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http://hdl.handle.net/2445/124482
Title: | Mutations in sphingosine-1-phosphate lyase cause nephrosis with ichthyosis and adrenal insufficiency |
Author: | Lovric, Svjetlana Goncalves, Sara Gee, Heon Yungy Oskouian, Babak Srinivas, Honnappa Choi, Won-Il Shril, Shirlee Ashraf, Shazia Tan, Weizhen Rao, Jia Airik, Merlin Schapiro, David Braun, Daniela A. Sadowski, Carolin E. Widmeier, Eugen Jobst-Schwan, Tilman Schmidt, Johanna Magdalena Girik, Vladimir Capitani, Guido Suh, Jung H. Lachaussée, Noëlle Arrondel, Christelle Patat, Julie Gribouval, Olivier Furlano, Monica Boyer, Olivia Schmitt, Alain Vuiblet, Vincent Hashmi, Seema Wilcken, Rainer Bernier, Francois P. Innes, A. Micheil Parboosingh, Jillian S. Lamont, Ryan E. Midgley, Julian P. Wright, Nicola Majewski, Jacek Zenker, Martin Schaefer, Franz Kuss, Navina Greil, Johann Giese, Thomas Schwarz, Klaus Catheline, Vilain Schanze, Denny Franke, Ingolf Sznajer, Yves Truant, Anne S. Adams, Brigitte Desir, Julie Biemann, Ronald Pei, York Ars, Elisabet Lloberas Blanch, Núria Madrid, Alvaro Dharnidharka, Vikas R. Connolly, Anne M. Willing, Marcia C. Cooper, Megan A. Lifton, Richard P Simons, Matias Riezman, Howard Antignac, Corinne Saba, Julie D. Hildebrandt, Friedhelm |
Keywords: | Síndrome nefròtica Insuficiència renal crònica Nephrotic syndrome Chronic renal failure |
Issue Date: | 1-Mar-2017 |
Publisher: | American Society for Clinical Investigation |
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 dpl1. 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. |
Note: | Reproducció del document publicat a: https://doi.org/10.1172/JCI89626 |
It is part of: | Journal of Clinical Investigation, 2017, vol. 127, num. 3, p. 912-928 |
URI: | http://hdl.handle.net/2445/124482 |
Related resource: | https://doi.org/10.1172/JCI89626 |
Appears in Collections: | Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL)) Publicacions de projectes de recerca finançats per la UE |
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File | Description | Size | Format | |
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LovricS.pdf | 6.41 MB | Adobe PDF | View/Open |
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