Von Hippel-Lindau disease (VHL) is caused by mutations in a specific gene known as the Von Hippel–Lindau tumor suppressor gene, located on the short arm of chromosome 3. This gene normally produces a protein that helps regulate cell growth and prevent tumors. When this gene is mutated, it leads to the production of a faulty protein that cannot perform its normal function, which increases the risk of developing tumors and cysts in various parts of the body.
Every person has two copies of most genes, including the VHL gene—one inherited from each parent. In VHL disease, one of these copies carries a mutation that disrupts the gene’s function. Because the disease is inherited in an autosomal dominant pattern, having just one mutated copy is enough to cause the disorder. This means that if a parent has the mutation, there is a 50% chance of passing it on to their child.
The mutations in the VHL gene vary widely. Some mutations involve large deletions that remove part or all of the gene, while others are smaller changes such as nonsense mutations, insertions, deletions, or mutations affecting how the gene’s RNA is spliced. These mutations lead to a truncated or nonfunctional protein. The defective protein fails to regulate certain cellular processes, especially those related to oxygen sensing and the degradation of hypoxia-inducible factors (HIFs). When HIFs accumulate abnormally, they trigger the growth of blood vessels and promote tumor formation.
About 80% of VHL cases are inherited from a parent who carries the mutation, while roughly 20% arise from new mutations that occur spontaneously in an individual without a family history. These new mutations are called de novo mutations.
The loss of normal VHL protein function disrupts the cell’s ability to control growth signals, leading to the development of various tumors and cysts. These can occur in multiple organs, including the brain, spinal cord, eyes, kidneys, pancreas, and adrenal glands. The tumors are often highly vascular, meaning they have many blood vessels, which is a direct consequence of the abnormal regulation of blood vessel growth caused by the defective VHL protein.
In summary, Von Hippel-Lindau disease is caused by inherited or spontaneous mutations in the VHL tumor suppressor gene on chromosome 3. These mutations impair the gene’s ability to produce a functional protein that normally helps regulate cell growth and oxygen sensing, leading to the development of multiple tumors and cysts throughout the body.
