title: Screening the 3' region of the polycystic kidney disease 1 (PKD1) gene reveals six novel mutations.
abstract: Recently, the gene for the most common form of autosomal dominant polycystic kidney disease (ADPKD), PKD1 (polycystic kidney disease 1), has been fully characterized and shown to encode an integral membrane protein, polycystin, involved in cell-cell and/or cell-matrix interactions. Study of the PKD1 gene has been complicated because most of the gene lies in a genomic region reiterated several times elsewhere on the same chromosome, and consequently only seven mutations have been described so far. Here we report a systematic screen covering approximately 80% of the approximately 2.75 kb of translated transcript that is encoded by single-copy DNA. We have identified and characterized six novel mutations that, together with the previously described changes, amount to a detection rate of 10%-15% in the population studied. The newly described mutations are two deletions, an insertion of a T-nucleotide causing a frame shift, two single-base-pair substitutions resulting in premature stop codons, and a G-->C transversion that may be a missense mutation. These results have important implications for genetic diagnosis of PKD1 because they indicate that the majority of mutations lie within the duplicated area, which is difficult to study. The regions of polycystin removed in each mutation so far described are assessed for their functional significance; an area disrupted by two new small in-frame changes is highlighted. PKD1 mutations are contrasted with those in the PKD1/TSC2 contiguous-gene syndrome, and the likely mutational mechanism in PKD1 is considered.
authors.affiliation: MRC Molecular Haematology Unit, Institute of Molecular Medicine, John Radcliffe Hospital, Headington, Oxford, United Kingdom.
authors.forename: B
authors.initials: B
authors.lastname: Peral
authors.forename: J L
authors.initials: JL
authors.lastname: San Millán
authors.forename: A C
authors.initials: AC
authors.lastname: Ong
authors.forename: V
authors.initials: V
authors.lastname: Gamble
authors.forename: C J
authors.initials: CJ
authors.lastname: Ward
authors.forename: C
authors.initials: C
authors.lastname: Strong
authors.forename: P C
authors.initials: PC
authors.lastname: Harris
mesh_terms: D017398:Alternative Splicing; D001483:Base Sequence; D017931:DNA Primers; D005091:Exons; D005260:Female; D016368:Frameshift Mutation; D006801:Humans; D007438:Introns; D007676:Kidney Failure, Chronic / Q000453:epidemiology / Q000235:genetics; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D017354:Point Mutation; D016891:Polycystic Kidney, Autosomal Dominant / Q000235:genetics*; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D018807:Polymorphism, Single-Stranded Conformational; D014176:Protein Biosynthesis; D017433:Protein Structure, Secondary; D011506:Proteins / Q000737:chemistry / Q000235:genetics*; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000737:chemistry; D017384:Sequence Deletion; D050396:TRPP Cation Channels
chemical_list: D017931:DNA Primers; D011506:Proteins; D011994:Recombinant Proteins; D050396:TRPP Cation Channels