Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Video Abstracts
  • Reviews
    • View all reviews ...
    • Pancreatic Cancer (Jul 2025)
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • Sex Differences in Medicine (Sep 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Video Abstracts
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
Mutations in sphingosine-1-phosphate lyase cause nephrosis with ichthyosis and adrenal insufficiency
Svjetlana Lovric, … , Julie D. Saba, Friedhelm Hildebrandt
Svjetlana Lovric, … , Julie D. Saba, Friedhelm Hildebrandt
Published February 6, 2017
Citation Information: J Clin Invest. 2017;127(3):912-928. https://doi.org/10.1172/JCI89626.
View: Text | PDF
Research Article Genetics Nephrology

Mutations in sphingosine-1-phosphate lyase cause nephrosis with ichthyosis and adrenal insufficiency

  • Text
  • PDF
Abstract

Steroid-resistant nephrotic syndrome (SRNS) causes 15% of chronic kidney disease cases. A mutation in 1 of over 40 monogenic genes can be detected in approximately 30% of individuals with SRNS whose symptoms manifest before 25 years of age. However, in many patients, the genetic etiology remains unknown. Here, we have performed whole exome sequencing to identify recessive causes of SRNS. In 7 families with SRNS and facultative ichthyosis, adrenal insufficiency, immunodeficiency, and neurological defects, we identified 9 different recessive mutations in SGPL1, which encodes sphingosine-1-phosphate (S1P) lyase. All mutations resulted in reduced or absent SGPL1 protein and/or enzyme activity. Overexpression of cDNA representing SGPL1 mutations resulted in subcellular mislocalization of SGPL1. Furthermore, expression of WT human SGPL1 rescued growth of SGPL1-deficient dpl1Δ yeast strains, whereas expression of disease-associated variants did not. Immunofluorescence revealed SGPL1 expression in mouse podocytes and mesangial cells. Knockdown of Sgpl1 in rat mesangial cells inhibited cell migration, which was partially rescued by VPC23109, an S1P receptor antagonist. In Drosophila, Sply mutants, which lack SGPL1, displayed a phenotype reminiscent of nephrotic syndrome in nephrocytes. WT Sply, but not the disease-associated variants, rescued this phenotype. Together, these results indicate that SGPL1 mutations cause a syndromic form of SRNS.

Authors

Svjetlana Lovric, Sara Goncalves, Heon Yung Gee, Babak Oskouian, Honnappa Srinivas, Won-Il Choi, Shirlee Shril, Shazia Ashraf, Weizhen Tan, Jia Rao, Merlin Airik, David Schapiro, Daniela A. Braun, Carolin E. Sadowski, Eugen Widmeier, Tilman Jobst-Schwan, Johanna Magdalena Schmidt, Vladimir Girik, Guido Capitani, Jung H. Suh, Noëlle Lachaussée, Christelle Arrondel, Julie Patat, Olivier Gribouval, Monica Furlano, Olivia Boyer, Alain Schmitt, Vincent Vuiblet, Seema Hashmi, Rainer Wilcken, Francois P. Bernier, A. Micheil Innes, Jillian S. Parboosingh, Ryan E. Lamont, Julian P. Midgley, Nicola Wright, Jacek Majewski, Martin Zenker, Franz Schaefer, Navina Kuss, Johann Greil, Thomas Giese, Klaus Schwarz, Vilain Catheline, Denny Schanze, Ingolf Franke, Yves Sznajer, Anne S. Truant, Brigitte Adams, Julie Désir, Ronald Biemann, York Pei, Elisabet Ars, Nuria Lloberas, Alvaro Madrid, Vikas R. Dharnidharka, Anne M. Connolly, Marcia C. Willing, Megan A. Cooper, Richard P. Lifton, Matias Simons, Howard Riezman, Corinne Antignac, Julie D. Saba, Friedhelm Hildebrandt

×

Figure 3

Effect of Sgpl1 knockdown on RHO GTPase activity in RMCs and patient fibroblasts.

Options: View larger image (or click on image) Download as PowerPoint
Effect of Sgpl1 knockdown on RHO GTPase activity in RMCs and patient fib...
(A) Effect of SGPL1 knockdown on rat RMCs using the xCELLigence system. RMC transfected with 2 different SGPL1 siRNAs exhibited decreased serum-induced migration rate (blue and red lines) compared with scrambled siRNA control (black line). (B) Diminished cell migration rate in patients with SGPL1 mutations. Using the xCELLigence system, fibroblasts from individuals with SGPL1 mutations (blue, red, and orange lines) showed decreased migration rate compared with control (black solid line). (C) Active GTP-bound RAC1 and CDC42 precipitated from RMCs transfected with scrambled (Scr) or SGPL1 siRNA using a GST-PAK1 (CRIB) pulldown assay. Compared with control cells, RMCs transfected with SGPL1 siRNA exhibited a significant decrease in relative CDC42 and RAC1 activity. The efficiency of knockdown by siRNA was confirmed by immunoblotting with an anti-SGPL1 antibody (second to lowest panel). (D) Active GTP-bound RHOA precipitated from RMCs using a GST-rhotekin (RBD) pulldown assay. RMCs transfected with scrambled control siRNA versus SGPL1 siRNA exhibited no significant differences in relative RHOA activity. C and D represent 3 experiments each. (E) Effect of S1PR antagonists on RMC migration rate. SGPL1 knockdown caused decreased migration rate (red line) (Supplemental Figure 3B), which was partially rescued by VPC23109 (green line), but not by JTE013 (orange line). VPC23109 is an antagonist that selectively inhibits S1PR1 and S1PR3, whereas JTE013 is an antagonist for S1PR2. Each cell index value corresponds to the average of more than triplicates and SD is in only 1 direction for clarity in A, B, and E.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts