Pflügers Archiv - European Journal of Physiology

, Volume 463, Issue 2, pp 247–256

ClC-5 mutations associated with Dent’s disease: a major role of the dimer interface

  • Stéphane Lourdel
  • Teddy Grand
  • Johanna Burgos
  • Wendy González
  • Francisco V. Sepúlveda
  • Jacques Teulon
Invited Review

DOI: 10.1007/s00424-011-1052-0

Cite this article as:
Lourdel, S., Grand, T., Burgos, J. et al. Pflugers Arch - Eur J Physiol (2012) 463: 247. doi:10.1007/s00424-011-1052-0

Abstract

Dent’s disease is an X-linked recessive disorder affecting the proximal tubules. Mutations in the 2Cl/H+ exchanger ClC-5 gene CLCN5 are frequently associated with Dent’s disease. Functional characterization of mutations of CLCN5 have helped to elucidate the physiopathology of Dent’s disease and provided evidence that several different mechanisms underlie the ClC-5 dysfunction in Dent’s disease. Modeling studies indicate that many CLCN5 mutations are located at the interface between the monomers of ClC-5, demonstrating that this protein region plays an important role in Dent’s disease. On the basis of functional data, CLCN5 mutations can be divided into three different classes. Class 1 mutations impair processing and folding, and as a result, the ClC-5 mutants are retained within the endoplasmic reticulum and targeted for degradation by quality control mechanisms. Class 2 mutations induce a delay in protein processing and reduce the stability of ClC-5. As a consequence, the cell surface expression and currents of the ClC-5 mutants are lower. Class 3 mutations do not alter the trafficking of ClC-5 to the cell surface and early endosomes but induce altered electrical activity. Here, we discuss the functional consequences of the three classes of CLCN5 mutations on ClC-5 structure and function.

Keywords

Dent’s diseaseChloride/proton exchangerCLCN5ClC-5Mutation

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Stéphane Lourdel
    • 1
    • 2
    • 3
    • 6
  • Teddy Grand
    • 1
    • 2
    • 3
  • Johanna Burgos
    • 4
  • Wendy González
    • 5
  • Francisco V. Sepúlveda
    • 4
  • Jacques Teulon
    • 1
    • 2
    • 3
  1. 1.UPMC Univ Paris 06, UMR_S 872Laboratoire de génomique, physiologie et physiopathologie rénalesParisFrance
  2. 2.INSERM, UMR_S 872Laboratoire de génomique, physiologie et physiopathologie rénalesParisFrance
  3. 3.CNRS, ERL 7226Laboratoire de génomique, physiologie et physiopathologie rénalesParisFrance
  4. 4.Centro de Estudios Científicos (CECs)ValdiviaChile
  5. 5.Centro de Bioinformática y Simulación MolecularUniversidad de TalcaTalcaChile
  6. 6.UMR_S 872, ERL 7226Laboratoire de génomique, physiologie et physiopathologie rénalesParis cedex 06France