MLH1 and PMS2: Gene Mutations and Lynch Syndrome

Certain genes in our body function as diligent guardians of our genetic code, including MLH1 and PMS2. They can be thought of as cellular proofreaders, constantly scanning our DNA to ensure its integrity. These genes provide instructions for making proteins that are fundamental to keeping our genetic blueprint stable and free from errors that arise as cells divide. Their correct operation is a background process that supports healthy cell function throughout our lives.

The Role of MLH1 and PMS2 in DNA Repair

To maintain genetic stability, human cells rely on a system called DNA mismatch repair (MMR). This process acts like a biological spell-checker, identifying and correcting errors that occur during DNA replication. When a cell divides, its entire genetic code must be copied, and mistakes can lead to mismatched base pairs. The proteins produced by the MLH1 and PMS2 genes are central to this repair mechanism.

The MLH1 and PMS2 proteins join to form a heterodimer known as MutLα. This protein complex is recruited to the site of a DNA mismatch after the error has been recognized by another set of proteins. The primary job of the MutLα complex is to coordinate the subsequent steps of the repair. It directs the removal of the section of the newly synthesized DNA strand that contains the error, allowing it to be replaced with the correct sequence. This function is important for correcting small insertions and deletions that can otherwise disrupt a gene’s function.

Consequences of MLH1 and PMS2 Mutations

A gene mutation is a change in the DNA sequence that can alter the function of the protein it codes for. When a mutation occurs in the MLH1 or PMS2 gene, the resulting protein may be non-functional or absent altogether. This defect cripples the DNA mismatch repair system. As a result, errors that occur during DNA replication are no longer corrected efficiently.

This failure of the repair machinery leads to a condition known as microsatellite instability (MSI). Microsatellites are short, repetitive sequences of DNA that are particularly prone to replication errors. In a healthy cell, the MMR system corrects these slips, but in a cell with a faulty MLH1 or PMS2 gene, these errors accumulate rapidly. This genomic instability increases the likelihood of mutations occurring in other genes that regulate cell growth, creating a pathway for abnormal cells to develop and multiply unchecked.

Association with Lynch Syndrome

The inherited condition most directly linked to mutations in the MLH1 and PMS2 genes is Lynch syndrome. Historically known as Hereditary Non-Polyposis Colorectal Cancer (HNPCC), Lynch syndrome is an inherited disorder that confers a much higher risk of developing certain types of cancer. It is caused by a germline mutation—one present in all cells of the body—in one of the mismatch repair genes.

Individuals with Lynch syndrome have an increased lifetime risk for several cancers. Colorectal cancer is the most common, followed closely by endometrial cancer in women. The syndrome also raises the risk for cancers of the:

• Ovary
• Stomach
• Small intestine
• Pancreas
• Biliary tract
• Urinary tract
• Brain

Lynch syndrome is inherited in an autosomal dominant pattern, meaning a person only needs to inherit one copy of the mutated gene from one parent to have the condition. A child of an affected parent has a 50% chance of inheriting the mutation.

Diagnosis and Medical Management

Identifying Lynch syndrome begins after a cancer diagnosis through testing of the tumor itself. Two screening tests are used: immunohistochemistry (IHC) and microsatellite instability (MSI) analysis. IHC checks for the presence of the MLH1 and PMS2 proteins in tumor cells; their absence suggests a defect in the corresponding gene. MSI testing determines if the microsatellites in the tumor DNA have changed in length. If these tumor tests are abnormal, a definitive diagnosis is made through germline genetic testing, usually from a blood or saliva sample, to find the inherited mutation.

For individuals confirmed to have Lynch syndrome, medical management focuses on proactive surveillance and risk reduction. This includes starting cancer screenings at a much earlier age and having them more frequently than the general population. For example, colonoscopies may be recommended every one to two years, beginning as early as age 20-25.

For women, discussions may include risk-reducing surgeries such as a hysterectomy and oophorectomy to prevent endometrial and ovarian cancers. The diagnosis can also influence cancer treatment, as tumors with MSI-high status often respond well to a class of drugs called checkpoint inhibitor immunotherapies.