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
109.20200522	current	GRCh38.p13 (GCF_000001405.39)	3	NC_000003.12 (10141778..10153667)
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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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 Functions

What's a GeneRIF?

Comparative analyses of screening results not only confirmed a well-known role for mTOR signaling in renal carcinoma, but also identified DNA damage response and selenocysteine biosynthesis pathways as novel SL targets in VHL-inactivated cancer cells.
Title: <i>VHL</i> Synthetic Lethality Signatures Uncovered by Genotype-Specific CRISPR-Cas9 Screens.
The mutation c.414A > G translates to p.Pro138Pro, yet it is not functionally silent, because it causes aberrant splicing by skipping exon 2. The reduced but not completely abolished pVHL protein in a loss-of-heterozygosity genetic backdrop may underlie the etiology of VHL disease.
Title: Case report: a synonymous VHL mutation (c.414A > G, p.Pro138Pro) causes pathogenic familial hemangioblastoma through dysregulated splicing.
VHL targets microtubule-associated protein 1 light chain 3B (MAP1LC3B) and downregulates autophagy.
Title: Ubiquitination of MAP1LC3B by pVHL is associated with autophagy and cell death in renal cell carcinoma.
ufmylation, a novel ubiquitin-like modification, was not associated with mutations of the von Hippel-Lindau (VHL) gene, a specific E3 ligase of the ubiquitin-proteasome and has high mutation rate in renal cancer.
Title: Ufmylation Is Activated in Renal Cancer and Is Not Associated with <i>von Hippel-Lindau</i> Mutation.
Knockdown of HIF-1alpha by siRNA partially inhibited the growth of NCI-H28 cells, suggesting that an additional blockade may be required to completely inhibit growth signaling. The VHL mutation may predict tumor responses to YC-1, a HIF-1alpha inhibitor.
Title: Hypoxia Inducible Factor-1α Inhibition in Von Hippel Lindau-mutant Malignant Pleural Mesothelioma Cells.
In renal cell carcinoma patients with distant metastases, positive associations were found between the expression of VHL, VEGFR2 and CAIX.
Title: VHL Expression in Kidney Cancer: Relation to Metastasis Development, Transcription and Growth Factors and Component of Akt/m-TOR Signaling Pathway.
This iron dependency is introduced by VHL inactivation, revealing a novel interplay between VHL/HIF-alpha dysregulation and clear cell renal cell carcinoma (ccRCC) iron metabolism. Future study is warranted to determine if iron deprivation using chelator drugs provides an effective therapeutic strategy for targeting HIF-2alpha and suppressing tumor progression in ccRCC patients.
Title: Suppressive effects of iron chelation in clear cell renal cell carcinoma and their dependency on VHL inactivation.
It has been shown that different classes of VHL pathogenic variants predispose individuals to distinct spectra of prognostic implications for disease.
Title: Germline VHL gene variant in patients with von Hippel-Lindau disease does not predict renal tumor growth.
This report will add a new mutation site to VHL gene databases. The newly added gene mutation and its associated clinical phenotypes will help improve the accuracy of VHL diagnosis and benefit the community of VHL gene mutation carriers
Title: Novel gene mutation in von Hippel-Lindau disease - a report of two cases.
UBE2C increased HIF-1alpha by ubiquitinating and degrading its upstream regulator pVHL.
Title: Disturbed Flow Increases UBE2C (Ubiquitin E2 Ligase C) via Loss of miR-483-3p, Inducing Aortic Valve Calcification by the pVHL (von Hippel-Lindau Protein) and HIF-1α (Hypoxia-Inducible Factor-1α) Pathway in Endothelial Cells.

Submit: New GeneRIF Correction See all GeneRIFs (509)

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)

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: 279 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
protein binding, bridging involved in substrate recognition for ubiquitination	IDA Inferred from Direct Assay more info	PubMed
transcription factor binding	IPI Inferred from Physical Interaction 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	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
protein ubiquitination	TAS Traceable Author Statement more info
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
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

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_000551.4 → 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

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_001354723.2 → 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

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_198156.3 → 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

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)