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The G67E mutation in hMLH1 is associated with an unusual presentation of Lynch syndrome
journal contribution
posted on 2023-06-08, 09:26 authored by M Clyne, J Offman, S Shanley, J D Virgo, M Radulovic, Y Wang, A Ardern-Jones, R Eeles, E Hoffman, V P C C YuGermline 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.
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Publication status
- Published
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- Published version
Journal
British Journal of CancerISSN
0007-0920Publisher
Nature Publishing GroupExternal DOI
Volume
100Page range
376-380Department affiliated with
- Sussex Centre for Genome Damage Stability Publications
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- Yes
Peer reviewed?
- Yes
Legacy Posted Date
2012-02-06First Open Access (FOA) Date
2018-03-22First Compliant Deposit (FCD) Date
2018-03-22Usage metrics
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