A Novel CLCN5 Mutation Associated With Focal Segmental Glomerulosclerosis and Podocyte Injury
| Autor: | Ashish K. Solanki, Milos N. Budisavljevic, Juan Carlos Q. Velez, Gary Hardiman, Thomas A. Morinelli, Deepak Nihalani, John M. Arthur, Michael G. Janech, Ehtesham Arif, Peifeng Deng, Robert C. Wilson |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
030232 urology & nephrology medicine.disease_cause Podocyte 03 medical and health sciences 0302 clinical medicine Focal segmental glomerulosclerosis renal biopsy Translational Research medicine Mutation Dent's disease biology business.industry CLCN5 Glomerulosclerosis Cell migration medicine.disease FSGS podocytes 030104 developmental biology medicine.anatomical_structure Nephrology Slit diaphragm biology.protein Cancer research business |
| Zdroj: | Kidney International Reports |
| ISSN: | 2468-0249 |
| DOI: | 10.1016/j.ekir.2018.06.003 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|