title: Novel truncating mutations in the ClC-5 chloride channel gene in patients with Dent's disease.
abstract: BACKGROUND
  Dent's disease is characterized by low-molecular-weight proteinuria, hypercalciuria, nephrocalcinosis, nephrolithiasis, rickets and eventual renal failure. The disease is caused by mutations in the X-linked chloride channel CLCN5 gene, which encodes a 746-amino-acid protein expressed in renal tubules. These mutations have been reported in unrelated families from the UK, USA, Japan and other countries. We were interested in identifying additional mutations in the CLCN5 coding region of Spanish patients with Dent's disease.
  
  
  METHODS
  Five patients from three unrelated Spanish families were studied. Leukocyte genomic DNA from patients and their relatives was used with CLCN5-specific primers for polymerase chain reaction amplification of the coding region and exon-intron boundaries. Amplified products were analysed by single-strand conformational polymorphism analysis, DNA sequencing and restriction enzyme analysis.
  
  
  RESULTS
  Low-molecular-weight proteinuria and hypercalciuria were detected in all the patients, nephrocalcinosis in two patients, and rickets or osteopenia in three patients. We identified three new CLCN5 mutations consisting of two nonsense mutations, Leu433Stop and Arg718Stop, and an insertional frameshift mutation, 65insT, which results in a stop at codon 98. These three mutations predict truncated ClC-5 proteins that, respectively, lack 314, 649 and 28 amino acids at the carboxy terminus, and are likely to result in loss of function. These mutations were shown to co-segregate with the disease in each of the three families.
  
  
  CONCLUSIONS
  Our study is the first to characterize mutations in the CLCN5 gene in Spanish patients with Dent's disease and expands the spectrum of CLCN5 mutations associated with this disease.
authors.affiliation: Research Unit, Nuestra Señora de Candelaria University Hospital, Santa Cruz de Tenerife, Spain.
authors.forename: Irma
authors.initials: I
authors.lastname: Carballo-Trujillo
authors.forename: Victor
authors.initials: V
authors.lastname: Garcia-Nieto
authors.forename: Francisco J
authors.initials: FJ
authors.lastname: Moya-Angeler
authors.forename: Montserrat
authors.initials: M
authors.lastname: Antón-Gamero
authors.forename: Cesar
authors.initials: C
authors.lastname: Loris
authors.forename: Sebastián
authors.initials: S
authors.lastname: Méndez-Alvarez
authors.forename: Felix
authors.initials: F
authors.lastname: Claverie-Martin
mesh_terms: D000328:Adult; D002648:Child; D002675:Child, Preschool; D018118:Chloride Channels / Q000235:genetics*; D041321:Chromosomes, Human, X; D005198:Fanconi Syndrome / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D005828:Genetics, Population; D006801:Humans; D007223:Infant; D008297:Male; D020125:Mutation, Missense; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017422:Sequence Analysis, DNA; D013030:Spain
chemical_list: C097503:CLC-5 chloride channel; D018118:Chloride Channels