2. Academic Validation
  3. Steroid-sensitive nephrotic syndrome candidate gene CLVS1 regulates podocyte oxidative stress and endocytosis

Steroid-sensitive nephrotic syndrome candidate gene CLVS1 regulates podocyte oxidative stress and endocytosis

  • JCI Insight. 2022 Jan 25;7(2):e152102. doi: 10.1172/jci.insight.152102.
Brandon M Lane 1,  Megan Chryst-Stangl 1,  Guanghong Wu 1,  Mohamed Shalaby 2,  Sherif El Desoky 2,  Claire C Middleton 1,  Kinsie Huggins 1,  Amika Sood 3,  Alejandro Ochoa 3,  Andrew F Malone 4,  Ricardo Vancini 5,  Sara E Miller 5,  Gentzon Hall 1 6,  So Young Kim 7,  David N Howell 5,  Jameela A Kari 2,  Rasheed Gbadegesin 1 6
Affiliations

Affiliations

  • 1 Department of Pediatrics, Division of Nephrology, and Duke Molecular Physiology Institute, Duke University School of Medicine, Durham, North Carolina, USA.
  • 2 Pediatric Department, Pediatric Nephrology Center of Excellence, King Abdulaziz University, Jeddah, Saudi Arabia.
  • 3 Department of Biostatistics and Bioinformatics and Duke Center for Statistical Genetics and Genomics, Duke University, Durham, North Carolina, USA.
  • 4 Department of Medicine, Division of Nephrology, Washington University School of Medicine in St. Louis, St. Louis, Missouri, USA.
  • 5 Department of Pathology.
  • 6 Department of Medicine, Division of Nephrology; and.
  • 7 Department of Molecular Genetics and Microbiology, Duke University School of Medicine, Durham, North Carolina, USA.
PMID: 34874915 DOI: 10.1172/jci.insight.152102
Abstract

We performed next-generation Sequencing in patients with familial steroid-sensitive nephrotic syndrome (SSNS) and identified a homozygous segregating variant (p.H310Y) in the gene encoding clavesin-1 (CLVS1) in a consanguineous family with 3 affected individuals. Knockdown of the clavesin gene in zebrafish (clvs2) produced edema phenotypes due to disruption of podocyte structure and loss of glomerular filtration barrier integrity that could be rescued by WT CLVS1 but not the p.H310Y variant. Analysis of cultured human podocytes with CRISPR/Cas9-mediated CLVS1 knockout or homozygous H310Y knockin revealed deficits in clathrin-mediated endocytosis and increased susceptibility to Apoptosis that could be rescued with corticosteroid treatment, mimicking the steroid responsiveness observed in patients with SSNS. The p.H310Y variant also disrupted binding of clavesin-1 to α-tocopherol transfer protein, resulting in increased Reactive Oxygen Species (ROS) accumulation in CLVS1-deficient podocytes. Treatment of CLVS1-knockout or homozygous H310Y-knockin podocytes with pharmacological ROS inhibitors restored viability to control levels. Taken together, these data identify CLVS1 as a candidate gene for SSNS, provide insight into therapeutic effects of corticosteroids on podocyte cellular dynamics, and add to the growing evidence of the importance of endocytosis and oxidative stress regulation to podocyte function.

Keywords

Chronic kidney disease; Genetic diseases; Monogenic diseases; Nephrology.

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