Mutation Update of theCLCN5Gene Responsible for Dent Disease 1

Abstract

Dent disease is a rare X-linked tubulopathy characterized by low molecular weight proteinuria, 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 counseling. 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.

Observations of a large Dent disease cohort

“…5,6 Female carriers may have a mild phenotype, including LMWP and hypercalciuria, with nephrocalcinosis or chronic renal failure developing only in very rare cases. 7,8 Dent disease is genetically heterogeneous: 60 % of patients harbor an inactivating mutation of the chloride channel-gated 5 gene (CLCN5) (Dent-1, Online Mendelian Inheritance in Man 300009), 9 15% have inactivating mutations of the inositol polyphosphate-5-phosphatase gene (OCRL) (Dent-2, Online Mendelian Inheritance in Man 300355), [10][11][12] and 25% have no mutation of these genes. [10][11][12][13] ClC-5, the protein encoded by the CLCN5 gene, is expressed mostly in the kidney, in the endosomes of proximal tubular cells, and to a lesser extent in medullary thick ascending limb cells and the intercalated cells of the collecting duct.…”

Dent disease: Same <i>CLCN5</i> mutation but different phenotypes in two brothers in China

“…A considerable intrafamilial variability in disease severity has been observed. Dent disease patients have a variable phenotype ranging from renal Fanconi syndrome with or without rickets to the association of LMWP and hypercalciuria (with or without nephrocalcinosis or nephrolithiasis) (11). The severity of renal disease varies greatly among individuals within a family, and there is no relationship between the degree of LMW proteinuria and the severity of chronic kidney disease (CKD) or hypercalciuria (17).…”

“…The effects of Dent disease 1 are variable both within and between affected families (11). It is well known that a CLCN5 mutation could be a rare cause of inherited forms of induced Fanconi syndrome (12)(13)(14)(15)(16).…”

“…It is well known that a CLCN5 mutation could be a rare cause of inherited forms of induced Fanconi syndrome (12)(13)(14)(15)(16). Moreover, a considerable intra and between familial variability in disease severity has been observed and no genotypephenotype correlation has been described (11,17).…”

Chloride Intracellular Channel 4 Overexpression in the Proximal Tubules of Kidneys from the Spontaneously Hypertensive Rat: Insight from Proteomic Analysis

“…These findings raise the possibility that CLIC4 may also be involved in the regulation of ion transport through gap junctions and microvilli in the proximal tubules, structures which act as sensors of local tubular flow [35]. CLIC4 should not be confused with Clc5, an ion channel located in proximal tubular epithelial cells, mutations of which are related to Dent disease [36].…”