title: Renal chloride channel, CLCN5, mutations in Dent's disease.
abstract: Dent's disease is an X-linked renal tubular disorder characterized by low-molecular-weight proteinuria, hypercalciuria, nephrocalcinosis, nephrolithiasis, and renal failure. Patients with Dent's disease may also suffer from rickets and other features of the renal Fanconi Syndrome. Patients may have mutations in the X-linked renal chloride channel gene, CLCN5, which encodes a 746-amino-acid protein with 12-13 transmembrane domains. We have investigated the 11 coding exons of CLCN5 for mutations in eight unrelated patients with Dent's disease. Leukocyte DNA was used for the polymerase chain reaction amplification of CLCN5 and the products analyzed for single-stranded conformational polymorphisms (SSCPs). Abnormal SSCPs were sequenced and revealed eight mutations. These consisted of three nonsense mutations (Arg34Stop, Arg648Stop, Arg704Stop), four deletions involving codons 40, 86, 157, and 241, and one acceptor splice consensus sequence mutation tgcag --> tgaag. The mutations were confirmed either by restriction endonuclease or sequence-specific oligonucleotide hybridization analysis. In addition, an analysis of 110 alleles from 74 unrelated normal individuals demonstrated that the DNA sequence changes were not common polymorphisms. All of the mutations predict truncated chloride channels that are likely to result in a functional loss. Thus, our findings expand the spectrum of CLCN5 mutations associated with Dent's disease and the results will help to elucidate further the functional domains of this novel chloride channel.
authors.affiliation: MRC Molecular Endocrinology Group, MRC Clinical Sciences Center, Imperial College School of Medicine, Hammersmith Hospital, London, United Kingdom.
authors.forename: J P
authors.initials: JP
authors.lastname: Cox
authors.forename: K
authors.initials: K
authors.lastname: Yamamoto
authors.forename: P T
authors.initials: PT
authors.lastname: Christie
authors.forename: C
authors.initials: C
authors.lastname: Wooding
authors.forename: T
authors.initials: T
authors.lastname: Feest
authors.forename: F A
authors.initials: FA
authors.lastname: Flinter
authors.forename: P R
authors.initials: PR
authors.lastname: Goodyer
authors.forename: E
authors.initials: E
authors.lastname: Leumann
authors.forename: T
authors.initials: T
authors.lastname: Neuhaus
authors.forename: C
authors.initials: C
authors.lastname: Reid
authors.forename: P F
authors.initials: PF
authors.lastname: Williams
authors.forename: O
authors.initials: O
authors.lastname: Wrong
authors.forename: R V
authors.initials: RV
authors.lastname: Thakker
mesh_terms: D000595:Amino Acid Sequence; D018118:Chloride Channels / Q000737:chemistry / Q000235:genetics*; D005198:Fanconi Syndrome / Q000235:genetics*; D005260:Female; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D016133:Polymerase Chain Reaction; D018807:Polymorphism, Single-Stranded Conformational; D017433:Protein Structure, Secondary
chemical_list: C097503:CLC-5 chloride channel; D018118:Chloride Channels