2026-04-17T03:52:56Zhttps://recercat.cat/oai/request

oai:recercat.cat:2445/1244822025-12-05T12:20:05Zcom_2072_1057col_2072_478916col_2072_478917

00925njm 22002777a 4500 dc Lovric, Svjetlana author Goncalves, Sara author Gee, Heon Yungy author Oskouian, Babak author Srinivas, Honnappa author Choi, Won-Il author Shril, Shirlee author Ashraf, Shazia author Tan, Weizhen author Rao, Jia author Airik, Merlin author Schapiro, David author Braun, Daniela A. author Sadowski, Carolin E. author Widmeier, Eugen author Jobst-Schwan, Tilman author Schmidt, Johanna Magdalena author Girik, Vladimir author Capitani, Guido author Suh, Jung H. author Lachaussée, Noëlle author Arrondel, Christelle author Patat, Julie author Gribouval, Olivier author Furlano, Monica author Boyer, Olivia author Schmitt, Alain author Vuiblet, Vincent author Hashmi, Seema author Wilcken, Rainer author Bernier, Francois P. author Innes, A. Micheil author Parboosingh, Jillian S. author Lamont, Ryan E. author Midgley, Julian P. author Wright, Nicola author Majewski, Jacek author Zenker, Martin author Schaefer, Franz author Kuss, Navina author Greil, Johann author Giese, Thomas author Schwarz, Klaus author Catheline, Vilain author Schanze, Denny author Franke, Ingolf author Sznajer, Yves author Truant, Anne S. author Adams, Brigitte author Desir, Julie author Biemann, Ronald author Pei, York author Ars, Elisabet author Lloberas Blanch, Núria author Madrid, Alvaro author Dharnidharka, Vikas R. author Connolly, Anne M. author Willing, Marcia C. author Cooper, Megan A. author Lifton, Richard P author Simons, Matias author Riezman, Howard author Antignac, Corinne author Saba, Julie D. author Hildebrandt, Friedhelm author 2018-09-12T11:34:09Z 2018-09-12T11:34:09Z 2017-03-01 2018-07-24T12:10:32Z 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. Síndrome nefròtica Insuficiència renal crònica Nephrotic syndrome Chronic renal failure Mutations in sphingosine-1-phosphate lyase cause nephrosis with ichthyosis and adrenal insufficiency