A Novel CLCN5 Mutation Associated With Focal Segmental Glomerulosclerosis and Podocyte Injury

Ashish K. Solanki, Ehtesham Arif, Thomas Morinelli, Robert C. Wilson, Gary Hardiman, Peifeng Deng, John M. Arthur, Juan CQ Velez, Deepak Nihalani, Michael G. Janech, Milos N. Budisavljevic*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

8 Citations (Scopus)
10 Downloads (Pure)

Abstract

Introduction: Tubular dysfunction is characteristic of Dent's disease; however, focal segmental glomerulosclerosis (FSGS) can also be present. Glomerulosclerosis could be secondary to tubular injury, but it remains uncertain whether the CLCN5 gene, which encodes an endosomal chloride and/or hydrogen exchanger, plays a role in podocyte biology. Here, we implicate a role for CLCN5 in podocyte function and pathophysiology. Methods: Whole exome capture and sequencing of the proband and 5 maternally-related family members was conducted to identify X-linked mutations associated with biopsy-proven FSGS. Human podocyte cultures were used to characterize the mutant phenotype on podocyte function. Results: We identified a novel mutation (L521F) in CLCN5 in 2 members of a Hispanic family who presented with a histologic diagnosis of FSGS and low-molecular-weight proteinuria without hypercalciuria. Presence of CLCN5 was confirmed in cultured human podocytes. Podocytes transfected with the wild-type or the mutant (L521F) CLCN5 constructs showed differential localization. CLCN5 knockdown in podocytes resulted in defective transferrin endocytosis and was associated with decreased cell proliferation and increased cell migration, which are hallmarks of podocyte injury. Conclusions: The CLCN5 mutation, which causes Dent's disease, may be associated with FSGS without hyercalcuria and nepthrolithiasis. The present findings supported the hypothesis that CLCN5 participates in protein trafficking in podocytes and plays a critical role in organizing the components of the podocyte slit diaphragm to help maintain normal cell physiology and a functional filtration barrier. In addition to tubular dysfunction, mutations in CLCN5 may also lead to podocyte dysfunction, which results in a histologic picture of FSGS that may be a primary event and not a consequence of tubular damage.

Original languageEnglish
Pages (from-to)1443-1453
Number of pages11
JournalKidney International Reports
Volume3
Issue number6
Early online date18 Jun 2018
DOIs
Publication statusPublished - 01 Nov 2018
Externally publishedYes

Keywords

  • CLCN5
  • Dent's disease
  • FSGS
  • podocytes
  • renal biopsy

ASJC Scopus subject areas

  • Nephrology

Fingerprint Dive into the research topics of 'A Novel CLCN5 Mutation Associated With Focal Segmental Glomerulosclerosis and Podocyte Injury'. Together they form a unique fingerprint.

Cite this