Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2018 Oct;20(10):1266-1273.
doi: 10.1038/gim.2017.261. Epub 2018 Mar 29.

Genotype and phenotype correlation in von Hippel-Lindau disease based on alteration of the HIF-α binding site in VHL protein

Sheng-Jie Liu  1   2   3 , Jiang-Yi Wang  1   2   3 , Shuang-He Peng  1   2   3 , Teng Li  1   2   3 , Xiang-Hui Ning  1   2   3 , Bao-An Hong  1   2   3 , Jia-Yuan Liu  1   2   3 , Peng-Jie Wu  4 , Bo-Wen Zhou  1   2   3 , Jing-Cheng Zhou  1   2   3 , Nie-Nie Qi  1   2   3 , Xiang Peng  1   2   3 , Jiu-Feng Zhang  1   2   3 , Kai-Fang Ma  1   2   3 , Lin Cai  5   6   7 , Kan Gong  5   6   7
Affiliations
Free article

Genotype and phenotype correlation in von Hippel-Lindau disease based on alteration of the HIF-α binding site in VHL protein

Sheng-Jie Liu et al. Genet Med. 2018 Oct.
Free article

Abstract

Purpose: Von Hippel-Lindau (VHL) disease is a rare hereditary cancer syndrome that reduces life expectancy. We aimed to construct a more valuable genotype-phenotype correlation based on alterations in VHL protein (pVHL).

Methods: VHL patients (n = 339) were recruited and grouped based on mutation types: HIF-α binding site missense (HM) mutations, non-HIF-α binding site missense (nHM) mutations, and truncating (TR) mutations. Age-related risks of VHL-associated tumors and patient survival were compared.

Results: Missense mutations conferred an increased risk of pheochromocytoma (HR = 1.854, p = 0.047) compared with truncating mutations. The risk of pheochromocytoma was lower in the HM group than in the nHM group (HR = 0.298, p = 0.003) but was similar between HM and TR groups (HR = 0.901, p = 0.810). Patients in the nHM group had a higher risk of pheochromocytoma (HR = 3.447, p < 0.001) and lower risks of central nervous system hemangioblastoma (CHB) (HR = 0.700, p = 0.045), renal cell carcinoma (HR = 0.610, p = 0.024), and pancreatic tumor (HR = 0.382, p < 0.001) than those in the combined HM and TR (HMTR) group. Moreover, nHM mutations were independently associated with better overall survival (HR = 0.345, p = 0.005) and CHB-specific survival (HR = 0.129, p = 0.005) than HMTR mutations.

Conclusion: The modified genotype-phenotype correlation links VHL gene mutation, substrate binding site, and phenotypic diversity (penetrance and survival), and provides more accurate information for genetic counseling and pathogenesis studies.

Keywords: genotype–phenotype; protein binding site; survival; tumor risk; von Hippel–Lindau disease.

PubMed Disclaimer

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Gossage L, Eisen T, Maher ER. VHL, the story of a tumour suppressor gene. Nat Rev Cancer 2015;15:55–64. - DOI
    1. Maher ER, Neumann HP, Richard S. von Hippel-Lindau disease: a clinical and scientific review. Eur J Hum Genet 2011;19:617–623. - DOI
    1. Chou A, Toon C, Pickett J, Gill AJ. von Hippel-Lindau syndrome. Front Horm Res 2013;41:30–49. - DOI
    1. Lonser RR, Glenn GM, Walther M et al. von Hippel-Lindau disease. Lancet 2003;361:2059–2067. - DOI
    1. Nordstrom-O’Brien M, van der Luijt RB, van Rooijen E et al. Genetic analysis of von Hippel-Lindau disease. Hum Mutat 2010;31:521–537. - PubMed

Publication types

Substances

LinkOut - more resources