Von Hippel-Lindau disease: Encyclopedia II - Von Hippel-Lindau disease - Genetics

Von Hippel-Lindau disease - Genetics

The disease is caused by mutations of the VHL gene on the short arm of the third chromosome (3p26-p25). The resultant protein is produced in two forms, an 18 kDa and a 30 kDa protein that functions as a tumor suppressor gene. The main action of the VHL protein is thought to be its E3 ubiquitin ligase activity that results in specific target proteins being 'marked' for degradation. The most researched of these targets is hypoxia inducible factor 1a (HIF1a), a transcription factor that induces the expression of a number of angiogenesis related factors. It stands to reason that the loss of VHL protein activity results in an increased amount of HIF1a, and thus increased levels of angiongenic factors. In turn, this leads to unregulated blood vessel growth, one of the prerequesites of a tumour.

VHL is an autosomal dominant disorder, but there is a wide variation in the age of onset of the disease, the organ system affected and the severity of effect. Most people with von Hippel-Lindau syndrome inherit an altered copy of the gene from one parent. In about 20 percent of cases, however, the altered gene is the result of a new mutation that occurred during the formation of reproductive cells (eggs or sperm) or early in fetal development.

As long as one copy of the VHL gene is producing functional VHL protein in each cell, tumors do not form. If a mutation occurs in the second copy of the VHL gene during a person's lifetime, the cell will have no working copies of the gene and will produce no functional VHL protein. A lack of this protein allows tumors characteristic of von Hippel-Lindau syndrome to develop.

Adapted from the Wikipedia article "Genetics", under the G.N U Free Docmentation License. Please also see http://en.wikipedia.org/wiki