The G67E mutation in hMLH1 is associated with an unusual presentation of Lynch syndrome
| Autor: | Audrey Ardern-Jones, Susan Shanley, Eva Hoffmann, Marko Radulovic, Y Wang, Rosalind A. Eeles, Judith Offman, J D Virgo, M Clyne, Veronica P. C. C. Yu |
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| Rok vydání: | 2009 |
| Předmět: |
Male
congenital hereditary and neonatal diseases and abnormalities Cancer Research Immunoblotting HNPCC Biology hMLH1 medicine.disease_cause DNA Mismatch Repair Germline mutation medicine Humans Family Allele neoplasms Gene breast Adaptor Proteins Signal Transducing Genetics Mutation prostate Genetic Complementation Test Nuclear Proteins nutritional and metabolic diseases Genetics and Genomics Middle Aged medicine.disease Colorectal Neoplasms Hereditary Nonpolyposis Phenotype digestive system diseases Lynch syndrome Oncology G67E Saccharomycetales DNA mismatch repair MutL Protein Homolog 1 |
| Zdroj: | British Journal of Cancer |
| ISSN: | 1532-1827 0007-0920 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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