Familial Xp11.22 microdeletion including SHROOM4 and CLCN5 is associated with intellectual disability, short stature, microcephaly and Dent disease: a case report.
Expression of ClC-5 carrying Dent's disease-associated mutations in HEK293 cells had varying effects: (1) no detectable expression of mutant protein; (2) retention of a truncated protein in the endoplasmic reticulum; or (3) diminished protein expression with normal distribution in early endosomes.
Dent disease is a rare X-linked tubulopathy caused by mutations in the endosomal chloride-proton exchanger (ClC-5) resulting in defective receptor-mediated endocytosis and severe proximal tubule dysfunction.
These results reveal for the first time that the conversion of CLC-5 from a 2Cl(-)/H(+) exchanger into a Cl(-) channel induces Dent's disease in humans.
Here, employing a composite pipeline method derived from various inference-based programs, we have characterized 26 deletion CNVs [including three novel pathogenic CNVs involving an autosomal gene (EXT2) causing hereditary osteochondromas and an X-linked gene (CLCN5) causing Dent disease, as well as 23 CNVs previously identified by inference from a cohort of Canadian autism spectrum disorder families] to the single-base-pair level of accuracy from whole-genome sequencing data.
We present the case of a young boy with Dent's disease, identified as having a mutation in the kidney-specific chloride-proton antitransporter CLCN5 during investigation for nephrotic-range proteinuria.
Thus, our studies, which have established human Dent disease ciPTECs that will facilitate studies of mechanisms in renal reabsorption, demonstrate that Dent disease-causing CLC-5 mutations have differing effects on endosomal acidification and receptor-mediated endocytosis that may not be coupled.
Modeling studies indicate that many CLCN5 mutations are located at the interface between the monomers of ClC-5, demonstrating that this protein region plays an important role in Dent's disease.
In this review, we focus on recent discoveries regarding molecular mechanisms underlying the regulated chloride:proton antiporter activity of ClC-5, the protein mutated in the Dent's disease-a kidney disease presenting with proteinuria and renal failure in severe cases.
The aim of the study was to identify CLCN5 mutations in Jewish Israeli families with Dent's disease and to characterize the associated clinical syndromes.
We studied 31 patients showing a phenotype resembling Dent's disease but lacking any CLCN5 mutations by direct sequencing of the OCRL1 and TMEM27 genes.