The MSH6 gene plays a role in human health by contributing to the maintenance of genomic stability. This gene provides instructions for creating a protein that keeps the body’s genetic information accurate. The proper functioning of MSH6 is important for preventing errors in DNA, which in turn supports overall cellular health.
The Role of MSH6 in DNA Repair
The MSH6 protein functions as a component of the DNA mismatch repair (MMR) system that corrects errors occurring during DNA replication. MSH6 partners with another protein, MSH2, to form a complex known as MutS alpha (MutSα). This complex is responsible for recognizing specific types of errors, particularly single-base mismatches and small insertion-deletion loops (IDLs) of one or two base pairs that arise when DNA is copied.
Once MutSα identifies an error, it binds to the mismatched DNA, causing the DNA helix to bend. This binding initiates the repair process by recruiting other proteins, including the MutL alpha heterodimer, to the site of the error. The coordinated action of these proteins leads to the removal of the incorrect DNA segment and its replacement with the correct sequence, ensuring the fidelity of the genetic code.
MSH6 Mutations and Associated Health Conditions
Mutations in the MSH6 gene can disrupt its ability to perform DNA mismatch repair, leading to an accumulation of errors in the genetic code. This dysfunction increases an individual’s risk for certain health conditions, particularly various cancers. The most notable association is with Lynch syndrome, a hereditary cancer syndrome. MSH6 mutations are implicated in a variant often referred to as MSH6-associated Lynch Syndrome.
Individuals with MSH6-associated Lynch syndrome face risks for specific cancers, including colorectal cancer and endometrial (uterine) cancer. For men with an MSH6 mutation, the estimated cumulative risk for colorectal cancer by age 70 is about 22%, increasing to 44% by age 80. For women, these risks are slightly lower, estimated at 10% by age 70 and 20% by age 80. Endometrial cancer is a prominent risk for female MSH6 mutation carriers, with an estimated cumulative risk of 26% by age 70 and 44% by age 80. MSH6 mutations are also linked to other Lynch syndrome-associated cancers, such as ovarian, stomach, small intestine, and urinary tract cancers.
Constitutional Mismatch Repair Deficiency (CMMRD) syndrome is a condition linked to MSH6 mutations. This condition occurs when an individual inherits pathogenic variants in both copies of the MSH6 gene, one from each parent. CMMRD greatly increases the risk of developing various cancers, including those of the blood (leukemia or lymphoma), brain, and colon and rectum, often beginning in early childhood. Approximately 50% of individuals with CMMRD may develop cancer by age 10, and 90% by age 18.
Inheritance and Genetic Testing for MSH6
Mutations in the MSH6 gene associated with Lynch syndrome are inherited in an autosomal dominant pattern. An individual only needs to inherit one copy of the mutated gene from either parent to have an increased risk of developing associated cancers. If a parent carries an MSH6 mutation, each of their children has a 50% chance of inheriting the mutation.
Genetic testing for MSH6 mutations involves analyzing an individual’s DNA to identify specific changes in the gene. This testing is often considered for individuals with a personal or family history suggestive of Lynch syndrome, such as early-onset colorectal or endometrial cancers, or multiple family members affected by these or other Lynch syndrome-related cancers. A positive test result indicates an increased cancer risk for the individual and has implications for their immediate and extended family, as other relatives may also be carriers. Genetic counseling is recommended to discuss these implications and guide family members on potential testing.
Managing MSH6-Related Risks
For individuals identified with MSH6 mutations, managing associated health risks involves proactive surveillance and personalized strategies. Regular cancer screening protocols are recommended to detect cancers early. This includes initiating colonoscopies at an earlier age, typically between 30 and 35 years old, or 2-5 years before the earliest family diagnosis, with repeat screenings every 1 to 3 years.
For women, regular discussions about endometrial cancer surveillance, including endometrial biopsies every 1-2 years starting at age 30-35, and prompt attention to any abnormal uterine bleeding, are advised. Lifestyle considerations, such as maintaining a healthy diet and regular physical activity, are encouraged as part of overall health management. Genetic counseling remains important for affected individuals and their families to understand their specific risks and to develop a tailored management plan.