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

• Published in: The Journal of clinical investigation Vol. 127; no. 3; pp. 912 - 928
• Main Authors: Lovric, Svjetlana, Goncalves, Sara, Gee, Heon Yung, 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, Désir, Julie, Biemann, Ronald, Pei, York, Ars, Elisabet, Lloberas, Nuria, 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
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01.03.2017
• Subjects: Adrenal insufficiency; Aldehyde-Lyases - genetics; Aldehyde-Lyases - metabolism; Amino acids; Animals; Biomedical research; Cell Line; Cell Movement - genetics; Complications and side effects; Drosophila melanogaster; Drosophila Proteins - genetics; Drosophila Proteins - metabolism; Female; Gene mutation; Genes; Genetic aspects; Genomes; Genomics; Genotype & phenotype; Grants; Humans; Ichthyosis; Ichthyosis, Lamellar - enzymology; Ichthyosis, Lamellar - genetics; Ichthyosis, Lamellar - pathology; Kidney diseases; Lyases; Male; Medical research; Mesangial Cells - enzymology; Mesangial Cells - pathology; Metabolism; Mice; Mice, Knockout; Mutation; Nephrology; Nephrotic syndrome; Nephrotic Syndrome - enzymology; Nephrotic Syndrome - genetics; Nephrotic Syndrome - pathology; Pathogenesis; Physiological aspects; Protein Transport - genetics; Proteins; Rats; Risk factors; Rodents; Sphingosine
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/JCI89626

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.