title: The G67E mutation in hMLH1 is associated with an unusual presentation of Lynch syndrome.
abstract: 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.
authors.affiliation: MRC Genome Damage and Stability Centre, University of Sussex, Brighton, UK.
authors.forename: M
authors.initials: M
authors.lastname: Clyne
authors.forename: J
authors.initials: J
authors.lastname: Offman
authors.forename: S
authors.initials: S
authors.lastname: Shanley
authors.forename: J D
authors.initials: JD
authors.lastname: Virgo
authors.forename: M
authors.initials: M
authors.lastname: Radulovic
authors.forename: Y
authors.initials: Y
authors.lastname: Wang
authors.forename: A
authors.initials: A
authors.lastname: Ardern-Jones
authors.forename: R
authors.initials: R
authors.lastname: Eeles
authors.forename: E
authors.initials: E
authors.lastname: Hoffmann
authors.forename: V P C C
authors.initials: VP
authors.lastname: Yu
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics* / Q000378:metabolism; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D053843:DNA Mismatch Repair / Q000235:genetics*; D005190:Family; D005816:Genetic Complementation Test; D006801:Humans; D015151:Immunoblotting; D008297:Male; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D009154:Mutation / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D010641:Phenotype; D004718:Saccharomycetales
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C501486:MLH1 protein, human; D009687:Nuclear Proteins; D000070957:MutL Protein Homolog 1