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Von Hippel-Lindau (VHL) Syndrome is an inherited disorder that is caused by a mutation in the VHL gene, which leads to an increased risk of development of tumors in the central nervous system (CNS) and viscera. This occurs due to changes in the production of proteins in the body, which are involved in the regulation of cell growth and division.
The VHL gene is a tumor suppressor gene located on chromosome 3 at 3p25-26 that is responsible for monitoring cell growth and division and preventing the cells from multiplying uncontrollably.
There are several functions of the VHL gene within the body, one of which is to regulate the production of proteins in the VCB-CUL2 complex. This group of proteins ubiquitinates substrates in the body and marks them for degradation when they’re not needed.
One of the key target proteins is hypoxia-inducible factor 2-alpha (HIF-2α), which plays a significant role in another protein complex referred to as HIF that affects the ability of an individual to adapt to atmospheric oxygen changes. This complex regulates the erythropoietin, which acts to control the production of red blood cells.
The VHL gene is likely to be involved with several other cellular functions, particularly those that control the growth and multiplication of cells. The exact mechanism of tumorigenesis is unknown, although there are several theories to describes the relationship. The healthy gene itself may suppress the growth of tumors, resulting in uncontrolled cell growth when there is a mutation.
VHL gene mutations follow an autosomal dominant inheritance pattern. This means that one copy of the mutation, which may be inherited from either parent, is able to increase the risk of developing the tumors and VHL syndrome.
The majority of patients with the syndrome inherit the gene mutation from an affected parent, but approximately 1 in 5 patients have a spontaneous gene mutation with no family history of the disorder. This is likely to result from a mutation in the formation of the reproductive cells or early development of the fetus.
VHL syndrome is distinct from most other autosomal dominant conditions because there should be two gene mutations present in order for tumors to begin forming, leading the presentation of the syndrome. The second copy is altered during the person’s lifetime in the cells of the brain, retina or kidneys but eventually affects nearly all individuals that inherit one gene mutation.
When there are two mutations in the VHL gene, abnormal proteins are produced and the function of the gene is altered. In particular, the proteins in the VCB-CUL2 complex change and affect the regulation of cell growth in the body.
As a result of this, certain cells are able to divide more rapidly than usual and form tumors or cysts characteristic of VHL syndrome. These often include hemangioblastomas, renal cell carcinoma (RCC) renal cysts and phaeochromocytoma, as well as tumors in the pancreas, epididymis uterus or endolymphatic sac in the inner ear.