title: A homozygous germ-line mutation in the human MSH2 gene predisposes to hematological malignancy and multiple café-au-lait spots.
abstract: Individuals with a germ-line mutation in one of the DNA mismatch repair (MMR) genes are at significant risk for colorectal cancer and other tumors. Three families have previously been reported with individuals homozygous for mutations in the MMR gene MLH1 that are predicted to compromise MMR. These individuals develop hematological malignancies and/or neurofibromatosis type 1 at an early age. Here, in an individual, we demonstrate that a homozygous novel mutation in the MMR gene MSH2 is associated with leukemia and multiple café-au-lait spots, a feature of neurofibromatosis type 1. Because the hematological malignancies observed in the individuals homozygous for the loss of MMR are reflective of the lymphomas seen in mice lacking MMR, the mice may provide a useful model for human neoplasia.
authors.affiliation: Department of Medical Genetics, University of Alberta, Edmonton, Alberta, T6G 2H7 Canada.
authors.forename: Darcy
authors.initials: D
authors.lastname: Whiteside
authors.forename: Ross
authors.initials: R
authors.lastname: McLeod
authors.forename: Gail
authors.initials: G
authors.lastname: Graham
authors.forename: Jamie L
authors.initials: JL
authors.lastname: Steckley
authors.forename: Karen
authors.initials: K
authors.lastname: Booth
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Somerville
authors.forename: Susan E
authors.initials: SE
authors.lastname: Andrew
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D020137:Base Pair Mismatch; D019080:Cafe-au-Lait Spots / Q000235:genetics*; D002352:Carrier Proteins; D002675:Child, Preschool; D004260:DNA Repair; D004268:DNA-Binding Proteins; D005091:Exons / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006801:Humans; D008297:Male; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D009363:Neoplasm Proteins / Q000235:genetics; D009456:Neurofibromatosis 1 / Q000235:genetics; D009687:Nuclear Proteins; D010375:Pedigree; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics*; D011518:Proto-Oncogene Proteins / Q000235:genetics*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C501486:MLH1 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein