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., Hoffmann, E and Yu, V.P. (2009) The G67E mutation in hMLH1 is associated with an unusual presentation of Lynch syndrome. British Journal of Cancer, 100 (2). pp. 376-380. ISSN 0007-0920

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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
Keywords: G67E, HNPCC, hMLH1, breast, prostate
Schools and Departments: School of Life Sciences > Sussex Centre for Genome Damage and Stability
Subjects: Q Science > QH Natural history > QH0301 Biology > QH0426 Genetics
R Medicine > R Medicine (General)
R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology Including cancer and carcinogens
Depositing User: Gee Wheatley
Date Deposited: 23 Feb 2009
Last Modified: 07 Mar 2017 08:58
Google Scholar:5 Citations

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