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Diversity of functional alterations of the ClC-5 exchanger in the region of the proton glutamate in patients with Dent disease 1
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  • Imène Sakhi,
  • Yohan Bignon,
  • Nadia Frachon,
  • Marguerite Hureaux,
  • Bárbara Arévalo,
  • Wendy González,
  • Rosa Vargas-Poussou,
  • Stéphane Lourdel
Imène Sakhi
Sorbonne Universite
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Yohan Bignon
Université de Paris Centre Universitaire des Saints-Pères
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Nadia Frachon
Sorbonne Universite
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Marguerite Hureaux
Assistance Publique - Hopitaux de Paris
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Bárbara Arévalo
Universidad de Talca
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Wendy González
Universidad de Talca
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Rosa Vargas-Poussou
Assistance Publique-Hôpitaux de Paris
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Stéphane Lourdel
Sorbonne Universite
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Abstract

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.

Peer review status:ACCEPTED

24 Sep 2020Submitted to Human Mutation
26 Sep 2020Submission Checks Completed
26 Sep 2020Assigned to Editor
08 Oct 2020Reviewer(s) Assigned
27 Oct 2020Review(s) Completed, Editorial Evaluation Pending
30 Oct 2020Editorial Decision: Revise Major
04 Feb 20211st Revision Received
05 Feb 2021Submission Checks Completed
05 Feb 2021Assigned to Editor
14 Feb 2021Review(s) Completed, Editorial Evaluation Pending
15 Feb 2021Editorial Decision: Accept