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Functional characterization of a novel missense CLCN5 mutation causing alterations in proximal tubular endocytic

Atsuhito Tanuma1, Hiroyoshi Sato, Tetsuro Takeda

  • 1Division of Clinical Nephrology and Rheumatology, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.

Nephron. Physiology
|November 21, 2007
PubMed
Abstract

Insights

A novel CLCN5 mutation (G333R) causes Dent's disease by impairing endocytic machinery, specifically reducing megalin, cubilin, and Dab2 expression in kidney tubules.

Area of Science:

  • Nephrology
  • Molecular Genetics
  • Cell Biology

Background:

  • Dent's disease is an X-linked recessive proximal tubular disorder caused by mutations in the CLCN5 gene.
  • The renal endocytic system is affected in CLCN5 knockout mice, but patient-specific defects remain unclear.

Observation:

  • A novel missense mutation (G333R) in the CLCN5 gene was identified in a Japanese Dent's disease patient.
  • The G333R mutation led to abolished chloride currents and impaired N-glycosylation of the CLCN5 protein.
  • Kidney biopsy revealed significantly reduced and irregular expression of endocytic proteins megalin, cubilin, and Dab2 in proximal tubules.

Findings:

  • The identified G333R CLCN5 mutation results in a loss-of-function phenotype.
  • Defective CLCN5 expression directly impacts the expression of key endocytic machinery proteins, megalin, cubilin, and Dab2.

Implications:

  • This study elucidates the molecular mechanism underlying Dent's disease pathogenesis at the cellular level.
  • Understanding these defects provides insights into renal endocytic dysfunction and potential therapeutic targets.

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