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Review
. 2020 Jul 15:747:144662.
doi: 10.1016/j.gene.2020.144662. Epub 2020 Apr 11.

From protein uptake to Dent disease: An overview of the CLCN5 gene

Lisa Gianesello  1 , Dorella Del Prete  2 , Monica Ceol  3 , Giovanna Priante  4 , Lorenzo Arcangelo Calò  5 , Franca Anglani  6
Affiliations
Review

From protein uptake to Dent disease: An overview of the CLCN5 gene

Lisa Gianesello et al. Gene. .

Abstract

Proteinuria is a well-known risk factor, not only for renal disorders, but also for several other problems such as cardiovascular diseases and overall mortality. In the kidney, the chloride channel Cl-/H+ exchanger ClC-5 encoded by the CLCN5 gene is actively involved in preventing protein loss. This action becomes evident in patients suffering from the rare proximal tubulopathy Dent disease because they carry a defective ClC-5 due to CLCN5 mutations. In fact, proteinuria is the distinctive clinical sign of Dent disease, and mainly involves the loss of low-molecular-weight proteins. The identification of CLCN5 disease-causing mutations has greatly improved our understanding of ClC-5 function and of the ClC-5-related physiological processes in the kidney. This review outlines current knowledge regarding the CLCN5 gene and its protein product, providing an update on ClC-5 function in tubular and glomerular cells, and focusing on its relationship with proteinuria and Dent disease.

Keywords: ClC-5; ClC-5 mutant proteins; Endocytosis; Kidney; Podocytes; Proximal tubular cells.

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Conflict of interest statement

Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Figures

Fig. 1.
Fig. 1.. ClC-5 protein structure.
Schematic representation of the ClC-5 protein showing the 18 alpha-helixes (from A to R), the two CBS domains, and the main glycosylation site.
Fig. 2.
Fig. 2.. ClC-5 and its protein partners.
ClC-5 is involved in two different processes conducted by PTCs: the endocytosis of low-molecular-weight proteins (A); and endosomal-lysosomal acidification (B). These two processes are closely connected, and require collaboration between ClC-5 and several other actors with distinctive features.
Fig. 3.
Fig. 3.. ClC-5 expression in the kidney.
ClC-5 is expressed in various tubular segments (proximal tubule, thick ascending limb of Henle’s loop, alpha-intercalated cells of the collecting duct), and in glomerular cells (podocytes and parietal epithelial cells [PECs]).
Fig. 4.
Fig. 4.. Distribution of CLCN5 gene mutations.
The graph shows the pro-portions of the different CLCN5 mutations identified. Other: Alu insertion and 5′UTR mutations.
Fig. 5.
Fig. 5.. Dent disease 1, clinical phenotype.
DD1 is associated with the variable presence of a number of clinical signs.
See this image and copyright information in PMC

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