Mutation Update of the CLCN5 Gene Responsible for Dent Disease 1

Lamisse Mansour-Hendili, Anne Blanchard, Nelly Le Pottier, Isabelle Roncelin, Stéphane Lourdel, Cyrielle Treard, Wendy González, Ariela Vergara-Jaque, Gilles Morin, Estelle Colin, Muriel Holder-Espinasse, Justine Bacchetta, Véronique Baudouin, Stéphane Benoit, Etienne Bérard, Guylhène Bourdat-Michel, Karim Bouchireb, Stéphane Burtey, Mathilde Cailliez, Gérard Cardon, Claire Cartery, Gerard Champion, Dominique Chauveau, Pierre Cochat, Karin Dahan, Renaud De la Faille, François-Guillaume Debray, Laurenne Dehoux, Georges Deschenes, Estelle Desport, Olivier Devuyst, Stella Dieguez, Francesco Emma, Michel Fischbach, Denis Fouque, Jacques Fourcade, Hélène François, Brigitte Gilbert-Dussardier, Thierry Hannedouche, Pascal Houillier, Hassan Izzedine, Marco Janner, Alexandre Karras, Bertrand Knebelmann, Marie-Pierre Lavocat, Sandrine Lemoine, Valérie Leroy, Chantal Loirat, Marie-Alice Macher, Dominique Martin-Coignard, Denis Morin, Patrick Niaudet, Hubert Nivet, François Nobili, Robert Novo, Laurence Faivre, Claire Rigothier, Gwenaëlle Roussey-Kesler, Remi Salomon, Andreas Schleich, Anne-Laure Sellier-Leclerc, Kenza Soulami, Aurélien Tiple, Tim Ulinski, Philippe Vanhille, Nicole Van Regemorter, Xavier Jeunemaître, Rosa Vargas-Poussou
Human Mutation 2015, 36 (8): 743-52
Dent disease is a rare X-linked tubulopathy characterized by low molecular weight proteinuria, hypercalciuria, nephrocalcinosis and/or nephrolithiasis, progressive renal failure, and variable manifestations of other proximal tubule dysfunctions. It often progresses over a few decades to chronic renal insufficiency, and therefore molecular characterization is important to allow appropriate genetic counseling. Two genetic subtypes have been described to date: Dent disease 1 is caused by mutations of the CLCN5 gene, coding for the chloride/proton exchanger ClC-5; and Dent disease 2 by mutations of the OCRL gene, coding for the inositol polyphosphate 5-phosphatase OCRL-1. Herein, we review previously reported mutations (n = 192) and their associated phenotype in 377 male patients with Dent disease 1 and describe phenotype and novel (n = 42) and recurrent mutations (n = 24) in a large cohort of 117 Dent disease 1 patients belonging to 90 families. The novel missense and in-frame mutations described were mapped onto a three-dimensional homology model of the ClC-5 protein. This analysis suggests that these mutations affect the dimerization process, helix stability, or transport. The phenotype of our cohort patients supports and extends the phenotype that has been reported in smaller studies.

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