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

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 the second group of mutations in Xenopus laevis oocytes were reduced. Molecular dynamics simulations performed on a ClC-5 homology model demonstrated that such mutations might 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.

Chloride/proton antiporters ClC3 and ClC5 support bone formation in mice

“…Expression of ClC3 in additional tissues is reported, without detailed characterization; this includes possible function in intestinal epithelium ( Claud et al, 2008 ). In contrast, the association of ClC5 defects with specific kidney defects (Dent disease) is extensively described, although ClC5 is regarded as mainly endosomal ( Zifarelli, 2015 ), ClC5 plasma membrane distribution is described ( Sakhi et al, 2021 ).…”

Functional Characterization of CLCN4 Variants Associated With X-Linked Intellectual Disability and Epilepsy

“…ClC-4 homodimers are mainly found in the endoplasmic reticulum (ER), whereas heterodimerization with ClC-3 targets ClC-4 subunits to recycling and late endosomes/lysosomes ( Guzman et al, 2017 ). ClC-5 is expressed in early endosomes in the kidney, where it regulates endocytic uptake in the proximal tubule ( Jentsch and Pusch, 2018 ; Sakhi et al, 2021 ). ClC-6 and ClC-7 localize to late endosomes and lysosomes ( Jentsch and Pusch, 2018 ).…”