title: Mutational analysis of CLC-5, cofilin and CLC-4 in patients with Dent's disease.
abstract: OBJECTIVE
  Dent's disease is caused by mutations in the chloride/proton antiporter, CLC-5, or oculo-cerebro-renal-syndrome-of-Lowe (OCRL1) genes.
  
  
  METHODS
  Eighteen probands with Dent's disease were investigated for mutations in CLC-5 and two of its interacting proteins, CLC-4 and cofilin. Wild-type and mutant CLC-5s were assessed in kidney cells. Urinary calcium excretion following an oral calcium challenge was studied in one family.
  
  
  RESULTS
  Seven different CLC-5 mutations consisting of two nonsense mutations (Arg347Stop and Arg718Stop), two missense mutations (Ser244Leu and Arg516Trp), one intron 3 donor splice site mutation, one deletion-insertion (nt930delTCinsA) and an in-frame deletion (523delVal) were identified in 8 patients. In the remaining 10 patients, DNA sequence abnormalities were not detected in the coding regions of CLC-4 or cofilin, and were independently excluded for OCRL1. Patients with CLC-5 mutations were phenotypically similar to those without. The donor splice site CLC-5 mutation resulted in exon 3 skipping. Electrophysiology demonstrated that the 523delVal CLC-5 mutation abolished CLC-5-mediated chloride conductance. Sixty percent of women with the CLC-5 deletion-insertion had nephrolithiasis, although calcium excretion before and after oral calcium challenge was similar to that in unaffected females.
  
  
  CONCLUSIONS
  Three novel CLC-5 mutations were identified, and mutations in OCRL1, CLC-4 and cofilin excluded in causing Dent's disease in this patient cohort.
authors: Nuffield Department of Clinical Medicine, Academic Endocrine Unit, University of Oxford, and Churchill Hospital, Oxford Centre for Diabetes, Endocrinology and Metabolism, Oxford, UK.
authors: Fiona
authors: F
authors: Wu
authors: Anita A C
authors: AA
authors: Reed
authors: Sian E
authors: SE
authors: Williams
authors: Nellie Y
authors: NY
authors: Loh
authors: Jonathan D
authors: JD
authors: Lippiat
authors: Paul T
authors: PT
authors: Christie
authors: Oliver
authors: O
authors: Large
authors: Alberto
authors: A
authors: Bettinelli
authors: Michael J
authors: MJ
authors: Dillon
authors: Noemia P
authors: NP
authors: Goldraich
authors: Bernd
authors: B
authors: Hoppe
authors: Karl
authors: K
authors: Lhotta
authors: Chantal
authors: C
authors: Loirat
authors: Rayaz
authors: R
authors: Malik
authors: Delphine
authors: D
authors: Morel
authors: Peter
authors: P
authors: Kotanko
authors: Bernard
authors: B
authors: Roussel
authors: Dvora
authors: D
authors: Rubinger
authors: Connie
authors: C
authors: Schrander-Stumpel
authors: Erkin
authors: E
authors: Serdaroglu
authors: M Andrew
authors: MA
authors: Nesbit
authors: Frances
authors: F
authors: Ashcroft
authors: Rajesh V
authors: RV
authors: Thakker
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D002118:Calcium / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000652:urine; D002460:Cell Line; D018118:Chloride Channels / Q000235:genetics* / Q000502:physiology; D018389:Codon, Nonsense; D051338:Cofilin 1 / Q000235:genetics*; D004252:DNA Mutational Analysis; D004594:Electrophysiology; D005260:Female; D040181:Genetic Diseases, X-Linked / Q000235:genetics / Q000503:physiopathology; D006801:Humans; D007674:Kidney Diseases / Q000235:genetics* / Q000503:physiopathology; D008297:Male; D016254:Mutagenesis, Insertional; D009154:Mutation; D020125:Mutation, Missense; D010375:Pedigree; D017384:Sequence Deletion; D014162:Transfection
chemical_list: C495810:CFL1 protein, human; C097503:CLC-5 chloride channel; C484312:CLCN4 protein, human; D018118:Chloride Channels; D018389:Codon, Nonsense; D051338:Cofilin 1; D002118:Calcium