MLH1 – Lynch syndrome II

MLH1 encodes a core MutLα component of the post-replicative DNA mismatch repair (MMR) pathway. Germline MLH1 variants underlie Lynch syndrome II (MONDO:0012249), an autosomal dominant disorder predisposing to early-onset colorectal carcinoma and various extracolonic malignancies due to microsatellite instability.

Initial mRNA analysis in 17 English HNPCC kindreds identified MLH1 mutations co-segregating in 8 affected relatives ([PMID:8880570]). A larger collaborative study of 202 families ([PMID:9322509]) reported MLH1 mutations in 75 cases, confirming high prevalence in Lynch syndrome cohorts.

The MLH1 variant spectrum comprises missense substitutions (n=23 [PMID:9322509]), nonsense changes (n=30 [PMID:9322509]), frameshifts (n=18 [PMID:9322509]), and splice-site defects (n=19 [PMID:9322509]). A representative pathogenic allele is c.2102A>G (p.Gln701Arg), which disrupts the ATPase domain and abrogates repair activity.

In vitro MutLα ATPase assays demonstrate that alterations of conserved glutamic acid residues in MLH1 impair mismatch repair by >80% ([PMID:11897781]). Yeast complementation models of analogous mlh1 mutations yield strong mutator phenotypes, supporting a haploinsufficiency mechanism in tumorigenesis.

Mlh1⁻/⁻ mice recapitulate the human phenotype, exhibiting microsatellite instability, increased tumor burden, and reduced apoptotic responses in the intestinal epithelium ([PMID:12655562]). Exon-skipping splice acceptor mutations cause partial transcript loss and reduced MLH1 expression in patient cells ([PMID:11066084]).

Although most MLH1 missense variants are deleterious, some (e.g., p.Ser93Gly) retain in vitro repair proficiency, indicating that not all alterations confer equal risk ([PMID:11793442]). This underscores the importance of functional assays in variant interpretation.

Collectively, robust genetic and functional data definitively establish MLH1 as the causative gene for Lynch syndrome II. Clinical MLH1 testing enables early identification of at-risk individuals for tailored surveillance, prophylactic interventions, and informed family counseling.

References

• Journal of medical genetics • 1996 • Mutation screening of MSH2 and MLH1 mRNA in hereditary non-polyposis colon cancer syndrome. PMID:8880570
• Gastroenterology • 1997 • Mutations predisposing to hereditary nonpolyposis colorectal cancer: database and results of a collaborative study. PMID:9322509
• The Journal of biological chemistry • 2002 • Contribution of human mlh1 and pms2 ATPase activities to DNA mismatch repair. PMID:11897781
• Human mutation • 2003 • Identification of six novel MSH2 and MLH1 germline mutations in HNPCC. PMID:12655562
• Genes, chromosomes & cancer • 2000 • Pathological exon skipping in an HNPCC proband with MLH1 splice acceptor site mutation. PMID:11066084
• Genes, chromosomes & cancer • 2002 • Functional analysis of MLH1 mutations linked to hereditary nonpolyposis colon cancer. PMID:11793442

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