VHL von Hippel-Lindau tumor suppressor [Homo sapiens (human)] - Gene

Summary

Official Symbol: VHLprovided by HGNC
Official Full Name: von Hippel-Lindau tumor suppressorprovided by HGNC
Primary source: HGNC:HGNC:12687
See related: Ensembl:ENSG00000134086 MIM:608537
Gene type: protein coding
RefSeq status: REVIEWED
Organism: Homo sapiens
Lineage: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae; Homo
Also known as: RCA1; VHL1; pVHL; HRCA1
Summary: Von Hippel-Lindau syndrome (VHL) is a dominantly inherited familial cancer syndrome predisposing to a variety of malignant and benign tumors. A germline mutation of this gene is the basis of familial inheritance of VHL syndrome. The protein encoded by this gene is a component of the protein complex that includes elongin B, elongin C, and cullin-2, and possesses ubiquitin ligase E3 activity. This protein is involved in the ubiquitination and degradation of hypoxia-inducible-factor (HIF), which is a transcription factor that plays a central role in the regulation of gene expression by oxygen. RNA polymerase II subunit POLR2G/RPB7 is also reported to be a target of this protein. Alternatively spliced transcript variants encoding distinct isoforms have been observed. [provided by RefSeq, Jul 2008]
Expression: Ubiquitous expression in lymph node (RPKM 12.2), spleen (RPKM 10.0) and 25 other tissues See more
Orthologs: mouse all

Genomic context

Location:: 3p25.3

Exon count:: 4

Annotation release	Status	Assembly	Chr	Location
109	current	GRCh38.p12 (GCF_000001405.38)	3	NC_000003.12 (10141635..10153670)
105	previous assembly	GRCh37.p13 (GCF_000001405.25)	3	NC_000003.11 (10183319..10195354)

Chromosome 3 - NC_000003.12 Genomic Context describing neighboring genes

Genomic regions, transcripts, and products

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Go to reference sequence details

Genomic Sequence:

Go to nucleotide: Graphics FASTA GenBank

Expression

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See details

Project title: HPA RNA-seq normal tissues
Description: RNA-seq was performed of tissue samples from 95 human individuals representing 27 different tissues in order to determine tissue-specificity of all protein-coding genes
BioProject: PRJEB4337
Publication: PMID 24309898
Analysis date: Wed Apr 4 07:08:55 2018

Bibliography

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GeneRIFs: Gene References Into FunctionsWhat's a GeneRIF?

The sporadic hemangioblastoma can occur rarely without a somatic biallelic VHL mutation. The VHL protein was earlier found to be associated with the deposition of matrix fibronectin (FN) protein in the renal extracellular matrix.
Title: Exploring the role of defective fibronectin matrix assembly in the VHL-associated CNS hemangioblastoma.
aldehyde dehydrogenase 2 (ALDH2) is found to be transcriptionally regulated by VHL and contributes to enhanced anthracyclines cytotoxicity in clear cell renal cell carcinoma cells.
Title: VHL deficiency augments anthracycline sensitivity of clear cell renal cell carcinomas by down-regulating ALDH2.
Data show that von Hippel-Lindau-binding protein 1 (VBP1) enhances the stability of von Hippel-Lindau tumor suppressor protein (pVHL) and facilitates pVHL-mediated ubiquitination of hypoxia-inducible factor 1, alpha subunit (HIF-1alpha).
Title: VBP1 represses cancer metastasis by enhancing HIF-1α degradation induced by pVHL.
Study suggests that reduced expression of PBRM1 and VHL in clear cell renal cell carcinoma is correlated with an increased tumor aggressiveness. Low VHL expression identified as a risk factor for worse patient overall survival.
Title: PBRM1 and VHL expression correlate in human clear cell renal cell carcinoma with differential association with patient's overall survival.
The results of the present study also demonstrated a mutation in VHL associated with the VHL syndrome phenotype, which may be of future therapeutic benefit for the diagnosis of VHL syndrome.
Title: Identification of a VHL gene mutation in a Chinese family with Von Hippel‑Lindau syndrome.
Overexpression of VHL was more successful at inhibiting fibrosis compared with silencing HIF-1a plus HIF-2a. Normoxia-active HIF-1a or HIF-2a prevented the inhibitory effect of VHL on liver fibrosis, indicating that attenuating fibrosis via VHL is HIF-1a- and HIF-2a-dependent to some extent.
Title: Reduction of hepatic fibrosis by overexpression of von Hippel-Lindau protein in experimental models of chronic liver disease.
The inverse correlation between the VHL gene expression profile and alisertib sensitivity was further confirmed in human cancer xenografts models. Taken together, these results suggested that VHL loss could potentially serve as a biomarker for predicting the efficacy of AURKA inhibitors.
Title: VHL loss predicts response to Aurora kinase A inhibitor in renal cell carcinoma cells.
JMJD6 regulates VHL gene expression in the human placenta. VHL downregulation in preeclampsia is dependent on decreased JMJD6 demethylase activity due to hypoxia and reduced Fe2+ bioavailability.
Title: Compromised JMJD6 Histone Demethylase Activity Affects VHL Gene Repression in Preeclampsia.
Low VHL expression is associated with papillary thyroid carcinoma.
Title: Expression of VHL tumor suppressor mRNA and miR-92a in papillary thyroid carcinoma and their correlation with clinical and pathological parameters.
that the reduced expression of LimD1 and VHL might have synergistic effect on induction of HIF1alpha resulting increased cellular proliferation and progression of the disease.
Title: Over expression of HIF1α is associated with inactivation of both LimD1 and VHL in renal cell carcinoma: Clinical importance.

Submit: New GeneRIF Correction See all GeneRIFs (480)

Phenotypes

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Find tests for this gene in the NIH Genetic Testing Registry (GTR)

Review eQTL and phenotype association data in this region using PheGenI

Professional guidelines

Description
Professional guideline ACMG 2013 The ACMG recommends that laboratories performing clinical sequencing seek and report mutations in VHL that are pathogenic or expected to be pathogenic. GuidelinePubMed

Associated conditions

Description	Tests
Erythrocytosis, familial, 2 MedGen: C1837915 OMIM: 263400 GeneReviews: Not available	Compare labs
Pheochromocytoma MedGen: C0031511 OMIM: 171300 GeneReviews: Hereditary Paraganglioma-Pheochromocytoma Syndromes	Compare labs
Renal cell carcinoma, nonpapillary MedGen: C3160732 OMIM: 144700 GeneReviews: Not available	Compare labs
Von Hippel-Lindau syndrome MedGen: C0019562 OMIM: 193300 GeneReviews: Von Hippel-Lindau Syndrome	Compare labs

Copy number response

Description
Copy number response Triplosensitivity No evidence available (Last evaluated (2017-06-28) ClinGen Genome Curation Page Haploinsufficency Sufficient evidence for dosage pathogenicity (Last evaluated (2017-06-28) ClinGen Genome Curation PagePubMed

Variation

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See variants in ClinVar

See studies and variants in dbVar

See Variation Viewer (GRCh37.p13)

See Variation Viewer (GRCh38)

Pathways from BioSystems

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Adaptive Immune System, organism-specific biosystem (from REACTOME)
Adaptive Immune System, organism-specific biosystemAdaptive immunity refers to antigen-specific immune response efficiently involved in clearing the pathogens. The adaptive immune system is comprised of B and T lymphocytes that express receptors with...
Amplification and Expansion of Oncogenic Pathways as Metastatic Traits, organism-specific biosystem (from WikiPathways)
Amplification and Expansion of Oncogenic Pathways as Metastatic Traits, organism-specific biosystemThis pathway is based on Figure 4 of "Origins of metastatic traits."(See Bibliography).The majority of cancer cells released from tumors die off, so cancer biologists are trying to figure out exactly...
Antigen processing: Ubiquitination & Proteasome degradation, organism-specific biosystem (from REACTOME)
Antigen processing: Ubiquitination & Proteasome degradation, organism-specific biosystemIntracellular foreign or aberrant host proteins are cleaved into peptide fragments of a precise size, such that they can be loaded on to class I MHC molecules and presented externally to cytotoxic T ...
Cellular response to hypoxia, organism-specific biosystem (from REACTOME)
Cellular response to hypoxia, organism-specific biosystemOxygen plays a central role in the functioning of human cells: it is both essential for normal metabolism and toxic. To begin the annotation of stress responses in Reactome, we have annotated one asp...
Cellular responses to stress, organism-specific biosystem (from REACTOME)
Cellular responses to stress, organism-specific biosystemCells are subject to external molecular and physical stresses such as foreign molecules that perturb metabolic or signaling processes, and changes in temperature or pH. The ability of cells and tissu...
Class I MHC mediated antigen processing & presentation, organism-specific biosystem (from REACTOME)
Class I MHC mediated antigen processing & presentation, organism-specific biosystemMajor histocompatibility complex (MHC) class I molecules play an important role in cell mediated immunity by reporting on intracellular events such as viral infection, the presence of intracellular b...
ECV complex, organism-specific biosystem (from KEGG)
ECV complex, organism-specific biosystemStructural complex; Genetic information processing; Ubiquitin system
ECV complex, conserved biosystem (from KEGG)
ECV complex, conserved biosystemStructural complex; Genetic information processing; Ubiquitin system
HIF-1 signaling pathway, organism-specific biosystem (from KEGG)
HIF-1 signaling pathway, organism-specific biosystemHypoxia-inducible factor 1 (HIF-1) is a transcription factor that functions as a master regulator of oxygen homeostasis. It consists of two subunits: an inducibly-expressed HIF-1alpha subunit and a c...
HIF-2-alpha transcription factor network, organism-specific biosystem (from Pathway Interaction Database)
HIF-2-alpha transcription factor network, organism-specific biosystem
HIF-2-alpha transcription factor network
Hypoxic and oxygen homeostasis regulation of HIF-1-alpha, organism-specific biosystem (from Pathway Interaction Database)
Hypoxic and oxygen homeostasis regulation of HIF-1-alpha, organism-specific biosystem
Hypoxic and oxygen homeostasis regulation of HIF-1-alpha
Immune System, organism-specific biosystem (from REACTOME)
Immune System, organism-specific biosystemHumans are exposed to millions of potential pathogens daily, through contact, ingestion, and inhalation. Our ability to avoid infection depends on the adaptive immune system and during the first crit...
Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha, organism-specific biosystem (from REACTOME)
Oxygen-dependent proline hydroxylation of Hypoxia-inducible Factor Alpha, organism-specific biosystemHIF-alpha subunits, comprising HIF1A (Bruick and McKnight 2001, Ivan et al. 2001, Jaakkola et al. 2001), HIF2A (Percy et al. 2008, Furlow et al. 2009), and HIF3A (Maynard et al. 2003), are hydroxylat...
Pathways in cancer, organism-specific biosystem (from KEGG)
Pathways in cancer, organism-specific biosystem
Pathways in cancer
Regulation of Hypoxia-inducible Factor (HIF) by oxygen, organism-specific biosystem (from REACTOME)
Regulation of Hypoxia-inducible Factor (HIF) by oxygen, organism-specific biosystemIn the presence of oxygen members of the transcription factor family HIF-alpha, comprising HIF1A, HIF2A (EPAS1), and HIF3A, are hydroxylated on proline residues by PHD1 (EGLN2), PHD2 (EGLN1), and PHD...
Renal cell carcinoma, organism-specific biosystem (from KEGG)
Renal cell carcinoma, organism-specific biosystemRenal cell cancer (RCC) accounts for ~3% of human malignancies and its incidence appears to be rising. Although most cases of RCC seem to occur sporadically, an inherited predisposition to renal canc...
Renal cell carcinoma, conserved biosystem (from KEGG)
Renal cell carcinoma, conserved biosystemRenal cell cancer (RCC) accounts for ~3% of human malignancies and its incidence appears to be rising. Although most cases of RCC seem to occur sporadically, an inherited predisposition to renal canc...
Signaling events mediated by VEGFR1 and VEGFR2, organism-specific biosystem (from Pathway Interaction Database)
Signaling events mediated by VEGFR1 and VEGFR2, organism-specific biosystem
Signaling events mediated by VEGFR1 and VEGFR2
Ubiquitin mediated proteolysis, organism-specific biosystem (from KEGG)
Ubiquitin mediated proteolysis, organism-specific biosystemProtein ubiquitination plays an important role in eukaryotic cellular processes. It mainly functions as a signal for 26S proteasome dependent protein degradation. The addition of ubiquitin to protein...
Ubiquitin mediated proteolysis, conserved biosystem (from KEGG)
Ubiquitin mediated proteolysis, conserved biosystemProtein ubiquitination plays an important role in eukaryotic cellular processes. It mainly functions as a signal for 26S proteasome dependent protein degradation. The addition of ubiquitin to protein...

Interactions

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Products	Interactant	Other Gene	Complex	Source	Pubs	Description

General gene information

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Markers

L17688 (e-PCR)
- UniSTS:74509

GDB:434012 (e-PCR)
- UniSTS:157204

L17705 (e-PCR)
- UniSTS:66091

SHGC-31692 (e-PCR)
- UniSTS:82991

STS-L15409 (e-PCR)
- UniSTS:69168

VHL__5065 (e-PCR)
- UniSTS:463929

GDB:361137 (e-PCR)
- UniSTS:156737

GDB:361141 (e-PCR)
- UniSTS:156738

GDB:361144 (e-PCR)
- UniSTS:156739

GDB:361147 (e-PCR)
- UniSTS:156740

GDB:361151 (e-PCR)
- UniSTS:156741

GDB:375126 (e-PCR)
- UniSTS:157004

RH16642 (e-PCR)
- UniSTS:12631

L18426 (e-PCR)
- UniSTS:34648

SHGC-57727 (e-PCR)
- UniSTS:53086

RH71303 (e-PCR)
- UniSTS:44639

SHGC-33879 (e-PCR)
- UniSTS:69217

RH79802 (e-PCR)
- UniSTS:88688

D15S1477 (e-PCR)
- UniSTS:474482

D1S1423 (e-PCR)
- UniSTS:149619

GDB:532940 (e-PCR)
- UniSTS:157555

GDB:532945 (e-PCR)
- UniSTS:157556

GDB:532951 (e-PCR)
- UniSTS:157557

GDB:532957 (e-PCR)
- UniSTS:157558

GDB:532965 (e-PCR)
- UniSTS:157559

L17971 (e-PCR)
- UniSTS:43966

GDB:270439 (e-PCR)
- UniSTS:156352

GDB:631802 (e-PCR)
- UniSTS:158429

GDB:631813 (e-PCR)
- UniSTS:158430

D5S1597E (e-PCR)
- UniSTS:151019

Homology

Homologs of the VHL gene: The VHL gene is conserved in Rhesus monkey, dog, cow, mouse, rat, chicken, zebrafish, and frog.
Orthologs from Annotation Pipeline: 198 organisms have orthologs with human gene VHL
Orthologs

Gene Ontology Provided by GOA

Function	Evidence Code	Pubs
enzyme binding	IPI Inferred from Physical Interaction more info	PubMed
protein binding	IPI Inferred from Physical Interaction more info	PubMed
transcription factor binding	IPI Inferred from Physical Interaction more info	PubMed
ubiquitin protein ligase activity	IBA Inferred from Biological aspect of Ancestor more info	PubMed
ubiquitin protein ligase activity	IDA Inferred from Direct Assay more info	PubMed
ubiquitin-protein transferase activity	TAS Traceable Author Statement more info

Process	Evidence Code	Pubs
cell morphogenesis	NAS Non-traceable Author Statement more info	PubMed
negative regulation of JAK-STAT cascade	IMP Inferred from Mutant Phenotype more info	PubMed
negative regulation of apoptotic process	NAS Non-traceable Author Statement more info	PubMed
negative regulation of cell proliferation	IMP Inferred from Mutant Phenotype more info	PubMed
negative regulation of gene expression	IMP Inferred from Mutant Phenotype more info	PubMed
negative regulation of transcription by RNA polymerase II	TAS Traceable Author Statement more info	PubMed
negative regulation of transcription from RNA polymerase II promoter in response to hypoxia	IDA Inferred from Direct Assay more info	PubMed
positive regulation of cell differentiation	NAS Non-traceable Author Statement more info	PubMed
positive regulation of transcription, DNA-templated	IMP Inferred from Mutant Phenotype more info	PubMed
post-translational protein modification	TAS Traceable Author Statement more info
protein stabilization	NAS Non-traceable Author Statement more info	PubMed
protein ubiquitination	IBA Inferred from Biological aspect of Ancestor more info	PubMed
protein ubiquitination	IDA Inferred from Direct Assay more info	PubMed
protein ubiquitination	IEA Inferred from Electronic Annotation more info
protein ubiquitination	IMP Inferred from Mutant Phenotype more info	PubMed
proteolysis	TAS Traceable Author Statement more info	PubMed
regulation of transcription from RNA polymerase II promoter in response to hypoxia	TAS Traceable Author Statement more info
regulation of transcription, DNA-templated	IMP Inferred from Mutant Phenotype more info	PubMed

Component	Evidence Code	Pubs
VCB complex	IBA Inferred from Biological aspect of Ancestor more info	PubMed
cytosol	TAS Traceable Author Statement more info
endoplasmic reticulum	NAS Non-traceable Author Statement more info	PubMed
membrane	IEA Inferred from Electronic Annotation more info
mitochondrion	NAS Non-traceable Author Statement more info	PubMed
nucleoplasm	IDA Inferred from Direct Assay more info
nucleoplasm	TAS Traceable Author Statement more info
nucleus	IBA Inferred from Biological aspect of Ancestor more info	PubMed

General protein information

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Preferred Names: von Hippel-Lindau disease tumor suppressor

Names: elongin binding protein; protein G7; von Hippel-Lindau tumor suppressor, E3 ubiquitin protein ligase

NCBI Reference Sequences (RefSeq)

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RefSeqs maintained independently of Annotated Genomes

These reference sequences exist independently of genome builds. Explain

These reference sequences are curated independently of the genome annotation cycle, so their versions may not match the RefSeq versions in the current genome build. Identify version mismatches by comparing the version of the RefSeq in this section to the one reported in Genomic regions, transcripts, and products above.

Genomic

NG_008212.3 RefSeqGene

Range

5001..17036

Download

GenBank, FASTA, Sequence Viewer (Graphics), LRG_322

mRNA and Protein(s)

NM_000551.3 → NP_000542.1 von Hippel-Lindau disease tumor suppressor isoform 1

See identical proteins and their annotated locations for NP_000542.1

Status: REVIEWED

Description

Transcript Variant: This variant (1) encodes the longest isoform (1).

Source sequence(s)

AC034193, AK315799, BC058831, D58014, L15409

Consensus CDS

CCDS2597.1

UniProtKB/Swiss-Prot

P40337

UniProtKB/TrEMBL

A0A024R2F2

Related

ENSP00000256474.2, ENST00000256474.2

Conserved Domains (2) summary

cd05468
Location:64 → 203

pVHL; von Hippel-Landau (pVHL) tumor suppressor protein

cl25865
Location:7 → 86

Trypan_PARP; Procyclic acidic repetitive protein (PARP)
NM_001354723.1 → NP_001341652.1 von Hippel-Lindau disease tumor suppressor isoform 3

Status: REVIEWED

Description

Transcript Variant: This variant (3) lacks an alternate in-frame exon and contains another alternate exon compared to variant 1. The resulting isoform (3) has a shorter and distinct C-terminus compared to variant 1.

Source sequence(s)

AC034193, HY256093

Conserved Domains (2) summary

cl03381
Location:63 → 113

pVHL; von Hippel-Landau (pVHL) tumor suppressor protein

cl25865
Location:7 → 86

Trypan_PARP; Procyclic acidic repetitive protein (PARP)
NM_198156.2 → NP_937799.1 von Hippel-Lindau disease tumor suppressor isoform 2

See identical proteins and their annotated locations for NP_937799.1

Status: REVIEWED

Description

Transcript Variant: This variant (2) lacks an in-frame coding exon compared to variant 1. The resulting isoform (2) lacks an internal region, as compared to isoform 1.

Source sequence(s)

AC034193, AK315799, BC058831, D58014, L15409

Consensus CDS

CCDS2598.1

UniProtKB/Swiss-Prot

P40337

UniProtKB/TrEMBL

A0A0S2Z4K1

Related

ENSP00000344757.2, ENST00000345392.2

Conserved Domains (3) summary

pfam17211
Location:114 → 163

VHL_C; VHL box domain

cl03381
Location:63 → 113

pVHL; von Hippel-Landau (pVHL) tumor suppressor protein

cl25865
Location:7 → 86

Trypan_PARP; Procyclic acidic repetitive protein (PARP)