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

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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.

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Acknowledgements

Work in our laboratories was funded in part by grants from the French ANR program (ANR-05-MRAR-033-01), the Fondation du Rein and ECOS Conicyt C10S03. CECs is funded by Conicyt PFB. The English text has been edited by M. Ghosh.

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Authors and Affiliations

  1. UPMC Univ Paris 06, UMR_S 872, Laboratoire de génomique, physiologie et physiopathologie rénales, 75005, Paris, France

    Stéphane Lourdel, Teddy Grand & Jacques Teulon

  2. INSERM, UMR_S 872, Laboratoire de génomique, physiologie et physiopathologie rénales, 75005, Paris, France

    Stéphane Lourdel, Teddy Grand & Jacques Teulon

  3. CNRS, ERL 7226, Laboratoire de génomique, physiologie et physiopathologie rénales, 75005, Paris, France

    Stéphane Lourdel, Teddy Grand & Jacques Teulon

  4. Centro de Estudios Científicos (CECs), Valdivia, 5110466, Chile

    Johanna Burgos & Francisco V. Sepúlveda

  5. Centro de Bioinformática y Simulación Molecular, Universidad de Talca, Talca, Chile

    Wendy González

  6. UMR_S 872, ERL 7226, Laboratoire de génomique, physiologie et physiopathologie rénales, 15 rue de l’Ecole de Médecine, 75270, Paris cedex 06, France

    Stéphane Lourdel

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Lourdel, S., Grand, T., Burgos, J. et al. ClC-5 mutations associated with Dent’s disease: a major role of the dimer interface. Pflugers Arch - Eur J Physiol 463, 247–256 (2012). https://doi.org/10.1007/s00424-011-1052-0

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