title: Novel genomic insertion-- deletion in MLH1: possible mechanistic role for non-homologous end-joining DNA repair.
abstract: Hereditary non-polyposis colorectal cancer (HNPCC) is an inherited cancer syndrome caused by a defect in the mismatch repair pathway. The majority of HNPCC mutations have been detected in MLH1 and MSH2. Most reported mutations are substitutions, small insertions and deletions, but standard methods of mutation analysis do not detect large rearrangements. It is now established that large deletions, insertions and rearrangements account for a significant proportion of MLH1 and MSH2 mutations. We report an unusual rearrangement resulting in the deletion of exons 6, 7 and 8 of MLH1, with the retention of part of intron 6 and insertions of two nucleotides each flanking the retained sequence. The 349-bp-retained sequence is made up of two closely spaced Alu sequences. The mutation was initially detected by protein truncation test and cDNA sequencing. Multiplex ligation-dependent probe amplification confirmed the deletion of three exons. PCR and sequencing were used to characterize the breakpoint. Despite the high density of Alu elements in MLH1, there is no homology at the deletion breakpoints or insertion junctions in this case to suggest that homologous recombination has occurred. We propose a mechanism involving non-homologous end joining to explain the occurrence of this complex deletion.
authors.affiliation: Department of Human Genetics, SMBD Jewish General Hospital, McGill University, Quebec, Canada.
authors.forename: S
authors.initials: S
authors.lastname: McVety
authors.forename: R
authors.initials: R
authors.lastname: Younan
authors.forename: L
authors.initials: L
authors.lastname: Li
authors.forename: P H
authors.initials: PH
authors.lastname: Gordon
authors.forename: N
authors.initials: N
authors.lastname: Wong
authors.forename: W D
authors.initials: WD
authors.lastname: Foulkes
authors.forename: G
authors.initials: G
authors.lastname: Chong
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000328:Adult; D001483:Base Sequence; D002352:Carrier Proteins; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics*; D004260:DNA Repair; D018076:DNA, Complementary; D017353:Gene Deletion; D015321:Gene Rearrangement; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D000070957:MutL Protein Homolog 1; D000070956:MutL Proteins; D009363:Neoplasm Proteins / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics; D017385:Sequence Homology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D018076:DNA, Complementary; C501486:MLH1 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; C088996:PMS1 protein, human; D000070957:MutL Protein Homolog 1; D000070956:MutL Proteins