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Mutation Update of the Clcn5 Gene Responsible for Dent Disease 1


Mansour-Hendili, Lamisse; et al (2015). Mutation Update of the Clcn5 Gene Responsible for Dent Disease 1. Human Mutation:743-752.

Abstract

Dent disease is a rare X-linked tubulopathy characterised by low molecular weight proteinuria (LMWP), hypercalciuria, nephrocalcinosis and/or nephrolithiasis, progressive renal failure and variable manifestations of other proximal tubule dysfunctions. It often progresses over a few decades to chronic renal insufficiency, and therefore molecular characterization is important to allow appropriate genetic counselling. Two genetic subtypes have been described to date: Dent disease 1 is caused by mutations of the CLCN5 gene, coding for the chloride/proton exchanger ClC-5; and Dent disease 2 by mutations of the OCRL gene, coding for the inositol polyphosphate 5-phosphatase OCRL-1. Herein, we review previously reported mutations (n = 192) and their associated phenotype in 377 male patients with Dent disease 1 and describe phenotype and novel (n = 42) and recurrent mutations (n = 24) in a large cohort of 117 Dent disease 1 patients belonging to 90 families. The novel missense and in-frame mutations described were mapped onto a three-dimensional homology model of the ClC-5 protein. This analysis suggests that these mutations affect the dimerization process, helix stability or transport. The phenotype of our cohort patients supports and extends the phenotype that has been reported in smaller studies. This article is protected by copyright. All rights reserved.

Abstract

Dent disease is a rare X-linked tubulopathy characterised by low molecular weight proteinuria (LMWP), hypercalciuria, nephrocalcinosis and/or nephrolithiasis, progressive renal failure and variable manifestations of other proximal tubule dysfunctions. It often progresses over a few decades to chronic renal insufficiency, and therefore molecular characterization is important to allow appropriate genetic counselling. Two genetic subtypes have been described to date: Dent disease 1 is caused by mutations of the CLCN5 gene, coding for the chloride/proton exchanger ClC-5; and Dent disease 2 by mutations of the OCRL gene, coding for the inositol polyphosphate 5-phosphatase OCRL-1. Herein, we review previously reported mutations (n = 192) and their associated phenotype in 377 male patients with Dent disease 1 and describe phenotype and novel (n = 42) and recurrent mutations (n = 24) in a large cohort of 117 Dent disease 1 patients belonging to 90 families. The novel missense and in-frame mutations described were mapped onto a three-dimensional homology model of the ClC-5 protein. This analysis suggests that these mutations affect the dimerization process, helix stability or transport. The phenotype of our cohort patients supports and extends the phenotype that has been reported in smaller studies. This article is protected by copyright. All rights reserved.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Physiology
07 Faculty of Science > Institute of Physiology
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Date:23 April 2015
Deposited On:19 Feb 2016 12:17
Last Modified:14 Feb 2018 09:09
Publisher:Wiley-Blackwell Publishing, Inc.
ISSN:1059-7794
OA Status:Closed
Publisher DOI:https://doi.org/10.1002/humu.22804
PubMed ID:25907713

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