What is the MLH (MutL homolog) gene?

MLH Gene: A Critical Component of DNA Mismatch Repair

MLH1 (mutL homolog 1) is a gene that encodes a protein essential for DNA mismatch repair (MMR), playing a critical role in maintaining genomic integrity by correcting errors that occur during DNA replication. 1

Structure and Function

• MLH1 is one of four primary genes (along with MSH2, MSH6, and PMS2) that are critical components of the DNA mismatch repair system, which restores DNA integrity after mismatching errors occur 1
• The MLH1 protein functions as part of heterodimeric complexes, primarily partnering with PMS2 to form the MLH1-PMS2 complex that is essential for correcting single base mismatches or short insertions and deletions in DNA 1
• MLH1 is considered an obligatory partner in these heterodimers, meaning it is typically required for the MMR function to work properly 1

Protein Interactions

• MLH1 forms a heterodimer primarily with PMS2, but can also partner with other MMR proteins including MLH3 and PMS1 1
• In these partnerships, MLH1 and MSH2 are considered the primary proteins, while PMS2 and MSH6 are secondary partners 1
• When MLH1 is mutated, it typically results in proteolytic degradation of both the mutated MLH1 protein and its secondary partner PMS2 1
• Conversely, mutations in PMS2 may not affect MLH1 stability, as PMS2 can be substituted by PMS1 or MLH3 in the heterodimer 1

Clinical Significance

• Germline mutations in MLH1 are responsible for approximately 50% of hereditary non-polyposis colorectal cancer (HNPCC) cases, also known as Lynch syndrome 1
• Inactivation of MLH1 can occur due to germline mutations, somatic mutations, or epigenetic silencing (such as promoter methylation), resulting in defective MMR (dMMR) mechanism 1
• Defects in MLH1 lead to microsatellite instability (MSI), a condition of genetic hypermutability characterized by clustering of mutations in microsatellites 1
• MSI is a marker of dMMR and characterizes a hypermutable state of cells, which is found in both Lynch syndrome and approximately 15% of sporadic colorectal cancers 1

MLH1 in Cancer Development

• MLH1 mutations are associated with various cancer types, particularly colorectal and endometrial cancers 1
• Tumors with MLH1 deficiency typically show loss of both MLH1 and PMS2 proteins when assessed by immunohistochemistry 1
• In sporadic colorectal cancers, MLH1 deficiency is most commonly caused by somatic hypermethylation of the MLH1 gene promoter rather than germline mutations 1
• MLH1-deficient tumors often have a better prognosis and may respond differently to certain chemotherapies compared to microsatellite-stable tumors 1

Testing for MLH1 Deficiency

• Testing for MLH1 deficiency is commonly performed using immunohistochemistry to assess protein expression or through molecular tests for microsatellite instability 1
• These tests are particularly important for patients with colorectal cancer diagnosed before age 50, as they are more likely to have Lynch syndrome 1
• Some institutions perform MSI testing reflexively on all colorectal and endometrial tumors to identify potential Lynch syndrome cases 1

MLH1 in Biallelic Mismatch Repair Deficiency

• Biallelic (homozygous) mutations in MLH1 cause constitutional mismatch repair deficiency syndrome, a rare and aggressive cancer predisposition syndrome 1
• This condition is characterized by early-onset colorectal neoplasia, brain tumors, hematologic malignancies, and café au lait spots 1
• Unlike Lynch syndrome (heterozygous mutations), individuals with biallelic MLH1 mutations have no DNA MMR activity in any tissue from birth 1

Recent Research

• Recent studies have identified numerous missense mutations in MLH1 that can impair MMR activity to varying degrees 2
• Research continues to explore the association between specific MLH1 polymorphisms and colorectal cancer risk 3
• Some evidence suggests that MLH subunits may have coordinated and independent roles in DNA repair beyond their canonical functions 4