The Von Hippel–Lindau gene is a tumor suppressor gene on chromosome 3p25-26 that codes for Von Hippel–Lindau protein, which is part of protein complex VCB-CUL2. Biallelic inactivation (2-hit model) is required for tumor development.
Most patients inherit the autosomal dominant VHL gene (allele) with the germline mutation from the affected parent and a normal somatic (wild-type) VHL gene from the unaffected parent, with ≈ 95% penetrance by age 60 yrs 1) 2).
However, about 20% of cases result from a spontaneous mutation that occurs in the egg or sperm, or very early in development 3).
The disease is caused by mutations of the von Hippel–Lindau tumor suppressor (VHL) gene on the short arm of chromosome 3 (3p25-26). There are over 1500 germline mutations and somatic mutations found in VHL disease.
Von Hippel–Lindau disease is inherited in an autosomal dominant pattern. Every cell in the body has 2 copies of every gene. In VHL disease, one copy of the VHL gene has a mutation and produces a faulty VHL protein (pVHL). However, the second copy still produces a functional protein. Tumours form from only those cells where the second copy of the gene has been mutated. This is known as the two-hit hypothesis. A lack of this protein allows tumors characteristic of von Hippel–Lindau syndrome to develop
Approximately 20% of cases of VHL disease are found in individuals without a family history, known as de novo mutations. An inherited mutation of the VHL gene is responsible for the remaining 80 percent of cases.
30-40% of mutations in the VHL gene consist of 50-250kb deletion mutations that remove either part of the gene or the whole gene and flanking regions of DNA. The remaining 60-70% of VHL disease is caused by the truncation of pVHL by nonsense mutations, indel mutations or splice site mutations.