Genetic analyses in dent disease and characterization of CLCN5 mutations in kidney biopsies

Dent Disease Italian Network, Lisa Gianesello, Monica Ceol, Loris Bertoldi, Liliana Terrin, Giovanna Priante, Luisa Murer, Licia Peruzzi, Mario Giordano, Fabio Paglialonga, Vincenzo Cantaluppi, Claudio Musetti, Giorgio Valle, Dorella Del Prete, Franca Anglani

Research output: Contribution to journalArticlepeer-review


Dent disease (DD), an X‐linked renal tubulopathy, is mainly caused by loss‐of‐function mutations in CLCN5 (DD1) and OCRL genes. CLCN5 encodes the ClC‐5 antiporter that in proximal tubules (PT) participates in the receptor‐mediated endocytosis of low molecular weight proteins. Few studies have analyzed the PT expression of ClC‐5 and of megalin and cubilin receptors in DD1 kidney biopsies. About 25% of DD cases lack mutations in either CLCN5 or OCRL genes (DD3), and no other disease genes have been discovered so far. Sanger sequencing was used for CLCN5 gene analysis in 158 unrelated males clinically suspected of having DD. The tubular expression of ClC‐5, megalin, and cubilin was assessed by immunolabeling in 10 DD1 kidney biopsies. Whole exome sequencing (WES) was performed in eight DD3 patients. Twenty‐three novel CLCN5 mutations were identified. ClC‐5, megalin, and cubilin were significantly lower in DD1 than in control biopsies. The tubular expression of ClC‐5 when detected was irrespective of the type of mutation. In four DD3 patients, WES revealed 12 potentially pathogenic variants in three novel genes (SLC17A1, SLC9A3, and PDZK1), and in three genes known to be associated with monogenic forms of renal proximal tubulopathies (SLC3A, LRP2, and CUBN). The supposed third Dent disease-causing gene was not discovered.

Original languageEnglish
Article number516
JournalInternational Journal of Molecular Sciences
Issue number2
Publication statusPublished - Jan 2 2020


  • CLCN5 gene mutations
  • Cubilin
  • Dent disease
  • Immunohistochemistry
  • Kidney biopsies
  • Megalin
  • Proximal tubular ClC‐5 expression
  • Whole exome sequencing

ASJC Scopus subject areas

  • Catalysis
  • Molecular Biology
  • Spectroscopy
  • Computer Science Applications
  • Physical and Theoretical Chemistry
  • Organic Chemistry
  • Inorganic Chemistry


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