title: Analysis of hMLH1 missense mutations in East Asian patients with suspected hereditary nonpolyposis colorectal cancer.
abstract: OBJECTIVE
  Germ line mutations in the DNA mismatch repair gene hMLH1 are a frequent cause of hereditary nonpolyposis colorectal cancer and about one-third of these are missense mutations. Several missense mutations in hMLH1 have frequently been detected in East Asian patients with suspected hereditary nonpolyposis colorectal cancer, but their pathogenic role has not been extensively assessed. The aim of this study was to perform functional analyses of these variants and their association with gastrointestinal cancer in East Asians.
  
  
  METHODS
  Altogether, 10 hMLH1 variants were analyzed by yeast two-hybrid and coimmunoprecipitation assays.
  
  
  RESULTS
  The carboxyl-terminal replacements Q542L, L549P, L574P, and P581L in hMLH1 resulted in complete loss of activity in both yeast two-hybrid and coimmunoprecipitation tests and thus might be considered as pathogenic. The amino-terminal variants S46I, G65D, G67R, and R217C did not affect complex formation with hPMS2 in coimmunoprecipitation, but partly or fully lost their activity in yeast two-hybrid assay, and we suggested that these variants might reduce the efficiency of the heterodimer to go into the nucleus and thus the mismatch repair function might be blocked or reduced. The V384D and the Q701K variant resulted in the interaction of hMLH1 with hPMS2 at reduced efficiency and might raise the gastrointestinal cancer risk of the mutation carriers.
  
  
  CONCLUSIONS
  This work availably evaluated the functional consequences of some missense mutations not previously determined in the hMLH1 gene and might be useful for the clinical diagnosis of hereditary gastrointestinal cancer, especially in East Asians.
authors: Department of Medical Genetics, Medical School, Nanjing University, Nanjing, China.
authors: Yimei
authors: Y
authors: Fan
authors: Wei
authors: W
authors: Wang
authors: Ming
authors: M
authors: Zhu
authors: Jiji
authors: J
authors: Zhou
authors: Jingyuan
authors: J
authors: Peng
authors: Lizhi
authors: L
authors: Xu
authors: Zichun
authors: Z
authors: Hua
authors: Xiang
authors: X
authors: Gao
authors: Yaping
authors: Y
authors: Wang
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000328:Adult; D044466:Asian People / Q000235:genetics; D015153:Blotting, Western; D002681:China; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics*; D004252:DNA Mutational Analysis; D020022:Genetic Predisposition to Disease; D006801:Humans; D047468:Immunoprecipitation; D000070957:MutL Protein Homolog 1; D020125:Mutation, Missense; D009687:Nuclear Proteins / Q000235:genetics*; D020798:Two-Hybrid System Techniques
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C501486:MLH1 protein, human; D009687:Nuclear Proteins; D000070957:MutL Protein Homolog 1