Clinical presentation and mutation analysis of VHL disease in a large Chinese family.

Von Hippel-Lindau (VHL) disease is an autosomal dominantly inherited neoplastic disorder characterized by marked phenotypic variability and age-dependent penetrance. This disease is caused by germline mutations in the VHL tumor suppressor gene. Systematic physical examinations, imaging assessments and molecular genetic tests for the VHL gene were performed in a large Chinese VHL family. The examined Chinese VHL family, which has 25 members from four generations, including 7 diagnosed VHL patients and 2 asymptomatic mutation carriers. The average ages of first onset for generations I, II, and III were 37, 30 and 16, respectively. The male:female ratio among VHL patients was 6:1. Molecular genetic investigations detected the c.433C>T [p.Q145X] nonsense mutation in the VHL gene. Molecular modeling of the VHL-ElonginC- ElonginB-HIF-1α complex predicted that the p.Q145X mutation markedly alters the L7 loop structure of the β-domain of the VHL protein (pVHL), destabilizes the VHL-HIF-1αcomplex, and induces the truncation of pVHL. We speculate that the p.Q145X nonsense mutation leads to relatively obvious familial aggregation. This mutation causes the type I phenotype of VHL disease and is associated with a high risk of retinal and central nervous system (CNS) hemangioblastomas (HGBs) and visceral cysts, but a low risk of renal cell carcinoma. Moreover, within a VHL family, the average ages of first onset became younger in successive generations, and the CNS HGBs are more likely to occur in male patients.