VHL – von Hippel-Lindau disease

VHL encodes the von Hippel-Lindau tumor suppressor protein, whose germline alteration causes autosomal dominant von Hippel-Lindau disease characterized by hemangioblastomas, clear cell renal carcinoma, pheochromocytomas, pancreatic neuroendocrine tumors, and other lesions. Extensive analysis of 469 VHL families identified germline mutations in 300 pedigrees, demonstrating high penetrance and supporting genetic testing for diagnosis and surveillance ([PMID:8956040]).

Inheritance is autosomal dominant with both inherited and de novo events. Multi-family sequencing revealed 469 probands ([PMID:8956040]) and at least 2 de novo single-nucleotide deletions (c.444del (p.Phe148fs)) in exon 2 in sporadic cases ([PMID:8641695]). The variant spectrum spans missense, nonsense, frameshift, splice-site, large deletions, synonymous splice-altering, and deep-intronic mutations.

Segregation studies show segregation of disease in >300 affected relatives across multiple kindreds ([PMID:8956040]), with mosaicism detected in atypical renal presentations ([PMID:23384228]). Founder and recurrent alleles such as c.499C>T (p.Arg167Trp) and c.292T>C (p.Tyr98His) underscore population-specific variant distribution.

pVHL functions as the substrate recognition component of a Cullin2-based E3 ubiquitin ligase directing hydroxylated HIF1α to proteasomal degradation. Loss of VHL leads to HIF stabilization and upregulation of angiogenic and metabolic targets. Biochemical assays demonstrate pVHL binding to elongins B/C and the chaperonin TRiC, essential for complex assembly and substrate ubiquitination ([PMID:8674032], [PMID:10635329]).

Conditional Vhl inactivation in mice causes hepatic hemangiomas, vascular proliferation in multiple organs, and impaired spermatogenesis, supporting a two-hit tumor suppressor mechanism ([PMID:14500363]). Discrete missense mutations alter HIF regulation or matrix assembly, delineating genotype–phenotype correlations in type 2C disease ([PMID:11331612], [PMID:15060148]).

Robust genetic and functional evidence underpins clinical utility: VHL genetic testing is essential for early diagnosis, risk stratification, and implementation of surveillance protocols to detect life-threatening tumors. Key take-home: VHL mutation analysis is clinically actionable and guides personalized management of von Hippel-Lindau disease.

References

• Hum Mutat • 1996 • Germline mutations in the Von Hippel-Lindau disease (VHL) gene in families from North America, Europe, and Japan PMID:8956040
• Hum Genet • 1996 • Detection of a germline mutation and somatic homozygous loss of the von Hippel-Lindau tumor-suppressor gene in a family with a de novo mutation. A combined genetic study, including cytogenetics, PCR/SSCP, FISH, and CGH. PMID:8641695
• Clin Genet • 2013 • Mosaicism in von Hippel-Lindau disease with severe renal manifestations PMID:23384228
• Cancer Res • 1996 • Identification of a novel protein (VBP-1) binding to the von Hippel-Lindau tumor suppressor gene product PMID:8674032
• Mol Cell • 1999 • Formation of the VHL-elongin BC tumor suppressor complex is mediated by the chaperonin TRiC PMID:10635329
• Cancer Res • 2003 • Hepatic vascular tumors, angiectasis in multiple organs, and impaired spermatogenesis in mice with conditional inactivation of the VHL gene PMID:14500363
• Hum Mol Genet • 2001 • von Hippel-Lindau protein mutants linked to type 2C VHL disease preserve the ability to downregulate HIF PMID:11331612
• Mol Cell Biol • 2004 • pVHL modification by NEDD8 is required for fibronectin matrix assembly and suppression of tumor development PMID:15060148

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