Molecular characterization of the cancer-associated MLH1 mutation Asp132His

Introduction: DNA mismatch repair (MMR) is performed by heterodimers: MutSα (MSH2-MSH6) or Sβ (MSH2-MSH3) as mismatch detector and MutLα (MLH1-PMS2) or Lγ (MLH1-MLH3) for repair. Germline mutations in MLH1 and MSH2 genes are causative of Lynch syndrome (HNPCC). Recently, a novel MLH1 missense mutation was identified (D132H) and found to cause predisposition to HNPCC with a distinct phenotype. The effect of D132H and reasons for differing phenotypes have not determined yet. Results: We selected MLH1 mutations reported in Lynch syndrome, located in proximity to D132 in the conserved GHKL ATPase domain. D132 is con…