ABSTRACT
It is difficult to identify genes that predispose to prostate cancer due to late age at diagnosis, presence of phenocopies within high-risk pedigrees and genetic complexity. A genome-wide scan of large, high-risk pedigrees from Utah has provided evidence for linkage to a locus on chromosome 17p. We carried out positional cloning and mutation screening within the refined interval, identifying a gene, ELAC2, harboring mutations (including a frameshift and a nonconservative missense change) that segregate with prostate cancer in two pedigrees. In addition, two common missense variants in the gene are associated with the occurrence of prostate cancer. ELAC2 is a member of an uncharacterized gene family predicted to encode a metal-dependent hydrolase domain that is conserved among eukaryotes, archaebacteria and eubacteria. The gene product bears amino acid sequence similarity to two better understood protein families, namely the PSO2 (SNM1) DNA interstrand crosslink repair proteins and the 73-kD subunit of mRNA 3' end cleavage and polyadenylation specificity factor (CPSF73).
Subject(s)
Chromosomes, Human, Pair 17/genetics , Neoplasm Proteins/genetics , Prostatic Neoplasms/genetics , Amino Acid Sequence , Cloning, Molecular/methods , DNA, Complementary/genetics , Founder Effect , Genetic Linkage , Genetic Predisposition to Disease , Genotype , Humans , Male , Molecular Sequence Data , Mutation, Missense , Pedigree , RNA, Messenger/genetics , Sequence Analysis, DNA , Sequence Homology, Amino Acid , UtahABSTRACT
Breast carcinoma is the most common malignancy among women in developed countries. Because family history remains the strongest single predictor of breast cancer risk, attention has focused on the role of highly penetrant, dominantly inherited genes in cancer-prone kindreds (1). BRCA1 was localized to chromosome 17 through analysis of a set of high-risk kindreds (2), and then identified four years later by a positional cloning strategy (3). BRCA2 was mapped to chromosomal 13q at about the same time (4). Just fifteen months later, Wooster et al. (5) reported a partial BRCA2 sequence and six mutations predicted to cause truncation of the BRCA2 protein. While these findings provide strong evidence that the identified gene corresponds to BRCA2, only two thirds of the coding sequence and 8 out of 27 exons were isolated and screened; consequently, several questions remained unanswered regarding the nature of BRCA2 and the frequency of mutations in 13q-linked families. We have now determined the complete coding sequence and exonic structure of BRCA2 (GenBank accession #U43746), and examined its pattern of expression. Here, we provide sequences for a set of PCR primers sufficient to screen the entire coding sequence of BRCA2 using genomic DNA. We also report a mutational analysis of BRCA2 in families selected on the basis of linkage analysis and/or the presence of one or more cases of male breast cancer. Together with the specific mutations described previously, our data provide preliminary insight into the BRCA2 mutation profile.
Subject(s)
Chromosomes, Human, Pair 13 , Mutation , Neoplasm Proteins/genetics , Transcription Factors/genetics , BRCA2 Protein , Base Sequence , Breast Neoplasms, Male/genetics , Cell Line , Cloning, Molecular , DNA Primers , Exons , Female , Gene Expression , Genetic Linkage , Humans , Male , Molecular Sequence Data , Ovarian Neoplasms/genetics , Polymerase Chain Reaction , Polymorphism, Genetic , Sequence DeletionABSTRACT
Three hundred bacterial strains from positive urine cultures were isolated over a 10 months period in paediatric hospitalized and out-patients. In addition to commonly used antibiotics, each strain was tested for amoxycillin-clavulanic acid (Augmentin, Beecham) susceptibility. This antibiotic, which is a potent inhibitor of bacterial beta lactamases, may be of interest in the treatment of urinary tract infections because of its pharmacokinetics and activity. The antibacterial activity of amoxycillin and Augmentin against Enterobacteriaceae with special reference to Escherichia coli was compared. The resistance phenotype of Enterobacteriaceae to amoxycillin, carbenicillin and cephalothin allows to anticipate the nature of the beta-lactamase produced by a particular strain, and infer the activity of Augmentin. The overall activity of Augmentin should be interpreted taking into account the resistance phenotypes. In our study, Augmentin was active against 90% of E. coli strains, almost all Proteus mirabilis and vulgaris strains but 9 out of 24 Klebsiella strains were resistant. Augmentin had no activity against nosocomial Enterobacteriaceae, nor against Pseudomonas aeruginosa. On the other hand, its activity was of interest against penicillinase producing Staphylococcus. Our results confirm the interest of Augmentin as a preferential treatment of urinary tract infections in children.
