CLCN5 – Dent disease type 1

CLCN5 encodes the endosomal 2Cl⁻/H⁺ antiporter ClC-5, and pathogenic variants cause Dent disease type 1, an X-linked recessive tubulopathy. Affected individuals present with low-molecular-weight proteinuria, hypercalciuria, nephrocalcinosis, nephrolithiasis, and progressive renal failure, reflecting impaired proximal tubular endocytosis and acidification (PMID:9062355).

Genetic evidence for CLCN5 in Dent disease type 1 is robust and meets ClinGen criteria for a Definitive association. Over 162 genetically confirmed patients from 121 unrelated families have been described, including multiple pedigrees with segregation of truncating and missense variants consistent with X-linked inheritance (PMID:37284679). De novo mutations in females with skewed X-inactivation or isochromosome X have further underscored pathogenicity in atypical presentations (PMID:32393202).

The variant spectrum encompasses 51 truncating changes (nonsense, frameshift, canonical splicing) and 31 nontruncating alterations (missense, in-frame, noncanonical splicing) across the CLCN5 coding region. A recurrent founder allele, c.1249C>T (p.Arg417Ter), has been reported in multiple cohorts and functional studies (PMID:36726441). Missense mutations localize predominantly to transmembrane and CBS domains, whereas truncating variants are distributed throughout the protein.

Functional studies in heterologous systems and patient‐derived cells demonstrate loss-of-function as the predominant mechanism. Heterologous expression of missense mutants in Xenopus oocytes shows a ≥70% reduction in chloride conductance compared with wild‐type ClC-5 (PMID:9062355); immunohistochemistry of kidney biopsies reveals inversion of H⁺-ATPase polarity and defective receptor-mediated endocytosis (PMID:12631345). Cellular models confirm misfolding, ER retention, and proteasomal degradation of certain mutants, correlating intramolecular structural defects with functional impairment (PMID:23566014).

Genotype–phenotype analyses indicate that truncating variants are associated with earlier nephrolithiasis and accelerated CKD progression, whereas nontruncating changes cluster in the voltage‐gated domain and yield variable functional residual activity (PMID:37284679). This spectrum informs prognosis and genetic counseling, highlighting the importance of early molecular diagnosis in male and symptomatic female carriers.

Key Take-home: Definitive evidence supports CLCN5 loss-of-function as the cause of Dent disease type 1. Early genetic testing using NGS panels or targeted sequencing of CLCN5 expedites diagnosis in children with low‐molecular‐weight proteinuria and guides timely management to mitigate renal progression.

References

• The Journal of clinical investigation • 1997 • Idiopathic low molecular weight proteinuria associated with hypercalciuric nephrocalcinosis in Japanese children is due to mutations of the renal chloride channel (CLCN5). PMID:9062355
• Kidney international reports • 2023 • The Site and Type of CLCN5 Genetic Variation Impact the Resulting Dent Disease-1 Phenotype. PMID:37284679
• Kidney international • 2003 • Altered polarity and expression of H+-ATPase without ultrastructural changes in kidneys of Dent's disease patients. PMID:12631345
• The Biochemical journal • 2013 • Conformational defects underlie proteasomal degradation of Dent's disease-causing mutants of ClC-5. PMID:23566014

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