Functional implications of the p.Cys680Arg mutation in the MLH1 mismatch repair protein

Mev Dominguez-Valentin; Mark Drost; Christina Therkildsen; Eva Rambech; Hans Ehrencrona; Maria Angleys; Thomas Lau Hansen; Niels de Wind; Mef Nilbert; Lene Juel Rasmussen

doi:10.1002/mgg3.80

Functional implications of the p.Cys680Arg mutation in the MLH1 mismatch repair protein

Mol Genet Genomic Med. 2014 Jul;2(4):352-5. doi: 10.1002/mgg3.80. Epub 2014 May 6.

Authors

Affiliations

¹ Department of Oncology, Institute for Clinical Sciences, Lund University 22185, Lund, Sweden ; The Danish HNPCC-register, Clinical Research Centre, Hvidovre University Hospital, Copenhagen University Hvidovre, Denmark.
² Department of Toxicogenetics, Leiden University Medical Center Leiden, The Netherlands.
³ The Danish HNPCC-register, Clinical Research Centre, Hvidovre University Hospital, Copenhagen University Hvidovre, Denmark.
⁴ Department of Oncology, Institute for Clinical Sciences, Lund University 22185, Lund, Sweden.
⁵ Department of Clinical Genetics, University and Regional Laboratories, Skåne University Hospital, Lund University Lund, Sweden.
⁶ Center for Healthy Aging, Department of Cellular and Molecular Medicine, University of Copenhagen DK-2200, Copenhagen N, Denmark.

PMID: 25077178
PMCID: PMC4113276
DOI: 10.1002/mgg3.80

Abstract

In clinical genetic diagnostics, it is difficult to predict whether genetic mutations that do not greatly alter the primary sequence of the encoded protein causing unknown functional effects on cognate proteins lead to development of disease. Here, we report the clinical identification of c.2038 T>C missense mutation in exon 18 of the human MLH1 gene and biochemically characterization of the p.Cys680Arg mutant MLH1 protein to implicate it in the pathogenicity of the Lynch syndrome (LS). We show that the mutation is deficient in DNA mismatch repair and, therefore, contributing to LS in the carriers.

Keywords: Functional assay; Lynch syndrome; MLH1; mismatch repair.