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 diseaseassociated 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.
Bibliographical noteFunding Information:
Acknowledgments The authors thank the families who contributed to this study. We thank the Yale Center for Mendelian Genomics for WES analysis, U. Pannicke for help in analyzing data, and S. Braun for technical assistance. FH was supported by grants from the NIH (DK076683, DK068306). FH is the Warren E. Grupe Professor. HYG was supported by the Basic Science Research Program through the National Research Foundation of Korea, funded by the Ministry of Education (2015R1D1A1A01056685), by a Nephcure-ASN Foundation Kidney Research Grant, and by a faculty research grant of Yonsei University College of Medicine (6-2015-0175). C Antignac was supported by grants from the Agence Nationale de la Recherche (Gen-Pod project ANR-12-BSV1-0033.01), the European Union's Seventh Framework Programme (FP7/2007-2013/no 305608-EURenOmics), the Fondation Recherche M?dicale (DEQ20150331682), and the ''Investments for the Future'' program (ANR-10-IAHU-01). SG was supported by the Program Sant?-Science (MD-PhD) of Imagine Institute. FS was supported by the European Union's Seventh Framework Programme (FP7/2007-2013/n 305608-EURenOmics). Immunophenotyping was supported by the German Centre for Infectious Diseases (Thematical Translation Units: Infections of the immunocompromised host). JDS was supported by the John and Edna Beck Chair in Pediatric Cancer Research, the Swim Across America Foundation, and a grant from the NIH (GM66594, NCI CA129438). KS was supported by the Center for Personalized Immunology (supported by the National Health and Medical Research Council of Australia [NHMRC]), the Australian National University, Canberra, Australia. MZ was supported by the German Ministry of Education and Research (Bundesministerium f?ur Bildung und Forschung, project: GeNeRARe). EW was supported by the Leopoldina Fellowship Program, German National Academy of Sciences Leopoldina (LPDS 2015-07). TJS was supported by grant Jo 1324/1-1 of Deutsche Forschungsgemeinschaft (DFG). MF was supported by grants from the Spanish Society of Nephrology and the Catalan Society of Nephrology. HR was supported by grants from the Swiss National Science Foundation, SystemsX.CH, and the NCCR Chemical Biology. This work was performed under the Care4Rare Canada Consortium funded by Genome Canada, the Canadian Institutes of Health Research, the Ontario Genomics Institute, the Ontario Research Fund, Genome Quebec, and the Children's Hos-pital of Eastern Ontario Research Foundation. We acknowledge the contribution of the high-throughput sequencing platform of the McGill University and G?nome Qu?bec Innovation Centre, Montr?al, Canada. The names of Care4Rare Canada steering committee members appear in the Supplemental Acknowledgments.
All Science Journal Classification (ASJC) codes