title: Phenotypic and genetic heterogeneity in Dent's disease--the results of an Italian collaborative study.
abstract: BACKGROUND
  Dent's disease is an inherited tubulopathy caused by CLCN5 gene mutations. While a typical phenotype characterized by low-molecular-weight (LMW) proteinuria, hypercalciuria, nephrocalcinosis, nephrolithiasis, rickets and progressive renal failure in various combinations often enables a clinical diagnosis, less severe sub-clinical cases may go under-diagnosed.
  
  
  METHODS
  By single-strand conformation polymorphism analysis and direct sequencing, we screened 40 male patients from 40 unrelated families for CLCN5 gene mutations. Twenty-four of these patients had the prominent features of Dent's disease, including LMW proteinuria, hypercalciuria and nephrocalcinosis.
  
  
  RESULTS
  We identified 24 mutations in the CLCN5 gene in 21/24 patients with a typical phenotype and in 3/16 patients with a partial clinical picture of Dent's disease. Overall, 10 novel CLCN5 mutations were identified (E6fsX11, W58fsX97, 267 del E, Y272C, N340K, F444fsX448, W547X, Q600X, IVS3 +2 G>C and IVS3 -1 G>A), extending the number of mutations identified so far from 75 to 85. The CLCN5 coding sequence was normal in three patients. In the group with an incomplete Dent's disease phenotype, we detected two intronic mutations and one silent substitution leading to the up regulation of an alternatively spliced isoform.
  
  
  CONCLUSIONS
  Our data confirm the genetic heterogeneity of Dent's disease. In most classic cases, the clinical diagnosis is confirmed by genetic tests.
authors.affiliation: Division of Nephrology, Department of Medical and Surgical Sciences, University of Padua, via Giustiniani, 2 35128 Padova, Italy. enrica.tosetto@unipd.it
authors.forename: Enrica
authors.initials: E
authors.lastname: Tosetto
authors.forename: Gian Marco
authors.initials: GM
authors.lastname: Ghiggeri
authors.forename: Francesco
authors.initials: F
authors.lastname: Emma
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Barbano
authors.forename: Alba
authors.initials: A
authors.lastname: Carrea
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Vezzoli
authors.forename: Rossella
authors.initials: R
authors.lastname: Torregrossa
authors.forename: Marilena
authors.initials: M
authors.lastname: Cara
authors.forename: Gabriele
authors.initials: G
authors.lastname: Ripanti
authors.forename: Anita
authors.initials: A
authors.lastname: Ammenti
authors.forename: Licia
authors.initials: L
authors.lastname: Peruzzi
authors.forename: Luisa
authors.initials: L
authors.lastname: Murer
authors.forename: Ilse Maria
authors.initials: IM
authors.lastname: Ratsch
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Citron
authors.forename: Giovanni
authors.initials: G
authors.lastname: Gambaro
authors.forename: Angela
authors.initials: A
authors.lastname: D'angelo
authors.forename: Franca
authors.initials: F
authors.lastname: Anglani
mesh_terms: D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D018118:Chloride Channels / Q000235:genetics*; D005260:Female; D016368:Frameshift Mutation; D006801:Humans; D007558:Italy / Q000453:epidemiology; D007669:Kidney Calculi / Q000453:epidemiology / Q000235:genetics*; D008297:Male; D010641:Phenotype; D016133:Polymerase Chain Reaction; D018807:Polymorphism, Single-Stranded Conformational; D015995:Prevalence; D012313:RNA / Q000235:genetics*
chemical_list: C097503:CLC-5 chloride channel; D018118:Chloride Channels; D012313:RNA