title: hMLH1 mutations in hereditary nonpolyposis colorectal cancer kindreds. Mutations in brief no. 182. Online.
abstract: Hereditary nonpolyposis colorectral cancer (HNPCC), an autosomal dominantly inherited predisposition for early onset colorectal cancer, accounts for at least 6% of all colorectal malignancies. HNPCC results from germ-line mutations in DNA mismatch repair (MMR) genes (hMSH2, hMLH1, hPMS1 and hPMS2) and is associated with a high rate of replication errors in tumor cells. Using PCR-SSCP, the protein truncation test and DNA sequencing we have analyzed the hMSH2 and hMLH1 genes in 10 Italian families that met the standard diagnostic criteria for HNPCC. We have identified three new mutations in the hMLH1 gene. One mutation consists in a deletion of one base pair at nucleotide 954 (954delC) in exon 11 that creates an early stop at codon 366 and is predicted to abolish normal protein function. The other two are missense mutations. Cys77Arg and Ser193Pro, that cause dramatic amino acid substitutions in two highly conserved MLH domains. The Cys77Arg mutation occurs within a domain (1-114 residues) that is very critical for MMR function. The Ser193Pro mutation occurs in a highly conserved central region of the MLH1 protein. No functional domains have yet been identified in this region. All mutant alleles cosegregate with the cancer phenotype.
authors.affiliation: Dipartimento di Biochimica e Biotecnologie Mediche, CEINGE-Biotechologie Avanzate, Universitá degli Studi "Fdererico II", Via S. Pansini 5, 80131 Naples, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Panariello
authors.forename: M I
authors.initials: MI
authors.lastname: Scarano
authors.forename: M
authors.initials: M
authors.lastname: de Rosa
authors.forename: L
authors.initials: L
authors.lastname: Capasso
authors.forename: A
authors.initials: A
authors.lastname: Renda
authors.forename: G
authors.initials: G
authors.lastname: Riegler
authors.forename: G B
authors.initials: GB
authors.lastname: Rossi
authors.forename: F
authors.initials: F
authors.lastname: Salvatore
authors.forename: P
authors.initials: P
authors.lastname: Izzo
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D020137:Base Pair Mismatch / Q000235:genetics; D002352:Carrier Proteins; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics*; D006801:Humans; D000070957:MutL Protein Homolog 1; D009154:Mutation / Q000235:genetics*; D009363:Neoplasm Proteins / Q000235:genetics*; D009687:Nuclear Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; C501486:MLH1 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D000070957:MutL Protein Homolog 1