of exon 2. The 2 patients from families F9 and F10 also had mutations in the HBB gene (141900), which may have compensated for the ECYT2.


.0031 ERYTHROCYTOSIS, FAMILIAL, 2

VHL, c.340+694_711dup
  
RCV001007627...

In 2 unrelated patients (families F4 and F5) with familial erythrocytosis-2 (ECYT2; 263400), Lenglet et al. (2018) identified compound heterozygous mutations in the VHL gene. Both patients carried an 18-bp duplication (c.340+694_711dup) in a newly identified cryptic exon 1-prime (E1-prime), resulting in a splicing alteration on that allele. The patient from F4 carried an R200W (608537.0019) mutation on the other allele, whereas the patient from F5 carried a G144R mutation on the other allele. The mutations segregated with the disorder in both families. Both patients had been thought to carry only 1 VHL mutation (Randi et al., 2005). The findings by Lenglet et al. (2018) confirmed that ECYT2 is an autosomal recessive disorder. RT-PCR analysis of transfected cells showed abnormal splicing.


.0032 VON HIPPEL-LINDAU SYNDROME

VHL, LEU128VAL AND LEU138PRO (rs73024533)
  
RCV001007628...

In 6 patients from a family (F8) with von Hippel-Lindau syndrome (VHLS; 193300), Lenglet et al. (2018) identified a heterozygous complex mutation in cryptic exon 1-prime of the VHL gene: a C-G transversion (c.340+617C-G) and a T-to-C transition (c.340+648T-C). The mutations, which were found by a combination of microsatellite analysis and gene sequencing, segregated with the disorder in the family. The mutations were predicted to result in leu128-to-val (L128V) and leu138-to-pro (L138P; rs73024533) substitutions in the newly identified X1 VHL protein isoform. Analysis of patient cells and tumor tissue showed upregulation of isoforms containing exon 1 and exon 1-prime, resulting in premature termination that would likely be degraded by nonsense-mediated mRNA. There was also lower expression of other VHL isoforms. Minigene assays in various cell lines showed a synergistic effect of the 2 mutations on abnormal splicing; the expression of exon 1-prime-containing isoforms was higher for mutations associated with cancer compared to erythrocytosis. The c.340+648T-C mutation was found at a low frequency in the 1000 Genomes Project database. Sequencing of tumor tissue from these patients did not identify loss of heterozygosity at the VHL locus, indicating that somatic VHL deletion may not be a prerequisite for developing cancer in patients with this genotype.


.0033 VON HIPPEL-LINDAU SYNDROME

VHL, PRO138PRO
  
RCV000208865...

In 7 members from 2 unrelated families (F11 and F12) with von Hippel-Lindau syndrome (VHLS; 193300), Lenglet et al. (2018), identified a heterozygous c.414A-G transition in the VHL gene, predicted to result in a synonymous pro138-to-pro (P138P) substitution. Analysis of patient cells and tumor tissue showed increased expression of E1-E3 transcripts, suggesting a splicing alteration with the skipping of exon 2. There was a severe decrease in expression of wildtype VHL. Patient tumor tissue showed loss of heterozygosity for VHL, consistent with the classic mechanism of VHL syndrome.


.0034 ERYTHROCYTOSIS, FAMILIAL, 2

VHL, VAL75VAL
  
RCV000984026

In a 22-year-old man, born of consanguineous Italian parents, with familial erythrocytosis-2 (ECYT2; 263400), Perrotta et al. (2020) identified a homozygous c.222C-A transversion in exon 1 of the VHL gene, predicted to result in a synonymous val75-to-val (V75V) substitution. The mutation, which was found by direct sequencing, segregated with the disorder in the family. Analysis of patient cells showed that the mutation created a alternative splice donor site, resulting in a frameshift and premature termination. Patient and paternal cells showed 80% and 40% lower levels of wildtype mRNA, respectively, compared to controls. Patient cells showed decreased amounts of the 3 main VHL protein isoforms (213, 160, and 172) as well as increased HIF1A, suggesting a loss of VHL function. Patient cells also showed increased levels of BNIP3L (605368) and MXI1 (600020) compared to controls, suggesting possible mitochondrial dysfunction. The patient presented at birth with severe hypoglycemia, erythrocytosis, and bradycardia. He later showed failure to thrive, exercise intolerance, and mitochondrial and metabolic abnormalities.


.0035 ERYTHROCYTOSIS, FAMILIAL, 2

VHL, PRO138LEU
  
RCV001007630...

In a 15-year-old girl of Asian Indian descent with familial erythrocytosis-2 (ECYT2; 263400), Lanikova et al. (2013) identified a homozygous c.413C-T transition in exon 2 of the VHL gene, resulting in a pro138-to-leu (P138L) substitution in the catalytic HIF1A (603348) ligand-binding domain. The mutation, which was found by direct sequencing of the VHL gene, segregated with the disorder in the family. Cellular transfection studies showed that the mutant protein had decreased stability compared to controls. Patient erythrocytes were hypersensitive to EPO in vitro, and there was overexpression of the NFE2 (601490) and RUNX1 (151385) genes, as well as an increase in HIF1A target genes. Immunoprecipitation studies showed that the mutation decreased the affinity of VHL to HIF1A, resulting in decreased ubiquitination under nonhypoxic conditions compared to controls. Lanikova et al. (2013) noted that a germline mutation in the VHL gene affecting this residue (P138T) had been identified in patients with von Hippel-Lindau syndrome (see Leonardi et al., 2011), but the parents, who were heterozygous carriers of the P138L mutation, had no signs of VHLS.


REFERENCES

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  2. Allen, R. C., Webster, A. R., Sui, R., Brown, J., Taylor, C. M., Stone, E. M. Molecular characterization and ophthalmic investigation of a large family with type 2A von Hippel-Lindau disease. Arch. Ophthal. 119: 1659-1665, 2001. [PubMed: 11709017, related citations] [Full Text]

  3. Ang, S. O., Chen, H., Gordeuk, V. R., Sergueeva, A. I., Polyakova, L. A., Miasnikova, G. Y., Kralovics, R., Stockton, D. W., Prchal, J. T. Endemic polycythemia in Russia: mutation in the VHL gene. Blood Cells Molec. Dis. 28: 57-62, 2002. [PubMed: 11987242, related citations] [Full Text]

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  90. Russell, R. C., Sufan, R. I., Zhou, B., Heir, P., Bunda, S., Sybingco, S. S., Greer, S. N., Roche, O., Heathcote, S. A., Chow, V. W. K., Boba, L. M., Richmond, T. D., Hickey, M. M., Barber, D. L., Cheresh, D. A., Simon, M. C., Irwin, M. S., Kim, W. Y., Ohh, M. Loss of JAK2 regulation via a heterodimeric VHL-SOCS1 E3 ubiquitin ligase underlies Chuvash polycythemia. Nature Med. 17: 845-853, 2011. [PubMed: 21685897, images, related citations] [Full Text]

  91. Sarangi, S., Lanikova, L., Kapralova, K., Acharya, S., Swierczek, S., Lipton, J. M., Wolfe, L., Prchal, J. T. The homozygous VHL-D126N missense mutation is associated with dramatically elevated erythropoietin levels, consequent polycythemia, and early onset severe pulmonary hypertension. Pediat. Blood Cancer 61: 2104-2106, 2014. [PubMed: 24729484, related citations] [Full Text]

  92. Schimke, R. N., Collins, D. L., Rothberg, P. G. Functioning carotid paraganglioma in the von Hippel-Lindau syndrome. (Letter) Am. J. Med. Genet. 80: 533-534, 1998. [PubMed: 9880225, related citations] [Full Text]

  93. Schoenfeld, A., Davidowitz, E. J., Burk, R. D. A second major native von Hippel-Lindau gene product, initiated from an internal translation start site, functions as a tumor suppressor. Proc. Nat. Acad. Sci. 95: 8817-8822, 1998. [PubMed: 9671762, images, related citations] [Full Text]

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  98. Tomasic, N. L., Piterkova, L., Huff, C., Bilic, E., Yoon, D., Miasnikova, G. Y., Sergueeva, A. I., Niu, X., Nekhai, S., Gordeuk, V., Prchal, J. T. The phenotype of polycythemia due to Croatian homozygous VHL (571C-G:H191D) mutation is different from that of Chuvash polycythemia (VHL 598C-T:R200W) Haematologica 98: 560-567, 2013. [PubMed: 23403324, images, related citations] [Full Text]

  99. Tyers, M., Willems, A. R. One ring to rule a superfamily of E3 ubiquitin ligases. Science 284: 601, 603-604, 1999. [PubMed: 10328744, related citations] [Full Text]

  100. van der Harst, E., de Krijger, R. R., Dinjens, W. N. M., Weeks, L. E., Bonjer, H. J., Bruining, H. A., Lamberts, S. W. J., Koper, J. W. Germline mutations in the vhl gene in patients presenting with phaeochromocytomas. Int. J. Cancer. 77: 337-340, 1998. [PubMed: 9663592, related citations] [Full Text]

  101. Vasserman, N. N., Karzakova, L. M., Tverskaya, S. M., Saperov, V. N., Muchukova, O. M., Pavlova, G. P., Efimova, N. K., Vankina, N. N., Evgrafov, O. V. Localization of the gene responsible for familial benign polycythemia to chromosome 11q23. Hum. Hered. 49: 129-132, 1999. [PubMed: 10364675, related citations] [Full Text]

  102. Vogelstein, B. Personal Communication. Baltimore, Md. 1/6/1995.

  103. Wait, S. D., Vortmeyer, A. O., Lonser, R. R., Chang, D. T., Finn, M. A., Bhowmick, D. A., Pack, S. D., Oldfield, E. H., Zhuang, Z. Somatic mutations in VHL germline deletion kindred correlate with mild phenotype. Ann. Neurol. 55: 236-240, 2004. [PubMed: 14755727, related citations] [Full Text]

  104. Wang, Y., Roche, O., Yan, M. S., Finak, G., Evans, A. J., Metcalf, J. L., Hast, B. E., Hanna, S. C., Wondergem, B., Furge, K. A., Irwin, M. S., Kim, W. Y., Teh, B. T., Grinstein, S., Park, M., Marsden, P. A., Ohh, M. Regulation of endocytosis via the oxygen-sensing pathway. Nature Med. 15: 319-324, 2009. [PubMed: 19252501, related citations] [Full Text]

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  106. Weirich, G., Klein, B., Wohl, T., Engelhardt, D., Brauch, H. VHL2C phenotype in a German von Hippel-Lindau family with concurrent VHL germline mutations P81S and L188V. J. Clin. Endocr. Metab. 87: 5241-5246, 2002. [PubMed: 12414898, related citations] [Full Text]

  107. Wiesener, M. S., Seyfarth, M., Warnecke, C., Jurgensen, J. S., Rosenberger, C., Morgan, N. V., Maher, E. R., Frei, U., Eckardt, K.-U. Paraneoplastic erythrocytosis associated with an inactivating point mutation of the von Hippel-Lindau gene in a renal cell carcinoma. Blood 99: 3562-3565, 2002. [PubMed: 11986208, related citations] [Full Text]

  108. Yang, H., Minamishima, Y. A., Yan, Q., Schlisio, S., Ebert, B. L., Zhang, X., Zhang, L., Kim, W. Y., Olumi, A. F., Kaelin, W. G., Jr. pVHL acts as an adaptor to promote the inhibitory phosphorylation of the NF-kappa-B agonist Card9 by CK2. Molec. Cell 28: 15-27, 2007. [PubMed: 17936701, images, related citations] [Full Text]

  109. Yoshida, M., Yao, M., Ishikawa, I., Kishida, T., Nagashima, Y., Kondo, K., Nakaigawa, N., Hosaka, M. Somatic von Hippel-Lindau disease gene mutation in clear-cell renal carcinomas associated with end-stage renal disease/acquired cystic disease of the kidney. Genes Chromosomes Cancer 35: 359-364, 2002. [PubMed: 12378530, related citations] [Full Text]

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  111. Zatyka, M., Morrissey, C., Kuzmin, I., Lerman, M. I., Latif, F., Richards, F. M., Maher, E. R. Genetic and functional analysis of the von Hippel-Lindau (VHL) tumour suppressor gene promoter. J. Med. Genet. 39: 463-472, 2002. [PubMed: 12114475, related citations] [Full Text]

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ckniffin : 3/19/2004

* 608537

VON HIPPEL-LINDAU TUMOR SUPPRESSOR; VHL


HGNC Approved Gene Symbol: VHL

SNOMEDCT: 46659004;   ICD10CM: Q85.83;  


Cytogenetic location: 3p25.3     Genomic coordinates (GRCh38): 3:10,141,778-10,153,667 (from NCBI)


Gene-Phenotype Relationships

Location Phenotype Phenotype
MIM number
Inheritance Phenotype
mapping key
3p25.3 Erythrocytosis, familial, 2 263400 Autosomal recessive 3
Hemangioblastoma, cerebellar, somatic 3
Pheochromocytoma 171300 Autosomal dominant 3
Renal cell carcinoma, somatic 144700 3
von Hippel-Lindau syndrome 193300 Autosomal dominant 3

TEXT

Description

The protein products of the VHL gene play a role in the oxygen-sensing pathway, in microtubule stability and orientation, tumor suppression, cilia formation, regulation of senescence, cytokine signaling, collagen IV (see 120130) regulation, and assembly of a normal extracellular fibronectin matrix (summary by Nordstrom-O'Brien et al., 2010).


Cloning and Expression

By positional cloning, Latif et al. (1993) identified the VHL tumor suppressor gene. The gene encodes a 213-amino acid protein with a predicted acidic repeat domain found in the procyclic surface membrane glycoprotein of Trypanosoma brucei. The authors identified 2 widely expressed mRNA transcripts of approximately 6 and 6.5 kb.

Iliopoulos et al. (1995) demonstrated that the VHL protein has a molecular mass of approximately 30-kD.

By screening a rat liver cDNA library, Duan et al. (1995) isolated the rat VHL gene, which is predicted to encode a 185-amino acid protein. The rat protein is 88% identical to the aligned 213-amino acid human VHL gene product. The human and rat proteins had molecular masses of 28 and 21 kD, respectively.

Richards et al. (1996) used in situ hybridization to investigate the principal sites of VHL expression during embryogenesis. They also analyzed a variety of fetal tissues for levels of 2 VHL isoforms, isoform 1, which contains all 3 exons, and isoform 2, which contains only exons 1 and 3. Although VHL expression was found to be ubiquitous, particularly high levels of expression were detected in the urogenital system, brain, spinal cord, sensory ganglia, eyes, and bronchial epithelium. Richards et al. (1996) noted that this expression pattern correlated to some extent with the pattern of organ involvement in VHL syndrome but that there were significant differences. Both isoforms of VHL were detected in all tissues, and the ratio of isoforms was similar between tissues.

Schoenfeld et al. (1998) identified a second native VHL gene product. They showed that this 18-kD protein is initiated from the second translation start site at codon 54, which contains a more conserved Kozak consensus sequence and thus may serve as a second, internal, translation initiation site. The significance of a second translation start site is underscored by the lack of mutations found between the first and second methionine codons of the VHL gene in both sporadic and VHL-associated renal carcinomas. This observation suggested that mutation in this region may not lead to VHL inactivation if translation could be initiated at the second methionine codon, producing a functional VHL protein. Furthermore, both the rat and mouse contain only 19 of the 53 amino acids present in this region in the human VHL ORF. Schoenfeld et al. (1998) concluded that the 18-kD protein contains the biologic activity of the VHL gene.

Iliopoulos et al. (1998) also demonstrated that in addition to the 213-amino acid VHL protein with an apparent molecular mass of 30 kD (VHL30), a second VHL protein (VHL19) resulted from internal translation from the second methionine within the VHL ORF. VHL30 resides primarily in the cytosol, with lower amounts found in the nucleus or associated with cell membranes. In contrast, VHL19 is equally distributed between the nucleus and cytosol and is not found in association with membranes. VHL19, like VHL30, can bind to elongin B (ELOB; 600787), elongin C (ELOC; 600788), and Hs-Cul2 in coimmunoprecipitation assays and can inhibit the production of hypoxia-inducing proteins such as VEGF (192240) and GLUT1 (138140) when reintroduced into renal carcinoma cells that lack a wildtype VHL allele. Thus, cells contain 2 biologically active VHL gene products.

The commonly described VHL transcript contains all 3 exons that encode a 213-residue protein (termed VHL213 or VHL30). A smaller isoform, VHL160 or VHL19, is initiated from an in-frame internal translation start site in exon 1. VHL isoform VHL172 lacks exon 2. Lenglet et al. (2018) identified a cryptic exon deep in intron 1 of the VHL gene, termed E1-prime, which is naturally expressed in many tissues. Isoforms containing E1-prime with VHL exons produce a protein termed X1. Isoforms containing exon 1 spliced with E1-prime theoretically encode a protein of 193 amino acids (114 encoded by exon 1, and 79 encoded by E1-prime) (summary by Lenglet et al., 2018).


Gene Structure

Latif et al. (1993) determined that the VHL gene contains at least 3 exons.

Zatyka et al. (2002) analyzed the promoter region of the VHL gene and found 4 regions of conservation between human, primate, and rodent sequences. In silico analysis identified binding sites for numerous transcription factors within the conserved regions, and deletion analysis of the promoter in a reporter assay in 293 and HeLa cells identified 1 negative and 2 positive regulatory elements. The promoter contains a functional SP1 (189906) site and overlapping SP1/AP2 (107580) sites.

Lenglet et al. (2018) identified a cryptic exon, termed E1-prime, deep in intron 1 of the VHl gene.


Gene Function

Role in Tumor Suppression

Maher et al. (1990) compared age incidence curves for sporadic cerebellar hemangioblastoma and sporadic renal cell carcinoma to those for familial forms of these tumors that occur as part of von Hippel-Lindau syndrome (193300). The curves for tumors in VHL syndrome were compatible with a single mutation model, whereas the age incidence curves for sporadic tumors suggested a 2-stage mutation process. On the whole, the findings suggested that the VHL gene functions as a recessive tumor suppressor gene.

Crossey et al. (1994) presented convincing evidence that the VHL syndrome gene functions as a recessive tumor suppressor gene and that inactivation of both alleles of the VHL gene is a critical event in the pathogenesis of VHL neoplasms. Studies of loss of heterozygosity (LOH) showed that in 7 tumors from 7 familial cases in which the parental origin of the 3p26-p25 allele loss could be determined, the allele had been lost from the chromosome inherited from the unaffected parent. In 4 VHL tumors, LOH on other chromosomes (5q21, 13q, 17q) was found, indicating that homozygous VHL gene mutations may be required but not sufficient for tumorigenesis in von Hippel-Lindau syndrome.

When expressed in COS-7 cells, Duan et al. (1995) found that both the human and the rat VHL proteins showed predominant nuclear, nuclear and cytosolic, or predominant cytosolic VHL staining by immunofluorescence. A complicated pattern of cellular proteins was seen that could be specifically coimmunoprecipitated with the introduced VHL protein. A complex containing VHL and proteins with apparent molecular masses of 16 and 9 kD was the most consistently observed. Certain naturally occurring VHL missense mutations demonstrated either complete or partial loss of the p16-p9 complex. Duan et al. (1995) concluded that the VHL tumor suppressor gene product is a nuclear protein, perhaps capable of specifically translocating between the nucleus and the cytosol. They suggested that VHL may execute its function via formation of specific multiprotein complexes.

Vogelstein (1995) referred to the VHL gene as a gatekeeper gene for cancers such as those of the kidney. Rubenstein and Yaari (1994) suggested that the VHL gene may serve that role in relation to astrocytoma. They presented the pedigree of a Puerto Rican family in which at least 9 members had von Hippel-Lindau syndrome and 2 of these had astrocytoma.

To elucidate the biochemical mechanisms underlying tumor suppression by the VHL protein, Duan et al. (1995) and Kibel et al. (1995) searched for cellular proteins that bind to wildtype VHL protein but not to tumor-derived VHL protein mutants. They found that 2 transcriptional elongation factors, elongin B (600787) and elongin C (600788), bind in vitro and in vivo to a short, colinear region of the VHL protein that is frequently mutated in human tumors. Kibel et al. (1995) showed that a peptide replica of this region inhibited binding of VHL protein to elongin B and elongin C, whereas a point-mutant derivative, corresponding to a naturally occurring VHL missense mutation, had no effect. Duan et al. (1995) showed that recombinant VHL competes with elongin A (ELOA; 600786) for elongin B and C binding in vitro. The results were interpreted as indicating that the normal tumor suppression function of VHL protein involves the inhibition of transcription elongation by its binding to elongin B and elongin C.

In a review article, Tyers and Willems (1999) stated that the VHL protein is part of a complex that includes elongin B, elongin C, and cullin-2 (CUL2; 603135), proteins that are associated with transcriptional elongation and ubiquitination. Components of the VCB (VHL/elongin C/elongin B) complex share sequence similarities with the E3 ubiquitin ligase complexes SCF (SKP1, (601434); CUL1, (603134); F-box protein) and APC (anaphase promoting complex; see 603462). Thus, elongin B is ubiquitin-like, and elongin C and CUL2 are similar to the SKP1 and CUL1 components of SCF, respectively. Substrate recognition by E3 enzymes such as SCF and APC is crucial because protein degradation must be highly selective. Both SCF and APC interact with a set of adaptor proteins that recruit different binding partners through specific protein-protein interaction domains. SOCS-box-containing proteins (see 603597) may act as adaptors for the VCB complex.

Feldman et al. (1999) demonstrated that the folding and assembly of VHL into a complex with its partner proteins, elongin B and elongin C, is directly mediated by the chaperonin TRiC, also called CCT (see 600114). Association of VHL with TRiC is required for formation of the VHL-ELOB-ELOC complex. A 55-amino acid domain of VHL (amino acids 100 to 155) is both necessary and sufficient for binding to TRiC. Mutation or deletion of this domain is associated with VHL syndrome, and 2 mutations that disrupt the normal interaction with TRiC and impair VHL folding were identified. These results defined a novel role for TRiC in mediating oligomerization and suggested that inactivating mutations can impair polypeptide function by interfering with chaperone-mediated folding.

Lee et al. (1996) demonstrated that there is a tightly regulated, cell-density-dependent transport of the VHL protein into and/or out of the nucleus. In densely grown cells, it is predominantly in the cytoplasm, whereas in sparse cultures, most of the protein can be detected in the nucleus. They identified a putative nuclear localization signal in the first 60 and first 28 amino acids of the human and rat VHL protein, respectively. Sequences in the C-terminal region of VHL protein may also be required for localization to the cytosol. The findings indicated a novel cell-density-dependent pathway responsible for the regulation of VHL cellular localization.

Iliopoulos et al. (1995) showed that the renal cell carcinoma cell line 786-O, which is known to harbor a VHL mutation, fails to produce a wildtype VHL protein. Reintroduction of wildtype, but not mutant, VHL into these cells had no demonstrable effect on their growth in vitro but inhibited their ability to form tumors in nude mice. Like many cancer cells, the 786-0 RCC fails to exit the cell cycle upon serum withdrawal. Pause et al. (1998) showed that reintroduction of the wildtype VHL gene restores the ability of VHL-negative RCC cells to exit the cell cycle and enter G0/quiescence in low serum. The cyclin-dependent kinase inhibitor p27 (CDKN1B; 600778) accumulates upon serum withdrawal, only in the presence of VHL, as a result of an increase in protein stability. Pause et al. (1998) proposed that loss of the wildtype VHL gene results in a specific cellular defect in serum-dependent growth control, which may initiate tumor formation. Thus, VHL appears to be the first tumor suppressor involved in the regulation of cell cycle exit, which is consistent with its gatekeeper function in the kidney.

To discover genes involved in VHL-mediated carcinogenesis, Ivanov et al. (1998) used renal cell carcinoma cell lines stably transfected with wildtype VHL-expressing transgenes. Large-scale RNA differential display technology applied to these cell lines identified several differentially expressed genes, including an alpha carbonic anhydrase gene, termed CA12 (603263). The deduced protein sequence was classified as a one-pass transmembrane carbonic anhydrase possessing an apparently intact catalytic domain in the extracellular CA module. Reintroduced wildtype VHL strongly inhibited the overexpression of the CA12 gene in the parental renal cell carcinoma cell lines. Similar results were obtained with CA9 (603179) which encodes another transmembrane carbonic anhydrase with an intact catalytic domain. Although both domains of the VHL protein contributed to regulation of CA12 expression, the elongin binding domain alone could effectively regulate CA9 expression. By fluorescence in situ hybridization, Ivanov et al. (1998) mapped CA12 and CA9 to chromosome bands 15q22 and 17q21.2, respectively, regions prone to amplification in some human cancers. Ivanov et al. (1998) stated that additional experiments were necessary to define the role of CA IX and CA XII enzymes in the regulation of pH in the extracellular microenvironment and its potential impact on cancer cell growth.

Roe et al. (2006) found that VHL directly associated with and stabilized p53 (TP53; 191170) by suppressing MDM2 (164785)-mediated ubiquitination and nuclear export of p53. Moreover, upon genotoxic stress, VHL invoked an interaction between p53 and p300 (EP300; 602700) and the acetylation of p53, which led to an increase in p53 transcriptional activity and cell cycle arrest and apoptosis. Roe et al. (2006) concluded that VHL has a function in upregulating p53.

Yang et al. (2007) noted that VHL-defective renal carcinoma cells exhibit increased NF-kappa-B (see 164011) activity, which can promote resistance to chemotherapy or cytokines. They showed that VHL downregulates NF-kappa-B activity by acting as an adaptor to promote casein kinase-2 (see 115440)-mediated inhibitory phosphorylation of CARD9 (607212), an NF-kappa-B agonist.

Using in situ hybridization, analysis of RNA sequencing data, and quantitative RT-PCR, Zhu et al. (2017) found that DAAM2 (606627) was more highly expressed in human low-grade glioma and glioblastoma multiforme (GBM; see 137800) than in normal brain tissue. DAAM2 was also highly expressed in xenograft tumors generated from primary human GBM cell lines and in tumors generated in a mouse model of GBM. Overexpression of DAAM2 in human GBM cell lines resulted in accelerated rates of cell growth and colony formation, whereas knockdown of DAAM2 via short hairpin RNA inhibited growth of these cell lines. Overexpression of Daam2 in 2 mouse models of malignant glioma also resulted in accelerated tumorigenesis. Protein screening and bioinformatic analysis revealed an inverse correlation of DAAM2 and VHL expression across a broad spectrum of cancers. Similarly, Vhl protein expression was reduced in Daam2 gain-of-function mouse tumors and increased in Daam2 loss-of-function mouse tumors. Gene expression analysis showed altered Vhl signaling in Daam2-expressing mouse gliomas. Biochemical analyses revealed that DAAM2 and VHL physically interacted and that DAAM2 overexpression resulted in decreased VHL protein levels and increased VHL ubiquitination levels, suggesting that DAAM2 facilitates ubiquitin-driven protein degradation of VHL. Zhu et al. (2017) concluded that DAAM2 is part of an upstream mechanism regulating VHL suppression in cancer.

Role in Oxygen-Related Gene Expression

The highly vascular tumors associated with von Hippel-Lindau syndrome overproduce angiogenic peptides such as vascular endothelial growth factor/vascular permeability factor (VEGF/VPF; 192240). Iliopoulos et al. (1996) found that renal carcinoma cells lacking wildtype VHL protein produce mRNAs encoding VEGF/VPF, the glucose transporter GLUT1 (SLC2A1; 138140), and the platelet-derived growth factor B chain (190040) under both normoxic and hypoxic conditions. Reintroduction of wildtype, but not mutant, VHL protein into these cells specifically inhibited production of these mRNAs under normoxic conditions, thus restoring their previously described hypoxia-inducible profile. Iliopoulos et al. (1996) concluded that the VHL protein appears to play a critical role in the transduction of signals generated by changes in ambient oxygen tension.

VEGF mRNA is upregulated in von Hippel-Lindau syndrome-associated tumors. Mukhopadhyay et al. (1997) assessed the effect of the VHL gene product on VEGF expression. Using a VEGF promoter-luciferase construct for cotransfection with a wildtype VHL vector in embryonic kidney and renal cell carcinoma cell lines, they showed that wildtype VHL protein inhibited VEGF promoter activity in a dose-dependent manner up to 5- to 10-fold. Deletion analysis defined a 144-bp region of the VEGF promoter necessary for VHL repression. This VHL-responsive element is GC rich and specifically bound the transcription factor Sp1 (189906) in crude nuclear extracts. They further demonstrated that VHL and Sp1 directly interact with an inhibitory effect on Sp1, suggesting that loss of Sp1 inhibition may be important in the pathogenesis of von Hippel-Lindau syndrome and renal cell carcinoma.

Maxwell et al. (1999) studied the involvement of VHL in oxygen-regulated gene expression using ribonuclease protection analysis of 2 VHL-deficient renal carcinoma cell lines, RCC4 and 786-O. Eleven genes encoding products involved in glucose transport, glycolysis, high energy phosphate metabolism, and angiogenesis were examined; 9 were induced by hypoxia in other mammalian cells and 2 were repressed by hypoxia. None of these responses were seen in the VHL-defective cell lines. Responses to hypoxia were restored by stable transfection of a wildtype VHL gene, with effects ranging from a modest action of hypoxia to substantial regulation. These results indicated that the previously described upregulation of hypoxia-inducible mRNAs in VHL-defective cells extend to a broad range of oxygen-regulated genes and involves a constitutive 'hypoxia pattern' for both positively and negatively regulated genes.

Hypoxia-inducible factor-1 (HIF1; 603348) has a key role in cellular response to hypoxia, including the regulation of genes involved in energy metabolism, angiogenesis, and apoptosis. The alpha subunits of HIF are rapidly degraded by the proteasome under normal conditions but are stabilized by hypoxia. Cobaltous ions or iron chelators mimic hypoxia, indicating that the stimuli may interact through effects on a ferroprotein oxygen sensor. Maxwell et al. (1999) demonstrated a critical role for the von Hippel-Lindau tumor suppressor gene product VHL in HIF1 regulation. In VHL-defective cells, HIF-alpha subunits were constitutively stabilized and HIF1 was activated. Reexpression of VHL restored oxygen-dependent instability. VHL and HIF-alpha subunits coimmunoprecipitated, and VHL was present in the hypoxic HIF1 DNA-binding complex. In cells exposed to iron chelation or cobaltous ions, HIF1 is dissociated from VHL. These findings indicated that the interaction between HIF1 and VHL is iron dependent and that it is necessary for the oxygen-dependent degradation of HIF-alpha subunits. Maxwell et al. (1999) suggested that constitutive HIF1 activation may underlie the angiogenic phenotype of VHL-associated tumors.

In the presence of oxygen, HIF is targeted for destruction by an E3 ubiquitin ligase containing the VHL tumor suppressor protein. Ivan et al. (2001) found that human VHL protein binds to a short HIF-derived peptide when a conserved proline residue at the core of this peptide is hydroxylated. Because proline hydroxylation requires molecular oxygen and iron, this protein modification may play a key role in mammalian oxygen sensing. Jaakkola et al. (2001) also demonstrated that the interaction between VHL protein and a specific domain of the HIF1-alpha subunit is regulated through hydroxylation of a proline residue (HIF1-alpha P564) by an enzyme which they termed HIF-alpha prolyl-hydroxylase (HIF-PH). An absolute requirement for dioxygen as a cosubstrate and iron as a cofactor suggests that HIF-PH functions directly as a cellular oxygen sensor.

Mahon et al. (2001) showed that the N-terminal 155 residues of VHL interact with HIF1AN (606615). They found that VHL functions as a transcriptional corepressor inhibiting HIF1A transactivation by recruiting HDAC1 (601241), HDAC2 (605164), and HDAC3 (605166). Epstein et al. (2001) defined a conserved HIF-VHL-prolyl hydroxylase pathway in C. elegans and identified Egl9 as a dioxygenase that regulates HIF by prolyl hydroxylation. In mammalian cells, they showed that the HIF-prolyl hydroxylases are represented by 3 proteins, PHD1 (606424), PHD2 (606425), and PHD3 (606426), with a conserved 2-histidine-1-carboxylate iron coordination motif at the catalytic site. Direct modulation of recombinant enzyme activity by graded hypoxia, iron chelation, and cobaltous ions mirrored the characteristics of HIF induction in vivo, fulfilling requirements for these enzymes being oxygen sensors that regulate HIF.

Hoffman et al. (2001) reported that the products of 4 different type 2C VHL alleles retain the ability to downregulate HIF but are defective for promotion of fibronectin (135600) matrix assembly. Furthermore, leu188 to val (L188V; 608537.0014), a well-studied type 2C mutation, retained the ability to suppress renal carcinoma growth in vivo.

Clifford et al. (2001) investigated in detail the effect of 13 naturally occurring VHL mutations (11 missense), representing each phenotypic subclass, on HIF-alpha subunit regulation. Mutations associated with the PHE-only phenotype (type 2C) promoted HIF-alpha ubiquitylation in vitro and demonstrated wildtype binding patterns with VHL interacting proteins, suggesting that loss of other VHL functions are necessary for PHE susceptibility. Mutations causing HAB susceptibility (types 1, 2A, and 2B) demonstrated variable effects on HIF-alpha subunit and elongin binding, but all resulted in defective HIF-alpha regulation and loss of fibronectin binding. All RCC-associated mutations caused complete HIF-alpha dysregulation and loss of fibronectin binding. These studies strengthened the notion that HIF deregulation plays a causal role in hemangioblastoma and renal carcinoma, and raised the possibility that abnormal fibronectin matrix assembly contributes to pheochromocytoma pathogenesis in the setting of VHL syndrome.

Hemangioblastomas of the central nervous system and retina in VHL patients overexpress vascular endothelial growth factor, which represents a potential target for anti-angiogenic drugs. In 3 VHL patients with CNS or retinal hemangioblastomas treated by the anti-VEGF receptor SU5416, Richard et al. (2002) observed, after 3 to 4 months of treatment, a secondary paradoxical polycythemia. Hematocrit was normal before the beginning of the trial, and no progression of hemangioblastomas was observed. Polycythemia had never been reported in SU5416 trials for advanced malignancies. In the studies of Richard et al. (2002), the polycythemia may have represented a specific action on red blood cell precursors occurring only in the absence of a functional VHL gene.

Staller et al. (2003) demonstrated that the VHL tumor suppressor protein negatively regulates CXCR4 (162643) expression owing to its capacity to target HIF1A (603348) for degradation under normoxic conditions. This process is suppressed under hypoxic conditions, resulting in HIF-dependent CXCR4 activation. An analysis of clear cell renal carcinoma that manifests mutations in the VHL gene in most cases revealed an association of strong CXCR4 expression with poor tumor-specific survival. Staller et al. (2003) concluded that their results suggest a mechanism for CXCR4 activation during tumor cell evolution and imply that VHL inactivation acquired by incipient tumor cells early in tumorigenesis confers not only a selective survival advantage but also the tendency to home to selected organs.

Corn et al. (2003) established that the VHL protein binds to Tat-binding protein-1 (TBP1; 186852). TBP1 associates with the beta-domain of VHL and complexes with VHL and HIF1A in vivo. Overexpression of TBP1 promotes degradation of HIF1A in a VHL-dependent manner that requires the ATPase domain of TBP1. Several distinct mutations in exon 2 of the VHL gene disrupt binding of VHL to TBP1. A VHL protein mutant containing an exon 2 missense substitution coimmunoprecipitated with HIF1A, but not TBP1, and did not promote degradation of HIF1A. Thus, the ability of the VHL protein to degrade HIF1A depends in part on its interaction with TBP1 and suggests a new mechanism for HIF1A stabilization in some VHL-deficient tumors.

To identify novel target genes of the VHL protein, Zatyka et al. (2002) investigated the effect of wildtype VHL protein on the expression of 588 cancer-related genes in 2 VHL-defective renal cell carcinoma cell lines. Expression array analysis identified 9 genes that demonstrated a greater than 2-fold decrease in expression in both RCC cell lines after restoration of wildtype VHL protein. Three of the 9 genes, VEGF, PAI1 (173360), and LRP1 (107770), had previously been reported as targets of the VHL protein and are hypoxia-inducible. In addition, 6 novel targets were detected, including cyclin D1 (CCND1; 168461). No evidence was found that CCND1 expression was influenced by hypoxia, suggesting that VHL protein downregulates these targets by an HIF-independent mechanism.

Using yeast 2-hybrid and pull-down assays, Li et al. (2003) showed that the KRAB-A domain of human VHLAK (618359) interacted with VHL. Immunoprecipitation and expression analyses in HEK293 and A498 cells showed that VHL repressed transactivation of HIF1-alpha and HIF1-alpha-induced expression of VEGF by recruiting VHLAK to HIF1-alpha.

Homozygous disruption of the Vhl gene in mice results in embryonic lethality from lack of placental vasculogenesis (Gnarra et al., 1997). To investigate Vhl function in the adult, Haase et al. (2001) generated a conditional Vhl-null allele (2-lox allele) and a null allele (1-lox allele) by Cre-mediated recombination in embryonic stem cells. They showed that mice heterozygous for the 1-lox allele developed cavernous hemangiomas of the liver, a rare manifestation in the human disease. Histologically, these tumors were associated with hepatocellular steatosis and focal proliferations of small vessels. To study the cellular origin of these lesions, Haase et al. (2001) inactivated VHL tissue specifically in hepatocytes. Deletion of VHL in the liver resulted in severe steatosis, many blood-filled vascular cavities, and foci of increased vascularization within the hepatic parenchyma. These histopathologic changes were similar to those seen in livers from mice heterozygous for the 1-lox allele. Hypoxia-inducible mRNAs encoding vascular endothelial growth factor, glucose transporter-1, and erythropoietin (EPO; 133170) were upregulated. Thus, targeted inactivation of mouse Vhl replicated clinical features of the human disease and underscored the importance of the VHL gene product in the regulation of hypoxia-responsive genes in vivo.

Wang et al. (2007) showed that mice overexpressing Hif1a in osteoblasts through selective deletion of Vhl expressed high levels of Vegf (192240) and developed extremely dense, heavily vascularized long bones. In contrast, mice lacking Hif1a in osteoblasts had long bones that were significantly thinner and less vascularized than those of controls. Loss of Vhl in osteoblasts increased endothelial sprouting from the embryonic metatarsals in vitro but had little effect on osteoblast function in the absence of blood vessels. Wang et al. (2007) concluded that activation of the HIF1A pathway in osteoblasts during bone development couples angiogenesis to osteogenesis.

Endocytosis plays a major role in the deactivation of receptors localized to the plasma membrane, and early endocytic events require the small GTPase RAB5 (179512) and its effector rabaptin-5 (RABEP1; 603616). Wang et al. (2009) found that hypoxia, via the VHL-HIF2A (603349) signaling pathway, downregulated rabaptin-5 expression, leading to decelerated endocytosis and prolonged activation of ligand-bound EGFR (131550). Primary kidney and breast tumors with strong hypoxic signatures showed significantly lower expression of rabaptin-5 RNA and protein. Wang et al. (2009) identified a conserved hypoxia-responsive element (HRE) in the rabaptin-5 promoter that bound in vitro-translated HIF1A and HIF2A, leading to displacement of RNA polymerase II and attenuating rabaptin-5 transcription.

Mehta et al. (2009) reported that in C. elegans the loss of VHL1 significantly increased life span and enhanced resistance to polyglutamine and beta-amyloid toxicity. Deletion of HIF1 (603348) was epistatic to VHL1, indicating that HIF1 acts downstream of VHL1 to modulate aging and proteotoxicity. VHL1 and HIF1 control longevity by a mechanism distinct from both dietary restriction and insulin-like signaling. Mehta et al. (2009) concluded that their findings define VHL1 and the hypoxic response as an alternative longevity and protein homeostasis pathway.

Russell et al. (2011) demonstrated that VHL binds to SOCS1 (603597) and promotes degradation of phosphorylated JAK2 (147796) via ubiquitin-mediated destruction.

Guo et al. (2016) explored a possible link between hypoxia and AKT (608537) activity. They found that AKT was prolyl-hydroxylated by the oxygen-dependent hydroxylase EGLN1 (606425). The VHL protein bound directly to hydroxylated AKT and inhibited AKT activity. In cells lacking oxygen or functional VHL, AKT was activated to promote cell survival and tumorigenesis. Guo et al. (2016) also identified cancer-associated AKT mutations that impair AKT hydroxylation and subsequent recognition by VHL, thus leading to AKT hyperactivation. Guo et al. (2016) concluded that microenvironmental changes, such as hypoxia, can affect tumor behaviors by altering AKT activation, which has a critical role in tumor growth and therapeutic resistance.

Role in Protein Assembly

Ohh et al. (1998) showed that fibronectin coimmunoprecipitated with normal VHL protein but not tumor-derived VHL mutants. Immunofluorescence and biochemical fractionation experiments showed that fibronectin colocalized with a fraction of VHL associated with the endoplasmic reticulum, and cold competition experiments suggested that complexes between fibronectin and VHL protein exist in intact cells. Assembly of an extracellular fibronectin matrix by VHL -/- renal carcinoma cells, as determined by immunofluorescence and ELISA assays, was grossly defective compared with VHL +/+ renal carcinoma cells. Reintroduction of wildtype, but not mutant, VHL protein into VHL -/- renal carcinoma cells partially corrected this defect. Extracellular fibronectin matrix assembly by VHL -/- mouse embryos and mouse embryo fibroblasts, unlike their VHL +/+ counterparts, was grossly impaired. Ohh et al. (1998) concluded that VHL protein is important in fibronectin matrix assembly.

Hergovich et al. (2003) found that VHL is a microtubule-associated protein that can protect microtubules from depolymerization in several cell lines. Both the microtubule binding and stabilization functions depended on amino acids 95-123, a hotspot for mutations in VHL syndrome. They found that the syndrome-associated mutations Y98H (608537.0009) and Y112H (608537.0012) disrupted the microtubule-stabilizing function of the protein.

Role in Ciliary Maintenance

Using immunofluorescence and confocal microscopy, Lolkema et al. (2008) showed that Vhl localized to cilia extending from basal bodies stained with gamma-tubulin (TUBG1; 191135) in primary mouse kidney cells. Cilia were absent in renal cell carcinoma cells derived from a VHL patient, but reintroduction of VHL into these cells resulted in rapid cilia assembly. The cilia function of VHL required residues 1 to 53, which constitute an acidic domain, and residues 95 to 123, which were previously implicated in microtubule binding and tumor suppression.

Role in Central Nervous System Development

Kanno et al. (2000) investigated the role of the VHL gene in CNS development using rodent CNS progenitor cells. They showed that expression of the VHL protein is correlated with neuronal differentiation but not with glial differentiation in CNS progenitor cells, and also that VHL gene transduction induces neuronal differentiation. Furthermore, a VHL mRNA antisense oligonucleotide inhibited differentiation of CNS progenitor cells and upregulated their cell cycle.


Biochemical Features

Crystal Structure

The ubiquitination of HIF by VHL plays a central role in the cellular response to changes in oxygen availability. VHL protein binds to HIF only when a conserved proline in HIF is hydroxylated, a modification that is oxygen-dependent. Min et al. (2002) determined the 1.85-angstrom structure of a 20-residue HIF1A-VHL protein-elongin B-elongin C complex that shows that HIF1A binds to VHL protein in an extended beta strand-like conformation. The hydroxyproline inserts into a gap in the VHL hydrophobic core, at a site that is a hotspot for tumorigenic mutations, with its 4-hydroxyl group recognized by buried serine and histidine residues. Although the beta sheet-like interactions contribute to the stability of the complex, the hydroxyproline contacts are central to the strict specificity characteristic of signaling.

Hon et al. (2002) determined the crystal structure of a hydroxylated HIF1A peptide bound to the VHL protein, elongin C, and elongin B and performed solution binding assays, which revealed a single, conserved hydroxyproline-binding pocket in the VHL protein. They found that optimized hydrogen bonding to the buried hydroxyprolyl group confers precise discrimination between hydroxylated and unmodified prolyl residues. Hon et al. (2002) concluded that this mechanism provides a new focus for development of therapeutic agents to modulate cellular responses to hypoxia.


Molecular Genetics

Nordstrom-O'Brien et al. (2010) provided a review of the molecular genetics of the VHL gene, including the mutational spectrum and associated phenotypes.

Von Hippel-Lindau Syndrome, Autosomal Dominant

Using restriction fragment analysis, Latif et al. (1993) identified rearrangements of the VHL gene in 28 of 221 kindreds with von Hippel-Lindau syndrome (VHLS; 193300). Eighteen of these rearrangements were due to deletion in the candidate gene. Using pulsed field gel electrophoresis and cosmid mapping, Latif et al. (1993) established a physical map of the VHL gene region and identified 3 large nonoverlapping constitutional deletions in 3 unrelated VHL patients; one of these was an in-frame 3-nucleotide deletion at nucleotide 434, predicted to remove ile146 in the gene product (608537.0001).

Using single-strand conformation polymorphism and heteroduplex analysis to investigate 94 VHLS patients without large deletions, Crossey et al. (1994) identified 40 different mutations in the VHL gene in 55 unrelated kindreds: 19 missense mutations, 6 nonsense mutations, 12 frameshift deletions or insertions, 2 in-frame deletions, and 1 splice donor site mutation. The 2 most frequent mutations were arg238-to-gln (608537.0005) and arg238-to-trp (608537.0003), which were detected in 5 and 4 unrelated kindreds, respectively.

Olschwang et al. (1998) screened 92 unrelated patients with VHL syndrome for point mutations and found 61 DNA variants. In addition, a search for EcoRI rearrangements revealed germline anomalies in 5 patients. The 61 variants could be subdivided into 20 mutations predicted to alter the open reading frame and 43 DNA sequence variants that on a priori grounds were of unknown biologic consequence. The 3-prime end of the coding sequence of the VHL gene, which encodes the elongin (see 600787)-binding domain, was the site of 5 of 20 truncating mutations (25%) and 18 of 41 DNA variants (44%) of uncertain functional significance. A similar screening in 18 patients with sporadic hemangioblastoma revealed 2 missense DNA variants.

Wait et al. (2004) performed genetic analysis of 5 CNS hemangioblastomas excised from 3 related VHL patients with the same germline VHL gene deletion. All of the tumors showed distinct 'second-hit' point mutations on the wildtype allele, even those tumors originating in the same patient. Moreover, the same types of tumors from the same locations also showed different point mutations. Wait et al. (2004) concluded that the somatic mutations were random, and that there is a unique mechanism underlying tumorigenesis in patients with germline deletion mutations.

Using markers specific for chromosome 3, Glasker et al. (2006) mapped the deletion size of the 'second-hit' in 16 tumor tissue specimens from a single patient with VHL syndrome who had a germline heterozygous partial deletion in the VHL gene. The tumors consisted of 3 central nervous system hemangioblastomas, 7 renal cell carcinomas, 3 cystic renal structures, 2 pancreatic tumors, and 1 pancreatic cyst. Deletion size was highly variable, ranging from short deletions around the VHL gene to complete deletion of chromosome 3. However, there was no correlation between deletion size and site of the germline mutation, affected organ, or type or biological behavior of the tumor. Glasker et al. (2006) concluded that loss of VHL gene function alone is not immediately causative for neoplastic growth and suggested that further molecular events may be required for tumor formation.

In 6 patients from a family (F8) with von Hippel-Lindau syndrome, Lenglet et al. (2018) identified heterozygosity for an in cis complex mutation in the cryptic exon 1-prime of the VHL gene (608537.0032). The mutations, which were found by a combination of microsatellite analysis and gene sequencing, segregated with the disorder in the family. The mutations were predicted to result in leu128-to-val (L128V) and leu138-to-pro (L138P) substitutions in the newly identified X1 VHL protein isoform. Analysis of patient cells and tumor tissue showed upregulation of isoforms containing exon 1 and exon 1-prime, predicted to result in premature termination that would likely be degraded by nonsense-mediated mRNA. There was also lower expression of other wildtype VHL isoforms. Minigene assays in various cell lines showed a synergistic effect of the 2 mutations on abnormal splicing; the expression of exon 1-prime-containing isoforms was higher for mutations associated with cancer than with erythrocytosis. The authors postulated downreguation of VHL isoforms as a pathogenic mechanism. Sequencing of tumor tissue from these patients did not identify VHL loss of heterozygosity, indicating that somatic VHL deletion may not be a prerequisite for developing cancer in patients with this genotype.

For a discussion of genotype/phenotype correlations in VHL syndrome, see 193300.

Cancer

The Knudson model predicts that sporadic cancers should be associated with mutations in the same locus affected in the corresponding hereditary cancer. Using SSCP and RT-PCR techniques, Latif et al. (1993) identified aberrant patterns in the VHL gene in 5 renal cell carcinoma (RCC) lines. In 4 of them, the pattern was due to small, 1- to 10-nucleotide deletions that created frameshift mutations and, presumably, truncated proteins. In the fifth RCC line, the change was a nonsense mutation, resulting from a 761C-A transversion.

Eng et al. (1995) identified mutations in the VHL gene in 4 of 48 sporadic pheochromocytomas (171300). Two mutations were somatic and 2 were germline. In a mother and 2 sons with pheochromocytoma, Crossey et al. (1995) identified a VHL mutation (R238W; 608537.0003) mutation. None of them had evidence of VHL syndrome.

In 30 (11%) of 271 unrelated patients with sporadic pheochromocytoma, Neumann et al. (2002) identified 22 different germline mutations in the VHL gene (see, e.g., 608537.0014 and 608537.0026).

Zhuang et al. (1996) analyzed VHL gene alterations in sporadic human colon carcinomas and adenomas using techniques that allowed for procurement and analysis of selected subpopulations of cells from paraffin embedded and frozen human tumor specimens. Allelic loss of the VHL gene was detected in 7 of 11 (64%) of informative patients with sporadic colon carcinoma. No allelic loss was shown in colon adenomas from 8 informative patients. The authors suggested that VHL gene loss may represent a relatively late event in colonic neoplasia progression.

Oberstrass et al. (1996) found abnormalities of the VHL gene in 10 of 20 capillary hemangioblastomas of the CNS. Seven tumors had a frameshift mutation due either to deletion of 1 or more basepairs (6 cases) or to insertion of 1 basepair (1 case). The remaining 3 tumors had either point mutations with intron splice site sequences (2 cases) or a point mutation resulting in an amino acid substitution (1 case). Evidence for germline alterations of the VHL gene was found in 2 patients who showed identical mutations in both tumors and corresponding leukocyte DNA. Oberstrass et al. (1996) noted that it is significant that one of the 2 tumors with a germline mutation was in an 18-year-old male, and the other in a 40-year-old female. The non-germline mutations included tumors from individuals 70, 62, 60, 55, and 52 years old.

Kenck et al. (1996) investigated 91 different parenchymal tumors of the kidney for mutation in the VHL gene by SSCP and/or heteroduplex techniques. Evidence of mutation of the VHL gene was associated exclusively with nonpapillary renal cell carcinoma.

Fearon (1997) reviewed more than 20 different hereditary cancer syndromes that had been defined and attributed to specific germline mutations in various inherited cancer genes. In a useful diagram, he illustrated the roles of allelic variation ('1 gene - different syndromes') and genetic heterogeneity ('different genes - 1 syndrome') in inherited cancer syndromes. VHL mutations were used as an example of the former: inactivating mutations, such as nonsense mutations or deletions, predisposed to clear-cell renal carcinoma, retinal angioma, and cerebellar and spinal hemangioblastoma; missense mutations, e.g., in codon 167, predisposed to these tumors and pheochromocytoma in addition.

Van der Harst et al. (1998) screened the VHL gene for germline mutations in 68 patients who were operated on for pheochromocytoma. This was undertaken to follow up on the work of Neumann et al. (1993), who reported that, according to clinical criteria, approximately 23% of the apparently sporadic pheochromocytomas may in fact be related to a familial disorder; these disorders are, in addition to von Hippel-Lindau syndrome, neurofibromatosis-1 (NF1; 162200) and multiple endocrine neoplasia types IIA (MEN2A; 171400) and IIB (MEN2B; 162300). They found mutations in the VHL gene in 8 patients; 2 patients were an uncle and nephew who had the same missense mutation, R64P (608537.0015). In 4 other patients, missense mutations, P25L, L63P (608537.0016), G144Q, and I147T, were identified. Three of these mutations (P25L, L63P, and R64P) were located closer to the N terminus of the VHL protein than any previously reported VHL mutation. In 2 other cases, the mutations were located not in the coding region but in the intronic sequence (but not within splice sites), adjacent to the exon, so that they were probably not related to the syndrome. The results suggested that 8.8% of patients (6 of 68) with apparently sporadic pheochromocytomas may carry germline mutations in the VHL gene. This is a relatively high proportion, although not as high as the 23% reported earlier.

Gallou et al. (1999) investigated the nature of somatic VHL mutations in 173 primary sporadic human renal cell carcinomas using PCR and SSCP analysis. They detected an abnormal SSCP pattern in 73 samples. After sequencing, they identified microdeletions in 58% of cases, microinsertions in 17%, nonsense mutations in 8%, and missense mutations in 17%. VHL mutations were found only in the nonpapillary renal cell carcinoma subtype, as previously reported. To compare somatic and germline mutations, they used the VHL database, which included 507 mutations. The study of mutational events revealed a significant difference between somatic and germline mutations. Mutations leading to truncated proteins were observed in 78% of somatic mutations but in only 37% of germline mutations (P less than 0.001). The authors postulated that a specific pattern of VHL mutations is associated with sporadic RCC. This pattern corresponds to mutations leading to truncated proteins, with few specific missense mutations.

Bender et al. (2000) studied 36 VHL-related pheochromocytomas for somatic VHL and RET gene alterations and LOH of markers on chromosome arms 1p, 3p, and 22q. For comparison, they performed the same analyses in 17 sporadic pheochromocytomas. They found significantly different LOH frequencies at 3 loci between sporadic and VHL tumors; the more than 91% LOH of markers on 3p and the relatively low frequencies of LOH at 1p and 22q (15% and 21%, respectively) in VHL pheochromocytomas argue for the importance of VHL gene dysregulation and dysfunction in the pathogenesis of almost all VHL pheochromocytomas. In contrast, the relatively low frequency of 3p LOH (24%) and the lack of intragenic VHL alterations compared with the high frequency of 1p LOH (71%) and the moderate frequency of 22q LOH (53%) in sporadic pheochromocytomas argue for genes other than VHL, especially on 1p, that are significant for sporadic tumorigenesis and suggest that the genetic pathways involved in sporadic versus VHL pheochromocytoma genesis are distinct.

Renal cell carcinomas occur frequently in patients treated with long-term dialysis, especially in cases of end-stage renal disease (ESRD)/acquired cystic disease of the kidney (ACDK). In patients receiving dialysis, Yoshida et al. (2002) examined 14 RCCs (7 clear-cell and 7 papillary carcinomas) for somatic mutations of the VHL gene as well as of the tyrosine kinase domain of the MET oncogene (164860) to address the molecular pathogenesis of ESRD/ACDK-associated RCCs. They found that 3 tumors had VHL frameshifts; 1 showed additional LOH at the VHL gene locus. All 3 tumors were clear-cell RCCs occurring in ESRD with 55, 106, and 156 months of dialysis, respectively. No mutations were found in the tyrosine kinase domain of the MET oncogene, where mutations had previously been found in cases of papillary RCCs.

Maranchie et al. (2004) observed a paradoxically lower prevalence of RCC in patients with complete germline deletion of VHL. They retrospectively evaluated 123 patients from 55 families with large germline VHL deletions, including 42 intragenic partial deletions and 13 complete VHL deletions. An age-adjusted comparison demonstrated a higher prevalence of RCC in patients with partial germline VHL deletions relative to complete deletions (48.9% vs 22.6%, p = 0.007). This striking phenotypic dichotomy was not seen for cystic renal lesions or for CNS (p = 0.22), pancreas (p = 0.72), or pheochromocytoma (p = 0.34). Deletion mapping demonstrated that development of RCC had an even greater correlation with retention of HSPC300 (C3ORF10; 611183), located within the 30-kb region of 3p, immediately telomeric to VHL (52.3% vs 18.9%, p less than 0.001), suggesting the presence of a neighboring gene or genes critical to the development and maintenance of RCC.

Gallou et al. (2004) studied the renal phenotype in 274 individuals from 126 unrelated VHL families in whom 92 different VHL mutations were identified. The incidence of renal involvement was increased in families with mutations leading to protein truncation or large rearrangement, as compared to families with missense mutations (81% vs 63%, respectively; p = 0.03). In the group with missense mutations, Gallou et al. (2004) identified 2 mutation cluster regions (MCRs) associated with a high risk of harboring renal lesions: MCR-1 (codons 74-90) and MCR-2 (codons 130-136). In addition, the incidence of RCCs was higher in families with mutations leading to protein truncation than in families with missense mutations (75% vs 57%, respectively; p = 0.04). Furthermore, missense mutations within MCR-1, but not MCR-2, conferred genetic susceptibility to RCC.

Chuvash Polycythemia

Chuvash polycythemia (see ECYT2, 263400) is an autosomal recessive disorder of erythrocytosis that is endemic to the mid-Volga River region. Ang et al. (2002) studied 5 multiplex Chuvash families and confirmed that polycythemia was associated with significant elevations of serum erythropoietin levels and ruled out a location of the gene on chromosome 11 that had previously been reported by Vasserman et al. (1999). They also ruled out mutation in the HIF1A gene, which is located on 14q. Using a genomewide screen, they identified a region on 3p with a lod score greater than 2 and identified a homozygous c.598C-T transition in the VHL gene, resulting in an arg200-to-trp mutation (R200W; 608537.0019) in all cases. Ang et al. (2002) concluded that the R200W substitution impairs the interaction of VHL with HIF1-alpha, reducing the rate of degradation of HIF1-alpha and resulting in increased expression of downstream target genes including EPO, SLC2A1 (138140), transferrin (TF; 190000), transferrin receptor (TFRC; 190010), and vascular endothelial growth factor (VEGF; 192240). Mutations in VHL had been associated with pheochromocytoma, hemangioblastoma, and renal cell carcinoma, none of which were observed in individuals with Chuvash polycythemia or obligate carriers of the R200W mutation. Ang et al. (2002) stated that more than 700 mutations had been reported in VHL (Beroud et al., 1998), but that no individual had been found to be homozygous or compound heterozygous for germline mutations.

Familial Erythrocytosis 2

Inheritance of germline mutations on both VHL alleles was found by Ang et al. (2002) and by others (Pastore et al., 2003; Percy et al., 2002) as the cause of autosomal recessive familial erythrocytosis (ECYT2; 263400; see, e.g., 608537.0019). The VHL protein plays an important role in hypoxia sensing. It binds to hydroxylated HIF1-alpha and serves as a recognition component of an E3 ubiquitin ligase complex. In hypoxia or secondary to a mutated VHL gene, the nondegraded HIF1-alpha forms a heterodimer with HIF1-beta and leads to increased transcription of hypoxia-inducible genes, including EPO. Pastore et al. (2003) reported 7 erythrocytosis patients with VHL mutations on both alleles (608537.0021-608537.0024). Two Danish sibs and an American boy were homozygous for the R200W mutation (608537.0019). Three unrelated white Americans were compound heterozygous for R200W and another VHL mutation: L188V (608537.0014) in 2 and P192A (608537.0023) in the third. Additionally, a Croatian boy was homozygous for an H191D mutation (608537.0024). Pastore et al. (2003) stated that they had not observed VHL syndrome-associated tumors in subjects with erythrocytosis or their heterozygous relatives. They found that up to half of the consecutive patients with apparent congenital erythrocytosis and increased serum EPO whom they had examined had mutations of both VHL alleles. They concluded that VHL mutations are the most frequent cause of recessive congenital erythrocytosis and define a class of disorders due to augmented hypoxia sensing.

In an 8-year-old boy with ECYT2, Bond et al. (2011) identified compound heterozygous missense mutations in the VHL gene (D126N, 608537.0028 and S183L, 608537.0029). The mutations were found by direct gene sequencing. Transfection of the mutations into renal carcinoma cells showed decreased protein levels consistent with instability of the mutant proteins, suggesting a loss-of-function effect. Transfected cells also showed decreased pH, decreased glucose, and increased lactate, consistent with upregulation of glycolysis. These changes were associated with increased expression of HIF1A, PHD3 (606426), and GLUT1 (138140), suggesting impaired ability of mutant VHL to regulate HIF. The patient presented at 2 months of age with right ventricular dysfunction and hypertrophy, pulmonary hypertension, increased hematocrit and hemoglobin, and significantly increased EPO. He was managed successfully by phlebotomy.

Sarangi et al. (2014) identified homozygosity for the D126N mutation in the VHL gene in a 2-year-old boy, born of consanguineous Bangladeshi parents, with fatal ECYT2. In vitro studies showed that patient erythroid progenitors were not hypersensitive to EPO and did not overexpress NFE2 (601490) or RUNX1 (151385) transcripts, which are associated with EPO hypersensitivity. This demonstrated a different pathogenic mechanism from patients with Chuvash polycythemia due to the R200W mutation (608537.0019). The patient reported by Sarangi et al. (2014) presented in infancy with failure to thrive, polycythemia, elevated EPO, pulmonary hypertension, and a thrombotic state. Neither parent had polycythemia or evidence of VHL-associated tumors.

Tomasic et al. (2013) reported a 5-year-old Croatian girl with early-onset ECYT2 due to a homozygous H191D mutation (608537.0024). Family history revealed that she was related to the Croatian patient reported by Pastore et al. (2003). Patient erythroid precursors showed normal growth and were not hypersensitive to EPO in vitro; these findings differed from those observed in Chuvash polycythemia in which the erythroid precursors are intrinsically hyperproliferative and also show hypersensitivity to EPO. Tomasic et al. (2013) concluded that the polycythemia in patients with the H191D mutation is solely driven by increased circulating EPO. Patient cells showed changes in gene expression, including increased expression of several HIF1A-related genes (TFRC, 190010; VEGF, 192240; and HK1, 142600), and decreased expression of other genes (BNIP3L, 605368 and ADM, 103275).

In a 15-year-old girl of Asian Indian descent with ECYT2, Lanikova et al. (2013) identified a homozygous missense mutation in the VHL gene (P138L; 608537.0035). The mutation, which was found by direct sequencing of the VHL gene, segregated with the disorder in the family.

In 10 patients from 9 unrelated families with familial ECYT2, Lenglet et al. (2018) identified compound heterozygous mutations in the VHL gene. All patients carried heterozygous mutations in the newly identified cryptic exon 1-prime (E1-prime) (see, e.g., 608537.0030 and 608537.0031) deep in intron 1, resulting in a splicing alteration. Prior to the study of Lenglet et al. (2018), several of these patients were thought to carry only 1 VHL mutation (e.g., R200W, consistent with Chuvash polycythemia; the patient from F2 had previously been reported by Cario et al., 2005). The mutations, which were found by a combination of whole-genome and Sanger sequencing, segregated with the disorder in the families. RT-PCR analysis from lymphocytes derived from these patients showed decreased mRNA levels, increased amounts of E1/E3 transcripts suggesting that the mutations resulted in the skipping of exon 2, and severe decreases in the wildtype VHL mRNA and protein isoforms compared to controls. The findings by Lenglet et al. (2018) confirmed that ECYT2 is an autosomal recessive disorder, and the authors postulated that the splice site mutations in these patients caused a global defect in VHL protein expression with downregulation of VHL, rather than reduced HIF1A binding.

In a 22-year-old man, born of consanguineous Italian parents, with ECYT2, Perrotta et al. (2020) identified a homozygous c.222C-A transversion in exon 1 of the VHL gene, predicted to result in a synonymous val75-to-val (V75V; 608537.0034) substitution. The mutation, which was found by direct sequencing, segregated with the disorder in the family. Analysis of patient cells showed that it created an alternative splice donor site, resulting in a frameshift and premature termination. Patient and paternal cells showed 80% and 40% lower levels of wildtype mRNA, respectively, compared to controls. Patient cells showed decreased amounts of the 3 main VHL protein isoforms (213, 160, and 172) as well as increased HIF1A, suggesting a loss of VHL function. Patient cells also showed increased levels of BNIP3L (605368) and MXI1 (600020) compared to controls.


Animal Model

Gemmill et al. (2002) isolated the Drosophila homolog of TRC8 (603046) and studied its function by genetic manipulations and a yeast 2-hybrid screen. Human and Drosophila TRC8 proteins localize to the endoplasmic reticulum. Loss of either Drosophila Trc8 or Vhl resulted in an identical ventral midline defect. Direct interaction between Trc8 and Vhl in Drosophila was confirmed by GST-pull-down and coimmunoprecipitation experiments. Gemmill et al. (2002) found that in Drosophila, overexpression of Trc8 inhibited growth consistent with its presumed role as a tumor suppressor gene. Human JAB1 (604850) localization was dependent on VHL mutant status. Thus, the VHL, TRC8, and JAB1 proteins appear to be linked both physically and functionally, and all 3 may participate in the development of kidney cancer.

Ding et al. (2006) used the Cre-loxP system to delete the Vhl gene from podocytes in the glomerular basement membrane of mice. At about 4 weeks of age, the mice developed rapidly progressive renal disease with hematuria, proteinuria, and renal failure with crescentic glomerulonephritis with prominent segmental fibrin deposition and fibrinoid necrosis. No immune deposits were present; the phenotype was similar to human 'pauci-immune' rapidly progressive glomerulonephritis (RPGN). Gene expression profiling showed increased expression of the HIF target gene Cxcr4 (162643) in glomeruli from both mice and humans with RPGN. Treatment of the mice with a Cxcr4 antibody resulted in clinical improvement, and isolated overexpression of Cxcr4 was sufficient to cause glomerular disease. Ding et al. (2006) hypothesized that upregulation of Cxcr4 allowed terminally differentiated podocytes to reenter the cell cycle, proliferate, and form cellular crescents.

Hickey et al. (2007) found that mice homozygous for the Chuvash polycythemia-associated VHL mutation (R200W; 608537.0019) developed polycythemia similar to the human disease. Although bone marrow cellularity and morphology was similar to controls, spleens from the mutant mice showed increased numbers of erythroid progenitors and megakaryocytes, as well as erythroid differentiation of splenic cells in vitro. Further analysis showed upregulation of HIF2A (603349) and of key target genes, including EPO, VEGF (192240), GLUT1 (138140), and PAI1 (173360), that contribute to polycythemia.

Using immunofluorescence microscopy, Zehetner et al. (2008) found that Vhl was expressed in mouse insulin-producing pancreatic beta cells. Conditional inactivation of Vhl in beta cells promoted a diversion of glucose away from mitochondria into lactate production, causing cells to produce high levels of glycolytically derived ATP and to secrete elevated levels of insulin at low glucose concentrations. Vhl-deficient mice exhibited diminished glucose-stimulated changes in cytoplasmic Ca(2+) concentration, electrical activity, and insulin secretion, which culminated in impaired systemic glucose tolerance. Vhl deletion was associated with upregulation of Hif1a and the glucose transporter Glut1, an Hif1a target gene. Combined deletion of Vhl and Hif1a rescued the defects due to Vhl deletion alone, implying that they resulted from Hif1a activation.

Lee et al. (2009) generated transgenic mouse embryonic stem cells with the homozygous VHL type 2B mutation R167Q (608537.0005). Mutant cells had preserved regulation of both HIF-alpha factors with slightly greater normotoxic dysregulation of HIF2-alpha. R167Q-derived teratomas had a growth advantage and showed hemangioma formation. Homozygous mice were embryonic lethal due to placental failure, and heterozygous mice developed renal cysts and were predisposed to the carcinogen-promoted renal carcinoma.


ALLELIC VARIANTS 35 Selected Examples):

.0001   VON HIPPEL-LINDAU SYNDROME

VHL, 3-BP DEL, ILE75DEL
SNP: rs794729660, ClinVar: RCV000002298

Following the revised codon numbering system of Kuzmin et al. (1995), the ILE146DEL mutation has been renumbered as ILE75DEL.

In a patient with von Hippel-Lindau syndrome (VHLS; 193300), Latif et al. (1993) identified an in-frame 3-nucleotide deletion at nucleotide 434 of the VHL gene, predicted to remove isoleucine-146 in the gene product.


.0002   RENAL CELL CARCINOMA, SOMATIC

VHL, SER183TER
SNP: rs5030823, gnomAD: rs5030823, ClinVar: RCV000002299, RCV000208867, RCV000703889, RCV003162205

Following the revised codon numbering system of Kuzmin et al. (1995), the SER254TER mutation has been renumbered as SER183TER (S183X).

In a cell line from a sporadic case of renal cell carcinoma (144700), Latif et al. (1993) identified a 761C-A transversion in the VHL gene, predicted to result in a ser254-to-ter (S254X) substitution.


.0003   VON HIPPEL-LINDAU SYNDROME

PHEOCHROMOCYTOMA, INCLUDED
VHL, ARG167TRP
SNP: rs5030820, gnomAD: rs5030820, ClinVar: RCV000002302, RCV000002303, RCV000132159, RCV000213079, RCV000435817, RCV000627746, RCV000763092

Following the revised codon numbering system of Kuzmin et al. (1995), the ARG238TRP mutation has been renumbered as ARG167TRP (R167W).

In a study of 94 patients with von Hippel-Lindau syndrome (VHLS; 193300) patients without large deletions, Crossey et al. (1994) found that the 2 most frequent mutations were missense mutations at codon 238: 4 kindreds had a 712C-T transition, resulting in an arg238-to-trp (R238W) substitution, and 5 kindreds had a 713G-A transition, leading to an arg238-to-gln (R238Q; 608537.0005) substitution. Another identified mutation was a 712C-G transversion, resulting in an arg238-to-gly (R238G) substitution (608537.0004). All 3 mutations at codon 238 occurred at a CpG dinucleotide. The authors noted that although pheochromocytoma occurs in only about 7% of patients with VHL, a codon 238 mutation carried a high risk (62%) of pheochromocytoma.

The R238W mutation was found by Garcia et al. (1997) in a Spanish family in which VHLS was manifested predominantly as familial pheochromocytoma in 2 generations, consistent with VHL syndrome type 2C.

In a mother and 2 sons with pheochromocytoma (171300), consistent with VHL syndrome type 2C, Crossey et al. (1995) identified the R238W mutation.

Zbar et al. (1996) confirmed previous observations that germline codon 167 mutations of the VHL gene (R167W and R167Q, 608537.0005) convey a high risk for the development of pheochromocytoma and renal cell carcinoma. In 21 of 33 families with mutations at codon 167, pheochromocytoma occurred, compared to 15 of 223 families without a mutation at codon 167. The association between codon 167 mutations and pheochromocytoma was detected in all nationalities tested. Two of 4 Japanese VHL pheochromocytoma families had mutations at codon 167; and 3 of 10 French VHL pheochromocytoma families had mutations at codon 167.

Neumann et al. (2002) identified the R167Q substitution in the germline of a patient with sporadic pheochromocytoma (171300).

In the germlines of 6 unrelated patients with sporadic pheochromocytoma, Neumann et al. (2002) identified the R167W substitution. The mutation was not identified in 600 control chromosomes.


.0004   VON HIPPEL-LINDAU SYNDROME

VHL, ARG167GLY
SNP: rs5030820, gnomAD: rs5030820, ClinVar: RCV000002304, RCV000466046, RCV002336073

Following the revised codon numbering system of Kuzmin et al. (1995), the ARG238GLY mutation has been renumbered as ARG167GLY (R167G).

See 608537.0003 and Crossey et al. (1994).


.0005   VON HIPPEL-LINDAU SYNDROME

VHL, ARG167GLN
SNP: rs5030821, gnomAD: rs5030821, ClinVar: RCV000002300, RCV000213850, RCV000325074, RCV000506694, RCV000627745, RCV003448242

Following the revised codon numbering system of Kuzmin et al. (1995), the ARG238GLN mutation has been renumbered as ARG167GLN (R167Q).

See 608537.0003 and Crossey et al. (1994).


.0006   VON HIPPEL-LINDAU SYNDROME

VHL, ARG161TER
SNP: rs5030818, ClinVar: RCV000002301, RCV000161091, RCV000437445, RCV000492225, RCV000791367, RCV001280922

Following the revised codon numbering system of Kuzmin et al. (1995), the ARG232TER mutation has been renumbered as ARG161TER (R161X).

In a patient with von Hippel-Lindau syndrome (VHLS; 193300), Loeb et al. (1994) identified a 694C-T transition in exon 3 of the VHL gene, resulting in an amber stop codon arg232-to-ter (R232X).

Gilcrease et al. (1995) found the identical 694C-T transition as a somatic mutation in a clear cell papillary cystadenoma of the epididymis in a patient who showed no evidence of von Hippel-Lindau syndrome and in whom somatic cells did not contain this mutation.


.0007   HEMANGIOBLASTOMA, SPORADIC CEREBELLAR, SOMATIC

VON HIPPEL-LINDAU SYNDROME, INCLUDED
VHL, TRP88SER
SNP: rs119103277, ClinVar: RCV000002306

Following the revised codon numbering system of Kuzmin et al. (1995), the TRP159SER mutation has been renumbered as TRP88SER (W88S).

In 13 sporadic cases of cerebellar hemangioblastoma, Kanno et al. (1994) sought somatic mutations in the VHL gene with single-strand conformation polymorphism analyses of the tumor DNAs. An abnormal SSCP pattern was detected in 7, and in 3 of these the mutation was successfully characterized by direct sequencing. The somatic mutations were 2 missense mutations and 1 deletion of a single base. One of the missense mutations was a 476G-C transversion, resulting in a trp-to-ser change. The codon number was not noted.

In a Japanese patient with von Hippel-Lindau syndrome (VHLS; 193300), the Clinical Research Group for VHL in Japan (1995) identified the 476G-C transversion, which resulted in a trp159-to-ser (W159S) substitution.


.0008   HEMANGIOBLASTOMA, SPORADIC CEREBELLAR, SOMATIC

VHL, LEU135PHE
SNP: rs119103278, ClinVar: RCV000002307

In a sporadic case of cerebellar hemangioblastoma, Kanno et al. (1994) identified a somatic missense mutation in exon 2 of the VHL gene: a 618A-C transversion, resulting in a leu135-to-phe substitution.


.0009   VON HIPPEL-LINDAU SYNDROME

VHL, TYR98HIS
SNP: rs5030809, gnomAD: rs5030809, ClinVar: RCV000002309, RCV000492094, RCV000679029, RCV000684783, RCV003891425

Following the revised codon numbering system of Kuzmin et al. (1995), the TYR169HIS mutation has been renumbered as TYR98HIS (Y98H), resulting from a 292T-C transition.

In 14 apparently unrelated families from the Black forest region of Germany with von Hippel-Lindau syndrome (VHLS; 193300), apparently VHL type 2A, Brauch et al. (1995) found a 505T-C transition in the VHL gene, resulting in a tyr169-to-his (Y169H) substitution. Brauch et al. (1995) suggested that more than 75 VHL germline mutations had been identified in VHL patients to that date. The same mutation, associated with pheochromocytoma, had been identified by Chen et al. (1995) in 2 VHL 2A families in Pennsylvania. All affected individuals in the 16 families shared the same VHL haplotype, indicating a founder effect. In at least one of the Pennsylvania families, the Y169H mutation probably derived from their Pfalz ancestors, who were among Germans who migrated to Pennsylvania.

In a patient with the Y169H mutation as the cause of VHLS, Schimke et al. (1998) found a functioning carotid paraganglioma.

Allen et al. (2001) performed a longitudinal clinical study and DNA analysis of 24 family members, 16 of whom exhibited a 505T-C change in exon 1 of the VHL gene. Two of the 16 were asymptomatic carriers of the 505T-C mutation. Twelve of 16 (75%) of the gene carriers had 1 or more ocular angiomas. The mean number of ocular angiomas per gene carrier was 3.3. Six eyes had optic disc angiomas. Five gene carriers (31%) lost vision because of ocular angiomatosis. Four patients (25%) had cerebellar hemangioblastomas and 11 patients (69%) had pheochromocytomas. No patient had renal cell carcinoma, consistent with the clinical diagnosis of VHL syndrome type 2A. The authors stated that recognition of the VHL syndrome 2A phenotype suggested the presence of a specific mutation (505T-C) in the VHL gene. They suggested that confirmation of this genotype would increase a clinician's ability to provide favorable prognostic information to affected family members.

Bender et al. (2001) studied 125 individuals in southern Germany carrying the 505T-C mutation. Forty-seven percent had pheochromocytoma; 36% had retinal angioma; 36%, hemangioblastoma of the spine; and 16% had hemangioblastoma of the brain. Forty-seven percent of patients were symptomatic; 30% were asymptomatic despite the presence of at least 1 VHL-related tumor; and 23% of the carriers had no detectable VHL lesion. Of the 19 patients who died, 10 died of symptomatic VHL lesions. Overall penetrance by cumulative incidence was estimated at 48% by 35 years and 88% by 70 years. Bender et al. (2001) suggested that the mortality rate for those carrying this mutation was much lower than in unselected VHL mutations and was comparable to that of the general population of Germany.


.0010   MOVED TO 608537.0003


.0011   MOVED TO 608537.0003


.0012   VON HIPPEL-LINDAU SYNDROME

VHL, TYR112HIS
SNP: rs104893824, ClinVar: RCV000002308, RCV000698407, RCV002321468, RCV003407257

In a large family with von Hippel-Lindau syndrome (VHLS; 193300) studied by Tisherman et al. (1962, 1993), Zbar et al. (1996) identified a tyr112-to-his (Y112H) mutation in the VHL gene. Of 22 affected family members, 19 were affected with pheochromocytoma; no affected family member had renal cell carcinoma. In the original report (Tisherman et al., 1962), at least 7 persons had pheochromocytoma. One or more cafe-au-lait spots (in 22 persons), extensive hemangiomas (in 2 persons), and angiomatosis retinae (in 2 persons) were discovered in the family.


.0013   VON HIPPEL-LINDAU SYNDROME

VHL, VAL166PHE
SNP: rs104893825, ClinVar: RCV000002310, RCV000220823, RCV001851578, RCV002288459

In a family with von Hippel-Lindau syndrome (VHLS; 193300), Gross et al. (1996) identified a val166-to-phe (V166F) mutation in the VHL gene. Seven members had pheochromocytoma, all without renal carcinoma.


.0014   VON HIPPEL-LINDAU SYNDROME

ERYTHROCYTOSIS, FAMILIAL, 2, INCLUDED
PHEOCHROMOCYTOMA, INCLUDED
VHL, LEU188VAL
SNP: rs5030824, gnomAD: rs5030824, ClinVar: RCV000002311, RCV000002312, RCV000002313, RCV000210199, RCV000480890, RCV000627743, RCV003330076

In a family with von Hippel-Lindau syndrome (VHLS; 193300), Neumann et al. (1995) identified a leu188-to-val (L188V) mutation in the VHL gene. Nine patients had pheochromocytoma without renal carcinoma (Zbar et al., 1996).

In 6 members of the same German family identified by Neumann et al. (1995) with von Hippel-Lindau syndrome type 2C, Weirich et al. (2002) found a P81S mutation in the VHL gene (608537.0020), which cosegregated with the L188V mutation. Weirich et al. (2002) discussed the possible impact of these mutations on protein function and phenotype.

In 2 unrelated white American children, a 15-year-old male and a 13-year-old female, who presented at 5 years of age with familial erythrocytosis (ECYT2; 263400), Pastore et al. (2003) identified a 562C-G transversion in the VHL gene, resulting in the L188V mutation. In both patients the mutation occurred in compound heterozygous state with the common R200W mutation (608537.0019).

Neumann et al. (2002) identified the L188V mutation in the germline of a patient with sporadic pheochromocytoma (171300). The mutation was not identified in 600 control chromosomes.


.0015   PHEOCHROMOCYTOMA

VHL, ARG64PRO
SNP: rs104893826, ClinVar: RCV000002314, RCV000132356, RCV000208872, RCV000475973, RCV000679019

In an uncle and his nephew with apparently isolated pheochromocytoma (171300), van der Harst et al. (1998) found an arg64-to-pro (R64P) mutation in the VHL gene. This mutation was 1 of 3 missense mutations identified by van der Harst et al. (1998) that were located closer to the N terminus of the VHL protein than any previously reported VHL mutation (see also 608537.0016).


.0016   PHEOCHROMOCYTOMA

VHL, LEU63PRO
SNP: rs104893827, ClinVar: RCV000002315, RCV000585971, RCV000704785

In a patient with apparently sporadic pheochromocytoma (171300), van der Harst et al. (1998) found a leu63-to-pro (L63P) mutation in the VHL gene. This mutation was 1 of 3 missense mutations identified by van der Harst et al. (1998) that were located closer to the N terminus of the VHL protein than any previously reported VHL mutation (see also 608537.0015).


.0017   VON HIPPEL-LINDAU SYNDROME

VHL, TYR112ASN
SNP: rs104893824, ClinVar: RCV000002316

In a family with von Hippel-Lindau syndrome (VHLS; 193300), Bradley et al. (1999) identified a 547T-A transversion in exon 1 of the VHL gene, resulting in a tyr112-to-asn (Y112N) substitution. Of 13 affected individuals, 7 had renal cell carcinoma and 1 had pheochromocytoma. The authors contrasted this family to 2 families reported by Chen et al. (1996) that had a mutation at the same position but causing a different amino acid change (tyr112 to his; 608537.0012). In these families, 19 of 22 affected individuals had pheochromocytoma and none had renal cell carcinoma. Bradley et al. (1999) concluded that different amino acid changes at the same position can cause very distinct clinical phenotypes.


.0018   RENAL CELL CARCINOMA WITH PARANEOPLASTIC ERYTHROCYTOSIS

VHL, LEU163PRO
SNP: rs28940297, ClinVar: RCV000002319, RCV001231697, RCV003298026

Wiesener et al. (2002) described a 50-year-old man, admitted to hospital for acute myocardial infarction, who was found to have marked erythrocytosis. Serum erythropoietin (EPO; 133170) was increased, and ultrasonography demonstrated a mass at the upper pole of the left kidney. Following nephrectomy, which confirmed the diagnosis of renal cell carcinoma (144700), EPO serum concentration decreased within 7 days and hemoglobin levels returned to normal. The patient was well 9 months later with normal EPO serum concentration. In this patient, Wiesener et al. (2002) reported that EPO mRNA was not detectable in normal kidney tissue but markedly upregulated in the tumor. Hypoxia-inducible genes, including VEGF (192240), GLUT1 (138140), carbonic anhydrase-9 (603179), lactate dehydrogenase-A (150000), and aldolase A (103850), were also strongly induced in the tumor. Immunoblots showed significant overexpression of the HIF1A (603348) and HIF2A (603349) subunits in the tumor, and immunohistochemistry performed for HIF1A showed nuclear accumulation of the transcription factor in virtually every tumor cell. A mutation analysis of the VHL gene in tumor cells revealed a leu163-to-pro (L163P) missense mutation due to a 701T-C transition in exon 3. This mutation had previously been identified in another RCC. The mutation was not present in other tissues of the patient. In this case, there was a clear indication that the pronounced erythrocytosis was a precipitating factor in the coronary thrombosis.


.0019   POLYCYTHEMIA, CHUVASH TYPE

VHL, ARG200TRP
SNP: rs28940298, gnomAD: rs28940298, ClinVar: RCV000002320, RCV000122262, RCV000148922, RCV000161094, RCV000574264, RCV000627742, RCV000722031, RCV002247239

Chuvash polycythemia (see ECYT2, 263400), caused by this specific arg200-to-trp (R200W) mutation in the VHL gene, is an autosomal recessive disorder of erythrocytosis that is endemic to the mid-Volga River region. Ang et al. (2002) studied 5 multiplex Chuvash families and confirmed that polycythemia was associated with significant elevations of serum erythropoietin (EPO; 133170) levels and ruled out a location of the gene on chromosome 11 as had been reported previously by Vasserman et al. (1999). They also ruled out mutation in the HIF1A gene (603348), which is located in 14q. Using a genomewide screen, they identified a region on 3p with a lod score greater than 2 and identified a 598C-T transition in the VHL gene, resulting in an arg200-to-trp (R200W) mutation in all cases. Ang et al. (2002) concluded that the R200W substitution impairs the interaction of VHL with HIF1-alpha, reducing the rate of degradation of HIF1-alpha and resulting in increased expression of downstream target genes including EPO, SLC2A1 (138140), transferrin (TF; 190000), transferrin receptor (TFRC; 190010), and vascular endothelial growth factor (VEGF; 192240). Mutations in VHL had been associated with pheochromocytoma, hemangioblastoma, and renal cell carcinoma, none of which were observed in individuals with Chuvash polycythemia or obligate carriers of the R200W mutation. Ang et al. (2002) stated that more than 700 mutations had been reported in VHL (Beroud et al., 1998), but that no individual had been found to be homozygous or compound heterozygous for germline mutations.

Pastore et al. (2003) evaluated the role of the VHL gene in 8 children with a history of polycythemia and an elevated serum EPO level and identified 3 different germline VHL mutations in 4 of them. One child was homozygous for the R200W mutation, and another was compound heterozygous for the R200W mutation and a val130-to-leu mutation (V130L; 608537.0021). Of 2 sibs who were heterozygous for an asp126-to-tyr mutation (D126Y; 608537.0022), 1 fulfilled some criteria of VHL syndrome (193300); a pulmonary angioma was discovered at 10 years of age and treated by coil embolization without effect on the polycythemia, and at 15 years of age nephrectomy was performed for a subcapsular hemangioma.

Percy et al. (2002) observed homozygosity for the R200W mutation in 3 Bangladeshi families with Chuvash-type congenital polycythemia living in the United Kingdom.

By haplotype analysis of 101 ethnically diverse individuals with the common R200W mutation, including 72 Chuvash individuals, Liu et al. (2004) determined that the R200W mutation is due to a founder effect that originated from 14,000 to 62,000 years ago.

In a matched cohort study, Gordeuk et al. (2004) found that homozygosity for the 598C-T transition in the VHL gene was associated with vertebral hemangiomas, varicose veins, lower blood pressures, and elevated serum VEGF concentrations (p less than 0.0005), as well as premature mortality related to cerebral vascular events and peripheral thrombosis. Spinocerebellar hemangioblastomas, renal carcinomas, and pheochromocytomas typical of classic VHL syndrome were not found, suggesting that overexpression of HIF1-alpha and VEGF is not sufficient for tumorigenesis. Although hemoglobin-adjusted serum erythropoietin concentrations were approximately 10-fold higher in 598C-T homozygotes than in controls, erythropoietin response to hypoxia was identical. Gordeuk et al. (2004) concluded that Chuvash polycythemia is a distinct VHL syndrome manifested by thrombosis, vascular abnormalities, and intact hypoxic regulation despite increased basal expression of hypoxia-regulated genes.

Cario et al. (2005) reported a Turkish patient who was homozygous for the R200W mutation. Haplotype analysis showed a different haplotype than that associated with the Chuvash population, indicating that the mutation arose independently and is not geographically restricted.

Perrotta et al. (2006) found that the R200W missense mutation (598C-T) causing Chuvash polycythemia is more frequent on the island of Ischia in the Bay of Naples (0.070) than it is in Chuvashia (0.057). The haplotype of all patients in Ischia matched that identified in the Chuvash cluster, thus supporting the single founder hypothesis. Perrotta et al. (2006) also found that unaffected heterozygotes had increased HIF1-alpha activity, which might confer a biochemical advantage for mutation maintenance. They suggested that this form of familial polycythemia may be endemic in other regions of the world, a hypothesis supported by the reports of Percy et al. (2002, 2003).

Russell et al. (2011) presented evidence suggesting 2 main molecular mechanisms by which the R200W and H191D (608537.0024) VHL mutations result in polycythemia. In vitro studies showed that the R200W mutation attenuated formation of the E3 ubiquitin ligase and attenuated binding of HIF1 (603348). In patients, this would lead to overproduction of the HIF-target erythropoietin (EPO; 133170) and thus secondary polycythemia. In addition, VHL mutations result in conformational changes causing increased binding to SOCS1 (603597), which inhibits binding and degradation of phosphorylated JAK2 (147796). The resulting pJAK2 stabilization promotes hyperactivation of the JAK2-STAT5 (601511) pathway in erythroid progenitors, causing hypersensitivity to erythropoietin and thereby to primary polycythemia. Treatment of R200W/R200W transgenic mice with a JAK2 inhibitor resulted in decreased hematocrit, smaller spleen, and decreased sensitivity to EPO compared to untreated transgenic mice.

Tomasic et al. (2013) stated that Russell et al. (2011) erroneously quoted the H191D mutation as a Chuvash polycythemia variant. The data presented by Tomasic et al. (2013) showed that erythrocyte precursors from homozygous H191D patients did not exhibit intrinsic hyperproliferation or a hyperproliferative response to EPO, as observed in R200W homozygotes. Their studies indicated different functional effects of the mutations.


.0020   VON HIPPEL-LINDAU SYNDROME

VHL, PRO81SER
SNP: rs104893829, gnomAD: rs104893829, ClinVar: RCV000002321, RCV000115744, RCV000213077, RCV000418681, RCV000656990, RCV001080004, RCV001843451, RCV002467489, RCV003225718

In 6 members of a German family in which the L188V mutation in the VHL gene (608537.0014) had previously been identified in association with von Hippel-Lindau syndrome type 2C (VHLS; 193300), Weirich et al. (2002) identified a 454C-T transition in exon 1 of the VHL gene, resulting in a pro81-to-ser (P81S) mutation. The concurrent P81S mutation was identified by novel screening approaches, including denaturing high-performance liquid chromatography (DHPLC) and sequencing. The 2 mutations cosegregated with the syndrome. Weirich et al. (2002) discussed the possible impact of the mutations on protein function and phenotype.


.0021   ERYTHROCYTOSIS, FAMILIAL, 2

VHL, VAL130LEU
SNP: rs104893830, ClinVar: RCV000002317, RCV000030586, RCV000492250, RCV001071915

See 608537.0019 and Pastore et al. (2003).


.0022   ERYTHROCYTOSIS, FAMILIAL, 2

VHL, ASP126TYR
SNP: rs104893831, gnomAD: rs104893831, ClinVar: RCV000002318, RCV001236092

See 608537.0019 and Pastore et al. (2003).


.0023   ERYTHROCYTOSIS, FAMILIAL, 2

VHL, PRO192SER
SNP: rs28940300, gnomAD: rs28940300, ClinVar: RCV000002322, RCV000236065, RCV000704063, RCV001024480, RCV002490296

In a 10-year-old white American boy who presented at age 9 years with familial erythrocytosis-2 (ECYT2; 263400), Pastore et al. (2003) identified compound heterozygosity for a 574C-T transition in the VHL gene, resulting in a pro192-to-ser (P192S) change, and the common R200W mutation (608537.0019).


.0024   ERYTHROCYTOSIS, FAMILIAL, 2

VHL, HIS191ASP
SNP: rs28940301, ClinVar: RCV000002323, RCV001219111

In a 17-year-old Croatian boy who presented at age 1 year with familial erythrocytosis-2 (ECYT2; 263400), Pastore et al. (2003) identified homozygosity for a 571C-G transversion in the VHL gene, resulting in a his191-to-asp (H191D) change.

Russell et al. (2011) presented evidence suggesting 2 main molecular mechanisms by which the H191D and R200W (608537.0019) VHL mutations result in polycythemia. In vitro studies showed that the H191D mutation attenuated formation of the E3 ubiquitin ligase and attenuated binding of HIF1 (603348). In patients, this would lead to overproduction of the HIF-target erythropoietin (EPO; 133170) and thus secondary polycythemia. In addition, VHL mutations result in conformational changes causing increased binding to SOCS1 (603597), which inhibits binding and degradation of phosphorylated JAK2 (147796). The resulting pJAK2 stabilization promotes hyperactivation of the JAK2-STAT5 (601511) pathway in erythroid progenitors, causing hypersensitivity to erythropoietin and thereby to primary polycythemia. Treatment of R200W/R200W transgenic mice with a JAK2 inhibitor resulted in decreased hematocrit, smaller spleen, and decreased sensitivity to EPO compared to untreated transgenic mice.

Tomasic et al. (2013) stated that Russell et al. (2011) erroneously quoted the H191D mutation as a Chuvash polycythemia variant. The data presented by Tomasic et al. (2013) showed that erythrocyte precursors from homozygous H191D patients did not exhibit intrinsic hyperproliferation or a hyperproliferative response to EPO, as observed in R200W homozygotes. Their study indicated different functional effects of the mutations.

Tomasic et al. (2013) reported a 5-year-old Croatian girl with early-onset ECYT2 due to a homozygous H191D mutation. Family history revealed that she was related to the patient reported by Pastore et al. (2003). Patient erythroid precursors showed normal growth and were not hypersensitive to EPO in vitro; these findings differed from those observed in Chuvash polycythemia in which the erythroid precursors are intrinsically hyperproliferative and also show hypersensitivity to EPO. Tomasic et al. (2013) concluded that the polycythemia in patients with the H191D mutation is solely driven by increased circulating EPO. Patient cells showed changes in gene expression, including increased expression of several HIF1A-related genes (TFRC, VEGF, and HK1), and decreased expression of other genes (BNIP3L and ADM). The patient presented at age 2 years with failure to thrive, increased hematocrit and hemoglobin, low ferritin, and extremely high erythropoietin. She also had delayed psychomotor development. Heterozygous carriers in the family did not have VHL-associated tumors.


.0025   VON HIPPEL-LINDAU SYNDROME

VHL, VAL84LEU
SNP: rs5030827, gnomAD: rs5030827, ClinVar: RCV000002324, RCV001851579, RCV002433440, RCV003884333

Following the revised codon numbering system of Kuzmin et al. (1995), the VAL155LEU (V155L) mutation has been renumbered as V84L.

In 2 sibs from Wales with bilateral pheochromocytoma without other features of von Hippel-Lindau syndrome (VHLS; 193300), consistent with VHL type 2C, Crossey et al. (1995) identified a heterozygous 463G-T transversion in exon 1 of the VHL gene, resulting in a val155-to-leu (V155L) substitution.

Abbott et al. (2006) identified the V84L substitution in affected individuals from 3 unrelated families with early-onset isolated pheochromocytoma consistent with VHL syndrome type 2C. Although no other signs of VHL syndrome were present in 7 patients, 1 patient was suspected to have a spinal hemangioblastoma based on imaging studies.


.0026   PHEOCHROMOCYTOMA

VHL, GLY93SER
SNP: rs5030808, gnomAD: rs5030808, ClinVar: RCV000002325, RCV000208813, RCV000698471, RCV002433441, RCV003460405

In the germlines of 2 unrelated patients with sporadic pheochromocytoma (171300), Neumann et al. (2002) identified a 490G-A transition in exon 1 of the VHL gene, resulting in a gly93-to-ser (G93S) substitution. The mutation was not identified in 600 control chromosomes.


.0027   VON HIPPEL-LINDAU SYNDROME

VHL, GLN164ARG
SNP: rs267607170, ClinVar: RCV000002326, RCV001023261, RCV001052383

In a 2.5-year-old girl who presented with a pheochromocytoma but no other manifestations of von Hippel-Lindau syndrome (VHLS; 193300), Sovinz et al. (2010) identified a heterozygous 491A-G transition in exon 3 of the VHL gene, resulting in an gln164-to-arg (Q164R) substitution in a protein surface residue. Genotyping of the family indicated that she inherited the mutation from her father, in whom it occurred de novo. Although he was in good health and asymptomatic, detailed physical examination found a retinal angioma, an adrenal adenoma, and bilateral pheochromocytoma, consistent with VHL syndrome. Sovinz et al. (2010) noted that Ong et al. (2007) had identified the Q164R mutation in a family in which a patient developed pheochromocytoma at age 10 years and retinal angioma at age 23 years, suggesting that this mutation may be associated with early onset of symptoms.


.0028   ERYTHROCYTOSIS, FAMILIAL, 2

VHL, ASP126ASN
SNP: rs104893831, gnomAD: rs104893831, ClinVar: RCV000129380, RCV000631273, RCV000663314, RCV000679037, RCV001007623, RCV003155081

In an 8-year-old boy with familial erythrocytosis-2 (ECYT2; 263400), Bond et al. (2011) identified compound heterozygous missense mutations in the VHL gene: a c.376G-A transition in exon 2, resulting in an asp126-to-asn (D126N) substitution, and a c.548C-T transition in exon 3, resulting in a ser138-to-leu (S183L; 608537.0029) substitution. The mutations were found by direct gene sequencing. Transfection of the mutations into renal carcinoma cells showed decreased protein levels consistent with instability of the mutant proteins and suggesting a loss-of-function effect. Transfected cells also showed decreased pH, decreased glucose, and increased lactate, consistent with upregulation of glycolysis. These changes were associated with increased expression of HIF1A (603348), PHD3 (606426), and GLUT1 (138140), suggesting impaired ability of mutant VHL to regulate HIF. The patient presented at 2 months of age with right ventricular dysfunction and hypertrophy, pulmonary hypertension, increased hematocrit and hemoglobin, and significantly increased EPO (133170). He was managed successfully by phlebotomy.

Sarangi et al. (2014) identified a homozygous D126N mutation in the VHL gene in a 2-year-old boy, born of consanguineous Bangladeshi parents, with fatal ECYT2. In vitro studies showed that patient erythroid progenitors were not hypersensitive to EPO and did not overexpress NFE2 (601490) or RUNX1 (151385) transcripts, which are associated with EPO hypersensitivity. This demonstrated a different pathogenic mechanism from patients with Chuvash polycythemia due to the R200W mutation (608537.0019). The patient reported by Sarangi et al. (2014) presented in infancy with failure to thrive, polycythemia, elevated EPO, pulmonary hypertension, and a thrombotic state. Neither parent had polycythemia or evidence of VHL-associated tumors.


.0029   ERYTHROCYTOSIS, FAMILIAL, 2

VHL, SER183LEU
SNP: rs5030823, gnomAD: rs5030823, ClinVar: RCV000476376, RCV001007624, RCV002349982, RCV003237874

For discussion of the c.548C-T transition in exon 3 of the VHL gene, resulting in a ser138-to-leu (S183L) substitution, that was found in compound heterozygous state in a patient with familial erythrocytosis-2 (ECYT2; 263400) by Bond et al. (2011), see 608537.0028.


.0030   ERYTHROCYTOSIS, FAMILIAL, 2

VHL, c.340+770T-C
SNP: rs1346312258, gnomAD: rs1346312258, ClinVar: RCV001007626, RCV001238805, RCV003320779, RCV003325984

In 4 patients from 3 unrelated families (F1, F2, and F3) with familial erythrocytosis-2 (ECYT2; 263400), Lenglet et al. (2018) identified compound heterozygous mutations in the VHL gene. All 4 patients carried a T-to-C transition (c.340+770T-C) in cryptic exon 1-prime (E1-prime), resulting in a splicing alteration, on 1 allele. Three patients from F2 and F3 had previously been diagnosed with Chuvash polycythemia since they were heterozygous for the R200W mutation (608537.0019) on the other allele. Prior to the study of Lenglet et al. (2018), these patients were thought to carry only 1 VHL mutation (the patient from F2 had previously been reported by Cario et al., 2005). The mutations, which were found by a combination of whole-genome and Sanger sequencing, segregated with the disorder in the families. RT-PCR analysis of lymphoblastoid cells from 1 patient (F1) showed a decrease in the exon 1/exon 2/exon 3 isoform and an increase in an exon 1/exon 3 isoform compared to wildtype. The patient from F1 carried a synonymous c.429C-T transition (asp143-to-asp, D143D) on the other allele, which also affected splicing. Two further unrelated patients with ECYT2 (families F9 and F10) were homozygous for the c.429C-T transition in the VHL gene. RT-PCR analysis from lymphocytes derived from these patients showed decreased mRNA levels, increased amounts of the E1/E3 transcripts, and severe decreases in the wildtype VHL mRNA and protein isoform compared to controls, suggesting that the mutation resulted in the skipping of exon 2. The 2 patients from families F9 and F10 also had mutations in the HBB gene (141900), which may have compensated for the ECYT2.


.0031   ERYTHROCYTOSIS, FAMILIAL, 2

VHL, c.340+694_711dup
SNP: rs1575923363, ClinVar: RCV001007627, RCV001066413

In 2 unrelated patients (families F4 and F5) with familial erythrocytosis-2 (ECYT2; 263400), Lenglet et al. (2018) identified compound heterozygous mutations in the VHL gene. Both patients carried an 18-bp duplication (c.340+694_711dup) in a newly identified cryptic exon 1-prime (E1-prime), resulting in a splicing alteration on that allele. The patient from F4 carried an R200W (608537.0019) mutation on the other allele, whereas the patient from F5 carried a G144R mutation on the other allele. The mutations segregated with the disorder in both families. Both patients had been thought to carry only 1 VHL mutation (Randi et al., 2005). The findings by Lenglet et al. (2018) confirmed that ECYT2 is an autosomal recessive disorder. RT-PCR analysis of transfected cells showed abnormal splicing.


.0032   VON HIPPEL-LINDAU SYNDROME

VHL, LEU128VAL AND LEU138PRO ({dbSNP rs73024533})
SNP: rs1575923261, rs73024533, gnomAD: rs73024533, ClinVar: RCV001007628, RCV001516863, RCV001785769, RCV002465825, RCV002552003, RCV003325985

In 6 patients from a family (F8) with von Hippel-Lindau syndrome (VHLS; 193300), Lenglet et al. (2018) identified a heterozygous complex mutation in cryptic exon 1-prime of the VHL gene: a C-G transversion (c.340+617C-G) and a T-to-C transition (c.340+648T-C). The mutations, which were found by a combination of microsatellite analysis and gene sequencing, segregated with the disorder in the family. The mutations were predicted to result in leu128-to-val (L128V) and leu138-to-pro (L138P; rs73024533) substitutions in the newly identified X1 VHL protein isoform. Analysis of patient cells and tumor tissue showed upregulation of isoforms containing exon 1 and exon 1-prime, resulting in premature termination that would likely be degraded by nonsense-mediated mRNA. There was also lower expression of other VHL isoforms. Minigene assays in various cell lines showed a synergistic effect of the 2 mutations on abnormal splicing; the expression of exon 1-prime-containing isoforms was higher for mutations associated with cancer compared to erythrocytosis. The c.340+648T-C mutation was found at a low frequency in the 1000 Genomes Project database. Sequencing of tumor tissue from these patients did not identify loss of heterozygosity at the VHL locus, indicating that somatic VHL deletion may not be a prerequisite for developing cancer in patients with this genotype.


.0033   VON HIPPEL-LINDAU SYNDROME

VHL, PRO138PRO
SNP: rs869025648, ClinVar: RCV000208865, RCV000216698, RCV000469600, RCV001636725

In 7 members from 2 unrelated families (F11 and F12) with von Hippel-Lindau syndrome (VHLS; 193300), Lenglet et al. (2018), identified a heterozygous c.414A-G transition in the VHL gene, predicted to result in a synonymous pro138-to-pro (P138P) substitution. Analysis of patient cells and tumor tissue showed increased expression of E1-E3 transcripts, suggesting a splicing alteration with the skipping of exon 2. There was a severe decrease in expression of wildtype VHL. Patient tumor tissue showed loss of heterozygosity for VHL, consistent with the classic mechanism of VHL syndrome.


.0034   ERYTHROCYTOSIS, FAMILIAL, 2

VHL, VAL75VAL
SNP: rs759737367, gnomAD: rs759737367, ClinVar: RCV000984026

In a 22-year-old man, born of consanguineous Italian parents, with familial erythrocytosis-2 (ECYT2; 263400), Perrotta et al. (2020) identified a homozygous c.222C-A transversion in exon 1 of the VHL gene, predicted to result in a synonymous val75-to-val (V75V) substitution. The mutation, which was found by direct sequencing, segregated with the disorder in the family. Analysis of patient cells showed that the mutation created a alternative splice donor site, resulting in a frameshift and premature termination. Patient and paternal cells showed 80% and 40% lower levels of wildtype mRNA, respectively, compared to controls. Patient cells showed decreased amounts of the 3 main VHL protein isoforms (213, 160, and 172) as well as increased HIF1A, suggesting a loss of VHL function. Patient cells also showed increased levels of BNIP3L (605368) and MXI1 (600020) compared to controls, suggesting possible mitochondrial dysfunction. The patient presented at birth with severe hypoglycemia, erythrocytosis, and bradycardia. He later showed failure to thrive, exercise intolerance, and mitochondrial and metabolic abnormalities.


.0035   ERYTHROCYTOSIS, FAMILIAL, 2

VHL, PRO138LEU
SNP: rs780178275, gnomAD: rs780178275, ClinVar: RCV001007630, RCV001064218, RCV001759686

In a 15-year-old girl of Asian Indian descent with familial erythrocytosis-2 (ECYT2; 263400), Lanikova et al. (2013) identified a homozygous c.413C-T transition in exon 2 of the VHL gene, resulting in a pro138-to-leu (P138L) substitution in the catalytic HIF1A (603348) ligand-binding domain. The mutation, which was found by direct sequencing of the VHL gene, segregated with the disorder in the family. Cellular transfection studies showed that the mutant protein had decreased stability compared to controls. Patient erythrocytes were hypersensitive to EPO in vitro, and there was overexpression of the NFE2 (601490) and RUNX1 (151385) genes, as well as an increase in HIF1A target genes. Immunoprecipitation studies showed that the mutation decreased the affinity of VHL to HIF1A, resulting in decreased ubiquitination under nonhypoxic conditions compared to controls. Lanikova et al. (2013) noted that a germline mutation in the VHL gene affecting this residue (P138T) had been identified in patients with von Hippel-Lindau syndrome (see Leonardi et al., 2011), but the parents, who were heterozygous carriers of the P138L mutation, had no signs of VHLS.


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Contributors:
Cassandra L. Kniffin - updated : 02/28/2020
Bao Lige - updated : 03/15/2019
Jane A. Welch - updated : 04/10/2018
Ada Hamosh - updated : 09/27/2016
Cassandra L. Kniffin - updated : 8/3/2011
Cassandra L. Kniffin - updated : 10/28/2010
Cassandra L. Kniffin - updated : 8/30/2010
Cassandra L. Kniffin - updated : 12/15/2009
Ada Hamosh - updated : 6/16/2009
Patricia A. Hartz - updated : 6/8/2009
Patricia A. Hartz - updated : 4/1/2009
Patricia A. Hartz - updated : 5/28/2008
Cassandra L. Kniffin - updated : 3/13/2008
Patricia A. Hartz - updated : 1/14/2008
Patricia A. Hartz - updated : 8/1/2007
Cassandra L. Kniffin - updated : 11/1/2006
Cassandra L. Kniffin - updated : 8/14/2006
Patricia A. Hartz - updated : 6/13/2006
Cassandra L. Kniffin - updated : 5/23/2006
Cassandra L. Kniffin - updated : 4/17/2006
Victor A. McKusick - updated : 3/28/2006
Cassandra L. Kniffin - updated : 1/6/2006
Victor A. McKusick - updated : 9/30/2004
Victor A. McKusick - updated : 8/24/2004
Cassandra L. Kniffin - updated : 6/2/2004

Creation Date:
Cassandra L. Kniffin : 3/17/2004

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