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

Clyne, M, Offman, J, Shanley, S, Virgo, J D, Radulovic, M, Wang, Y, Ardern-Jones, A, Eeles, R, Hoffman, E, Yu, V P C C and Unset (2009) The G67E mutation in hMLH1 is associated with an unusual presentation of Lynch syndrome. British Journal of Cancer. ISSN 0007-0920

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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.

Item Type: Article
Schools and Departments: School of Life Sciences > Sussex Centre for Genome Damage and Stability
Depositing User: Melanie Clyne
Date Deposited: 06 Feb 2012 21:14
Last Modified: 23 Jul 2013 11:45
URI: http://sro.sussex.ac.uk/id/eprint/30449
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