Skip to main content

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

Publication ,  Journal Article
Lane, BM; Chryst-Stangl, M; Wu, G; Shalaby, M; El Desoky, S; Middleton, CC; Huggins, K; Sood, A; Ochoa, A; Malone, AF; Vancini, R; Miller, SE ...
Published in: JCI Insight
January 25, 2022

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.

Duke Scholars

Altmetric Attention Stats
Dimensions Citation Stats

Published In

JCI Insight

DOI

EISSN

2379-3708

Publication Date

January 25, 2022

Volume

7

Issue

2

Location

United States

Related Subject Headings

  • Zebrafish Proteins
  • Zebrafish
  • Reactive Oxygen Species
  • Podocytes
  • Oxidative Stress
  • Nephrotic Syndrome
  • Humans
  • High-Throughput Nucleotide Sequencing
  • Genetic Association Studies
  • Gene Knockout Techniques
 

Citation

APA
Chicago
ICMJE
MLA
NLM
Lane, B. M., Chryst-Stangl, M., Wu, G., Shalaby, M., El Desoky, S., Middleton, C. C., … Gbadegesin, R. (2022). Steroid-sensitive nephrotic syndrome candidate gene CLVS1 regulates podocyte oxidative stress and endocytosis. JCI Insight, 7(2). https://doi.org/10.1172/jci.insight.152102
Lane, Brandon M., Megan Chryst-Stangl, Guanghong Wu, Mohamed Shalaby, Sherif El Desoky, Claire C. Middleton, Kinsie Huggins, et al. “Steroid-sensitive nephrotic syndrome candidate gene CLVS1 regulates podocyte oxidative stress and endocytosis.JCI Insight 7, no. 2 (January 25, 2022). https://doi.org/10.1172/jci.insight.152102.
Lane BM, Chryst-Stangl M, Wu G, Shalaby M, El Desoky S, Middleton CC, et al. Steroid-sensitive nephrotic syndrome candidate gene CLVS1 regulates podocyte oxidative stress and endocytosis. JCI Insight. 2022 Jan 25;7(2).
Lane, Brandon M., et al. “Steroid-sensitive nephrotic syndrome candidate gene CLVS1 regulates podocyte oxidative stress and endocytosis.JCI Insight, vol. 7, no. 2, Jan. 2022. Pubmed, doi:10.1172/jci.insight.152102.
Lane BM, Chryst-Stangl M, Wu G, Shalaby M, El Desoky S, Middleton CC, Huggins K, Sood A, Ochoa A, Malone AF, Vancini R, Miller SE, Hall G, Kim SY, Howell DN, Kari JA, Gbadegesin R. Steroid-sensitive nephrotic syndrome candidate gene CLVS1 regulates podocyte oxidative stress and endocytosis. JCI Insight. 2022 Jan 25;7(2).

Published In

JCI Insight

DOI

EISSN

2379-3708

Publication Date

January 25, 2022

Volume

7

Issue

2

Location

United States

Related Subject Headings

  • Zebrafish Proteins
  • Zebrafish
  • Reactive Oxygen Species
  • Podocytes
  • Oxidative Stress
  • Nephrotic Syndrome
  • Humans
  • High-Throughput Nucleotide Sequencing
  • Genetic Association Studies
  • Gene Knockout Techniques