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Novel CLCN5 mutations in patients with Dent's disease result in altered ion currents or impaired exchanger processing

Teddy Grand1, David Mordasini, Sébastien L'Hoste

  • 1UPMC Université Paris 06, UMR 7134, Paris, France.

Kidney International
|August 7, 2009
PubMed

Insights

Dent's disease, caused by CLCN5 mutations, impairs kidney function. Some mutations disrupt chloride-proton exchanger ClC-5 trafficking, while others reduce its ion current activity, explaining disease mechanisms.

Area of Science:

  • Molecular Biology
  • Genetics
  • Nephrology

Background:

  • Dent's disease is an X-linked disorder affecting kidney proximal tubules.
  • Mutations in the CLCN5 gene, encoding the ClC-5 chloride-proton exchanger, are frequently implicated.

Purpose of the Study:

  • To investigate the functional consequences of various CLCN5 mutations in Dent's disease.
  • To elucidate the distinct mechanisms by which these mutations impair ClC-5 function.

Main Methods:

  • Expression of wild-type and mutant ClC-5 in Xenopus laevis oocytes and HEK293 cells.
  • Analysis of protein trafficking, glycosylation, and ion channel activity.

Main Results:

  • Type-I mutant (G212A) showed normal trafficking but reduced ion currents.
  • Type-II mutants exhibited impaired N-glycosylation and endoplasmic reticulum retention, leading to non-functionality.
  • Identified distinct molecular mechanisms for ClC-5 dysfunction.

Conclusions:

  • CLCN5 mutations in Dent's disease lead to ClC-5 dysfunction through distinct pathways.
  • Understanding these mechanisms aids in comprehending disease pathogenesis and potential therapeutic strategies.

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