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Article Dans Une Revue Human Mutation Année : 2021

Diversity of functional alterations of the ClC‐5 exchanger in the region of the proton glutamate in patients with Dent disease 1

Résumé

Mutations in the CLCN5 gene encoding the 2Cl- /1H+ exchanger ClC-5 are associated with Dent disease 1, an inherited renal disorder characterized by low molecular weight (LMW) proteinuria and hypercalciuria. In the kidney, ClC-5 is mostly localized in proximal tubule cells where it is thought to play a key role in the endocytosis of LMW proteins. Here, we investigated the consequences of eight previously reported pathogenic missense mutations of ClC-5 surrounding the "proton glutamate" that serves as a crucial H+ -binding site for the exchanger. A complete loss of function was observed for a group of mutants that were either retained in the endoplasmic reticulum of HEK293T cells or unstainable at plasma membrane due to proteasomal degradation. In contrast, the currents measured for a second group of mutations in X. laevis oocytes were reduced. Molecular Dynamics simulations performed on a ClC-5 homology model demonstrated that such mutations may alter ClC-5 protonation by interfering with the water pathway. Analysis of clinical data from patients harboring these mutations demonstrated no phenotype/genotype correlation. This study reveals that mutations clustered in a crucial region of ClC-5 have diverse molecular consequences in patients with Dent disease 1, ranging from altered expression to defects in transport. This article is protected by copyright. All rights reserved.
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Dates et versions

hal-03148953 , version 1 (22-02-2021)

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Imène Sakhi, Yohan Bignon, Nadia Frachon, Marguerite Hureaux, Bárbara Arévalo, et al.. Diversity of functional alterations of the ClC‐5 exchanger in the region of the proton glutamate in patients with Dent disease 1. Human Mutation, 2021, ⟨10.1002/humu.24184⟩. ⟨hal-03148953⟩
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