title: CLCN5 chloride-channel mutations in six new North American families with X-linked nephrolithiasis.
abstract: BACKGROUND
  X-linked nephrolithiasis, or Dent's disease, encompasses several clinical syndromes of low molecular weight (LMW) proteinuria, hypercalciuria, nephrocalcinosis, nephrolithiasis, and renal failure, and is associated with mutations in the CLCN5 gene encoding a kidney-specific voltage-gated chloride channel. Some patients from Europe have rickets, and all symptomatic patients confirmed by mutation analysis have been male.
  
  
  METHODS
  We analyzed the CLCN5 DNA sequence in six new families with this disease.
  
  
  RESULTS
  In three probands, a single-base substitution yielded a nonsense triplet at codons 28, 34, and 343, respectively, and in two families, one of which was Hispanic, we found single-base deletions at codons 40 and 44, leading to premature termination of translation. In the sixth family, a single-base change from C to T predicted substitution of leucine for serine at codon 244, previously reported in two European families with prominent rickets, though this patient of Ashkenazi origin did not have rickets. Each of these mutations was confirmed by restriction endonuclease analysis, or repeat sequencing and CFLP. The R34X mutation occurred in a Canadian infant with severe rickets. The family with the R28X nonsense mutation included one woman with recurrent kidney stones and another woman with glomerular sclerosis. In another family, a woman heterozygous for the W343X mutation also had nephrolithiasis.
  
  
  CONCLUSIONS
  These studies expand the range of mutations identified in this disease, and broaden the phenotypic range to include clinically affected women and the first North American case with severe rickets.
authors.affiliation: Department of Medicine, SUNY Health Science Center, Syracuse, New York 13210, USA.
authors.forename: R R
authors.initials: RR
authors.lastname: Hoopes
authors.forename: P A
authors.initials: PA
authors.lastname: Hueber
authors.forename: R J
authors.initials: RJ
authors.lastname: Reid
authors.forename: G L
authors.initials: GL
authors.lastname: Braden
authors.forename: P R
authors.initials: PR
authors.lastname: Goodyer
authors.forename: A R
authors.initials: AR
authors.lastname: Melnyk
authors.forename: J P
authors.initials: JP
authors.lastname: Midgley
authors.forename: D I
authors.initials: DI
authors.lastname: Moel
authors.forename: A M
authors.initials: AM
authors.lastname: Neu
authors.forename: S K
authors.initials: SK
authors.lastname: VanWhy
authors.forename: S J
authors.initials: SJ
authors.lastname: Scheinman
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000595:Amino Acid Sequence; D002648:Child; D018118:Chloride Channels / Q000235:genetics*; D005260:Female; D008040:Genetic Linkage; D006801:Humans; D007669:Kidney Calculi / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D014960:X Chromosome
chemical_list: C097503:CLC-5 chloride channel; D018118:Chloride Channels