Referenced in: none

Automatically associated channels: ClC4 , ClC5

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

Authors: Teddy Grand, David Mordasini, Sébastien L'Hoste, Thomas Pennaforte, Mathieu Genete, Marie-Jeanne Biyeyeme, Rosa Vargas-Poussou, Anne Blanchard, Jacques Teulon, Stéphane Lourdel

Journal, date & volume: Kidney Int., 2009 Nov , 76, 999-1005

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/19657328

Abstract
Dent's disease is an X-linked recessive disorder affecting the proximal tubules and is frequently associated with mutations in CLCN5, which encodes the electrogenic chloride-proton exchanger ClC-5. To better understand the functional consequences of CLCN5 mutations in this disease, we screened four newly identified missense mutations (G179D, S203L, G212A, L469P), one new nonsense mutation (R718X), and three known mutations (L200R, C219R, and C221R), in Xenopus laevis oocytes and HEK293 cells expressing either wild-type or mutant exchanger. A type-I mutant (G212A) trafficked normally to the cell surface and to early endosomes, underwent complex glycosylation at the cell surface like wild-type ClC-5, but exhibited significant reductions in outwardly rectifying ion currents. The type-II mutants (G179D, L200R, S203L, C219R, C221R, L469P, and R718X) were improperly N-glycosylated and were non-functional due to retention in the endoplasmic reticulum. Thus these mutations have distinct mechanisms by which they could impair ClC-5 function in Dent's disease.