title: Contribution of large genomic rearrangements in Italian Lynch syndrome patients: characterization of a novel alu-mediated deletion.
abstract: Lynch syndrome is associated with germ-line mutations in the DNA mismatch repair (MMR) genes, mainly MLH1 and MSH2. Most of the mutations reported in these genes to date are point mutations, small deletions, and insertions. Large genomic rearrangements in the MMR genes predisposing to Lynch syndrome also occur, but the frequency varies depending on the population studied on average from 5 to 20%. The aim of this study was to examine the contribution of large rearrangements in the MLH1 and MSH2 genes in a well-characterised series of 63 unrelated Southern Italian Lynch syndrome patients who were negative for pathogenic point mutations in the MLH1, MSH2, and MSH6 genes. We identified a large novel deletion in the MSH2 gene, including exon 6 in one of the patients analysed (1.6% frequency). This deletion was confirmed and localised by long-range PCR. The breakpoints of this rearrangement were characterised by sequencing. Further analysis of the breakpoints revealed that this rearrangement was a product of Alu-mediated recombination. Our findings identified a novel Alu-mediated rearrangement within MSH2 gene and showed that large deletions or duplications in MLH1 and MSH2 genes are low-frequency mutational events in Southern Italian patients with an inherited predisposition to colon cancer.
authors.affiliation: Dipartmento di Biochimica e Biotecnologie Mediche, Università degli Studi di Napoli Federico II, Via Pansini, 5 80131 Napoli, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Duraturo
authors.forename: Angela
authors.initials: A
authors.lastname: Cavallo
authors.forename: Raffaella
authors.initials: R
authors.lastname: Liccardo
authors.forename: Bianca
authors.initials: B
authors.lastname: Cudia
authors.forename: Marina
authors.initials: M
authors.lastname: De Rosa
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Diana
authors.forename: Paola
authors.initials: P
authors.lastname: Izzo
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D020087:Alu Elements; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000453:epidemiology / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics; D005260:Female; D015321:Gene Rearrangement; D006801:Humans; D007558:Italy / Q000453:epidemiology; D008297:Male; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D017384:Sequence Deletion
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; C094443:G-T mismatch-binding protein; C501486:MLH1 protein, human; D009687:Nuclear Proteins; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein