The G67E mutation in hMLH1 is associated with an unusual presentation of Lynch syndrome

• Published in: British journal of cancer Vol. 100; no. 2; pp. 376 - 380
• Main Authors: Clyne, M, Offman, J, Shanley, S, Virgo, J D, Radulovic, M, Wang, Y, Ardern-Jones, A, Eeles, R, Hoffmann, E, Yu, V P C C
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 27.01.2009; Nature Publishing Group
• Subjects: Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Bacteria; Biomedical and Life Sciences; Biomedicine; Cancer Research; Colorectal cancer; Colorectal Neoplasms, Hereditary Nonpolyposis - genetics; Colorectal Neoplasms, Hereditary Nonpolyposis - metabolism; Colorectal Neoplasms, Hereditary Nonpolyposis - pathology; DNA Mismatch Repair - genetics; Drug Resistance; Epidemiology; Family; Genetic Complementation Test; Genetics and Genomics; Genotype & phenotype; Humans; Immunoblotting; Male; Medical research; Middle Aged; Molecular Medicine; Mutation; Mutation - genetics; MutL Protein Homolog 1; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Oncology; Phenotype; Proteins; Saccharomycetales; Tumors; Yeast; United Kingdom > UK; HNPCC; prostate; G67E; breast
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/sj.bjc.6604860

Germline mutations in the mismatch repair (MMR) genes are associated with Lynch syndrome, also known as hereditary non-polyposis colorectal cancer (HNPCC) syndrome. Here, we characterise a variant of hMLH1 that confers a loss-of-function MMR phenotype. The mutation changes the highly conserved Gly67 residue to a glutamate ( G67E ) and is reminiscent of the hMLH1-p.Gly67Arg mutation, which is present in several Lynch syndrome cohorts. hMLH1-Gly67Arg has previously been shown to confer loss-of-function ( Shimodaira et al, 1998 ), and two functional assays suggest that the hMLH1-Gly67Glu protein fails to sustain normal MMR functions. In the first assay, hMLH1-Gly67Glu abolishes the protein's ability to interfere with MMR in yeast. In the second assay, mutation of the analogous residue in yMLH1 ( yMLH1-Gly64Glu ) causes a loss-of-function mutator phenotype similar to yMLH1-Gly64Arg . Despite these molecular similarities, an unusual spectrum of tumours is associated with hMLH1-Gly67Glu, which is not typical of those associated with Lynch syndrome and differs from those found in families carrying the hMLH1-Gly67Arg allele. This suggests that hMLH1 may have different functions in certain tissues and/or that additional factors may modify the influence of hMLH1 mutations in causing Lynch syndrome.