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Heterogeneity in the processing of ClC-5 mutants related to Dent disease

Abstract : Mutations in the electrogenic Cl-/H+ exchanger ClC-5 gene CLCN5 are frequently associated with Dent disease, an X-linked recessive disorder affecting the proximal tubules. Here, we investigate the consequences in X. laevis oocytes and in HEK293 cells of 9 previously reported, pathogenic, missense mutations of ClC-5, most of them which are located in regions forming the subunit interface. Two mutants trafficked normally to the cell surface and to early endosomes, and displayed complex glycosylation at the cell surface like wild-type ClC 5, but exhibited reduced currents. Three mutants displayed improper N-glycosylation, and were non-functional due to being retained and degraded at the endoplasmic reticulum. Functional characterization of four mutants allowed us to identify a novel mechanism leading to ClC-5 dysfunction in Dent disease. We report that these mutant proteins were delayed in their processing and that the stability of their complex glycosylated form was reduced, causing lower cell surface expression. The early endosome distribution of these mutants was normal. Half of these mutants displayed reduced currents, whereas the other half showed abolished currents. Our study revealed distinct cellular mechanisms accounting for ClC-5 loss-of-function in Dent disease.
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Submitted on : Thursday, September 15, 2011 - 10:48:34 AM
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Teddy Grand, Sébastien l'Hoste, David Mordasini, Nadia Defontaine, Mathilde Keck, et al.. Heterogeneity in the processing of ClC-5 mutants related to Dent disease. Human Mutation, Wiley, 2011, 32 (4), pp.476. ⟨10.1002/humu.21467⟩. ⟨hal-00623788⟩



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