MSH6 gene

The MSH6 gene provides instructions for making a protein that plays an essential role in repairing DNA. This protein helps fix errors that are made when DNA is copied (DNA replication) in preparation for cell division. The MSH6 protein joins with another protein called MSH2 (produced from the MSH2 gene) to form a protein complex. This complex identifies locations on the DNA where errors have been made during DNA replication. Another group of proteins, the MLH1-PMS2 protein complex, then repairs the errors. The MSH6 gene is a member of a set of genes known as the mismatch repair (MMR) genes.


Normal Function
The MSH6 gene provides instructions for making a protein that plays an essential role in repairing DNA. This protein helps fix errors that are made when DNA is copied (DNA replication) in preparation for cell division. The MSH6 protein joins with another protein called MSH2 (produced from the MSH2 gene) to form a protein complex. This complex identifies locations on the DNA where errors have been made during DNA replication. Another group of proteins, the MLH1-PMS2 protein complex, then repairs the errors. The MSH6 gene is a member of a set of genes known as the mismatch repair (MMR) genes.

Lynch syndrome
Mutations in the MSH6 gene have been reported in about 10 percent of families with Lynch syndrome that have an identified gene mutation. Lynch syndrome increases the risk of many types of cancer, particularly cancers of the colon (large intestine) and rectum, which are collectively referred to as colorectal cancer. People with Lynch syndrome also have an increased risk of cancers of the endometrium (lining of the uterus), ovaries, stomach, small intestine, liver, gallbladder duct, upper urinary tract, and brain. Endometrial cancer is especially common in women with Lynch syndrome caused by MSH6 gene mutations.
MSH6 gene mutations involved in this condition lead to the production of an abnormally short, nonfunctional MSH6 protein or a partially active version of the protein. When the MSH6 protein is absent or nonfunctional, the number of errors that are left unrepaired during cell division increases substantially. The errors accumulate as the cells continue to divide, which may cause the cells to function abnormally, increasing the risk of tumor formation in the colon or another part of the body.
In a small number of people, mutations in the MSH6 gene cause a variant of Lynch syndrome called Muir-Torre syndrome. In addition to colorectal cancer, people with this condition have an increased risk of developing several uncommon skin tumors. These rare skin tumors include sebaceous adenomas and carcinomas, which occur in glands that produce an oily substance called sebum (sebaceous glands). Multiple rapidly growing tumors called keratoacanthomas may also occur, usually on sunexposed areas of skin.

Ovarian cancer
Other cancers While Lynch syndrome is associated with a mutation in one copy of the MSH6 gene, very rarely, individuals in affected families inherit two MSH6 gene mutations, one from each parent. Most often in these cases, the same mutation occurs in both copies of the gene (a homozygous mutation). People with a homozygous MSH6 gene mutation have a syndrome distinct from Lynch syndrome. In addition to colorectal cancer, they may develop cancers of the blood (leukemia or lymphoma). Some of these individuals will also develop characteristic features of a condition known as neurofibromatosis, including noncancerous tumors that grow along nerves (neurofibromas) and light brown patches of skin called café-au-lait spots. The onset of colon cancer in these individuals is extremely early, often occurring during childhood. This syndrome involving colon cancer, leukemia or lymphoma, and neurofibromatosis is sometimes called CoLoN.

Chromosomal Location
Cytogenetic Location: 2p16.3, which is the short (p) arm of chromosome 2 at position 16.3