CLCN5 – Dent Disease

Dent disease is an X-linked recessive proximal tubulopathy characterized by low-molecular-weight proteinuria, hypercalciuria, nephrocalcinosis, nephrolithiasis and progressive renal insufficiency. Affected males typically present in childhood or early adulthood with raised urinary β2-microglobulin and calcium wasting, leading to tubulointerstitial damage and eventual renal failure. Female carriers may exhibit milder tubular defects, including kidney stones and proteinuria, due to skewed X-inactivation.

CLCN5 (HGNC:2023) encodes the endosomal 2Cl–/1H+ exchanger ClC-5, which is expressed on apical endosomes and the plasma membrane of proximal tubular cells. Pathogenic variants lead to defective endosomal acidification, impaired receptor-mediated endocytosis of megalin/cubilin and disrupted trafficking of vacuolar H+-ATPase. Dent disease follows an X-linked recessive inheritance pattern, with hemizygous males manifesting full disease and heterozygous females variably affected.

Genetic evidence includes identification of over 60 distinct CLCN5 mutations—nonsense, frameshift, splice-site and missense—across more than 150 unrelated families ([PMID:9734595]). Variants cluster in transmembrane and CBS domains, e.g. c.941C>T (p.Ser314Leu), and consistently segregate with disease in multi-generational pedigrees. Truncating mutations are prevalent and recurrent, including hot-spot codons R28X, R104Ter and R718Ter, confirming a loss-of-function mechanism.

Functional studies in Xenopus oocytes and mammalian cell lines demonstrate that missense mutations abolish or markedly reduce ClC-5–mediated currents, impede endosomal acidification and disrupt endocytic uptake of albumin and transferrin ([PMID:9853249]). Computational and protease-sensitivity analyses show that many mutants are misfolded, retained in the endoplasmic reticulum and targeted for proteasomal degradation. Mutations truncating the CBS2 domain lead to Golgi retention and loss of channel trafficking.

There is no substantive conflicting evidence disputing CLCN5’s role in Dent disease. Cases lacking CLCN5/OCRL1 mutations suggest additional genetic heterogeneity, but the core phenotype in mutation-positive patients remains consistent. Experimental rescue of select truncating mutants by coexpression of complementary fragments restores currents, underscoring the critical structural integrity of ClC-5.

In summary, CLCN5 is definitively implicated in Dent disease through robust genetic segregation, a broad spectrum of pathogenic variants and concordant functional deficits. Diagnostic genetic testing for CLCN5 mutations informs early management, enables family counseling and guides therapeutic strategies to preserve renal function.

References

• Kidney international | 1998 | CLCN5 chloride-channel mutations in six new North American families with X-linked nephrolithiasis PMID:9734595
• Human molecular genetics | 1997 | Characterisation of renal chloride channel, CLCN5, mutations in hypercalciuric nephrolithiasis (kidney stones) disorders PMID:9259268
• Journal of the American Society of Nephrology | 2000 | Characterization of renal chloride channel (CLCN5) mutations in Dent's disease PMID:10906159
• American journal of physiology. Cell physiology | 2004 | Coexpression of complementary fragments of ClC-5 and restoration of chloride channel function in a Dent’s disease mutation PMID:12746443
• Human genetics | 2005 | Functional evaluation of Dent's disease-causing mutations: implications for ClC-5 channel trafficking and internalization PMID:15895257
• Pflügers Archiv | 2016 | A pure chloride channel mutant of CLC-5 causes Dent's disease via insufficient V-ATPase activation PMID:27044412

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