VHL

The VHL gene is a tumor suppressor gene, which means it prevents cells from growing and dividing too rapidly or in an uncontrolled way. The VHL gene provides instructions for making a protein that functions as part of a complex (a group of proteins that work together) called the VCB-CUL2 complex. This complex targets other proteins to be broken down (degraded) by the cell when they are no longer needed. Protein degradation is a normal process that removes damaged or unnecessary proteins and helps maintain the normal functions of cells.

The VCB-CUL2 complex targets large proteins, particularly a protein called hypoxia-inducible factor (HIF), to be broken down within cells. HIF controls several important genes involved in cell division and the formation of new blood vessels.

The VHL protein likely plays a role in other cellular functions, including the regulation of other genes and control of cell division. This protein is also involved in the formation of the extracellular matrix, which is an intricate lattice that forms in the spaces between cells and provides structural support to tissues.

von Hippel-Lindau syndrome - caused by mutations in the VHL gene

More than 370 inherited mutations in the VHL gene have been identified in people with von Hippel-Lindau syndrome. VHL mutations either prevent the production of any VHL protein or lead to the production of an abnormal version of the protein. Von Hippel-Lindau syndrome type 1, which is associated with a low risk of developing adrenal gland tumors called pheochromocytomas, most often results from mutations that prevent the production of any functional VHL protein. Most cases of von Hippel-Lindau syndrome type 2, which has a much higher risk of pheochromocytomas, are caused by mutations that change the structure of the VHL protein.

When the VHL protein is altered or missing, the VCB-CUL2 complex cannot target HIF and other proteins to be broken down. As a result, HIF can build up in cells. Excess HIF stimulates cells to divide abnormally and triggers the production of blood vessels when they are not needed. Rapid and uncontrolled cell division, along with the abnormal formation of new blood vessels, can lead to the development of cysts and tumors in people with von Hippel-Lindau syndrome.

cancers - associated with the VHL gene

While inherited mutations in the VHL gene cause von Hippel-Lindau syndrome, noninherited (somatic) mutations in this gene are associated with a form of kidney cancer called clear cell renal carcinoma. This type of cancer is described as sporadic when it develops in people without inherited VHL mutations.

Instead of occurring in every cell in the body, somatic VHL mutations occur only in certain kidney cells. These genetic changes prevent the cells from producing functional VHL protein. A lack of this protein allows the cells to grow and divide abnormally, which may contribute to the development of sporadic kidney tumors. In addition, somatic mutations in the VHL gene in kidney cells may promote the growth of existing kidney tumors.

other disorders - caused by mutations in the VHL gene

Mutations in the VHL gene have been identified in a type of noncancerous tumor called a hemangioblastoma. These tumors are made of newly formed blood vessels and tend to develop in the brain and spinal cord. Hemangioblastomas are a characteristic feature of von Hippel-Lindau syndrome, but they can also occur sporadically (without the other signs and symptoms of that condition). When these tumors develop in people without von Hippel-Lindau syndrome, they are associated with somatic mutations in the VHL gene. Somatic mutations are acquired during a person's lifetime and are present only in certain cells (in this case, cells that give rise to blood and blood vessels).

Inherited mutations in the VHL gene can cause a condition called Chuvash polycythemia or congenital polycythemia. Polycythemia is a disorder in which too many red blood cells are produced, increasing the risk for blood clots, excessive bleeding, and stroke. Researchers have found at least six mutations that can cause polycythemia. Each of these mutations changes a single protein building block (amino acid) in the VHL protein, which disrupts the protein's function. Researchers are uncertain why mutations in the VHL gene result in an increased number of red blood cells, but they suspect that the altered VHL protein may be unable to interact with other proteins, including HIF.