Svjetlana Lovric,¹ Sara Goncalves,^2,3 Heon Yung Gee,^1,4 Babak Oskouian,⁵ Honnappa Srinivas,⁶ Won-Il Choi,¹ Shirlee Shril,¹ Shazia Ashraf,¹ Weizhen Tan,¹ Jia Rao,¹ Merlin Airik,¹ David Schapiro,¹ Daniela A. Braun,¹ Carolin E. Sadowski,¹ Eugen Widmeier,^1,7 Tilman Jobst-Schwan,¹ Johanna Magdalena Schmidt,¹ Vladimir Girik,⁸ Guido Capitani,⁹ Jung H. Suh,⁵ Noelle Lachaussee,^2,3 Christelle Arrondel,^2,3 Julie Patat,^2,3 Olivier Gribouval,^2,3 Monica Furlano,^2,3,10 Olivia Boyer,^2,3,11 Alain Schmitt,^12,13 Vincent Vuiblet,^14,15 Seema Hashmi,¹⁶ Rainer Wilcken,⁶ Francois P. Bernier,¹⁷ A. Micheil Innes,¹⁷ Jillian S. Parboosingh,¹⁷ Ryan E. Lamont,¹⁷ Julian P. Midgley,¹⁸ Nicola Wright,¹⁸ Jacek Majewski,¹⁹ Martin Zenker,²⁰ Franz Schaefer,²¹ Navina Kuss,²² Johann Greil,²³ Thomas Giese,²⁴ Klaus Schwarz,²⁵ Vilain Catheline,²⁶ Denny Schanze,²⁰ Ingolf Franke,²⁷ Yves Sznajer,²⁸ Anne S. Truant,²⁹ Brigitte Adams,³⁰ Julie Desir,²⁶ Ronald Biemann,³¹ York Pei,³² Elisabet Ars,³³ Nuria Lloberas,³⁴ Alvaro Madrid,³⁵ Vikas R. Dharnidharka,³⁶Anne M. Connolly,³⁷ Marcia C. Willing,³⁸ Megan A. Cooper,³⁹ Richard P. Lifton,^40,41 Matias Simons,^3,42 Howard Riezman,⁸ Corinne Antignac,^2,3,43 Julie D. Saba,⁵ and Friedhelm Hildebrandt<sup>1

1</sup>Division of Nephrology, Boston Children’s Hospital, Harvard Medical School, Boston, Massachusetts, USA. ²Institut National de la Sante et de la Recherche Medicale, Unite Mixte de Recherche 1163, Laboratory of Hereditary Kidney Diseases, Paris, France. ³Universite Paris Descartes, Sorbonne Paris Cite, Imagine Institute, Paris, France. ⁴Department of Pharmacology, Brain Korea 21 PLUS Project for Medical Sciences, Yonsei University College of Medicine, Seoul, Republic of Korea. ⁵UCSF Benioff Children’s Hospital Oakland, Oakland, California, USA. ⁶Novartis Institutes for BioMedical Research, Basel, Switzerland. ⁷Department of Medicine, Renal Division, Medical Center . University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany. ⁸National Centre of Competence in Research (NCCR) Chemical Biology and Biochemistry Department, University of Geneva, Geneva, Switzerland. ⁹Laboratory of Biomolecular Research, Paul Scherrer Institute, Villigen, Switzerland. ¹⁰Nephrology Department, Fundacio Puigvert, Instituto de Investigaciones Biomedicas Sant Pau (IIB.Sant Pau), Universitat Autonoma de Barcelona, REDinREN, Instituto de Investigacion Carlos III, Barcelona, Spain. ¹¹Department of Pediatric Nephrology, Necker Hospital, Assistance Publique . Hopitaux de Paris, Paris, France. ¹²Plateforme de Microscopie Electronique, Institut National de la Sante et de la Recherche Medicale 1016, Institut Cochin, Paris, France. ¹³Centre National de la Recherche Scientifique, Unite Mixte de Recherche 81044, Paris, France. ¹⁴Centre National pour la Recherche Scientifique, Unite Mixte de Recherche 7369, Laboratory of Matrice Extracellulaire et Dynamique Cellulaire, Reims, France. ¹⁵Nephrology and Renal Transplantation Department and Biopathology Laboratory, Centre Hospitalier et Universitaire de Reims, Reims, France. ¹⁶Department of Pediatric Nephrology, Sindh Institute of Urology and Transplantation, Karachi, Pakistan. ¹⁷Department of Medical Genetics and ¹⁸Department of Pediatrics, University of Calgary, Alberta Health Services, Calgary, Canada. ¹⁹Department of Human Genetics, McGill University, Montreal, Quebec, Canada. ²⁰Institute of Human Genetics, University Hospital Magdeburg, Magdeburg, Germany. ²¹Division of Pediatric Nephrology, ²²Department of Neonatology, ²³Department of Pediatric Hematology and Oncology, Center for Pediatrics and Adolescent Medicine, and ²⁴Institute of Immunology, University of Heidelberg, Heidelberg, Germany. ²⁵Institute for Transfusion Medicine, University of Ulm, and Institute of Clinical Transfusion Medicine and Immunogenetics Ulm, German Red Cross Blood Service Baden-Wurttemberg . Hessen, Ulm, Germany. ²⁶ULB Center of Human Genetics. Hopital Erasme, Universite Libre de Bruxelles (ULB), Brussels, Belgium. ²⁷Department of Dermatology, University Hospital Magdeburg, Magdeburg, Germany. ²⁸Centre de Genetique Humaine, Cliniques Universitaires Saint Luc, ²⁹Pediatric Neonatology, Center for Human Genetics, Universite Catholique de Louvain (UCL), ³⁰Nephrology ped, Hopital universitaire des enfants Reine Fabiola (HUDERF), Universite Libre de Bruxelles (ULB), Brussels, Belgium. ³¹Institute of Clinical Chemistry and Pathobiochemistry, University Hospital Magdeburg, Magdeburg, Germany. ³²Division of Nephrology, Department of Internal Medicine, University Health Network and University of Toronto, Ontario, Canada. ³³Molecular Biology Laboratory, Fundacio Puigvert, IIB-Sant Pau, Universitat Autonoma de Barcelona, REDinREN, Instituto de Investigacion Carlos III, Barcelona, Spain. ³⁴Nephrology Service and Laboratory of Experimental Nephrology, Hospital Universitari de Bellvitge, Catalonia, Spain. ³⁵Nefrologia Pediatrica, Hospital Universitario Materno.Infantil Vall d’ Hebron, Barcelona, Spain. ³⁶Department of Pediatrics, Division of Pediatric Nephrology, Washington University School of Medicine, St. Louis, Missouri, USA. ³⁷Department of Neurology, Neuromuscular Division, ³⁸Department of Pediatrics, Division of Genetics and Genomic Medicine, and ³⁹Department of Pediatrics, Division of Rheumatology, Washington University School of Medicine, St. Louis, Missouri, USA. ⁴⁰Department of Genetics, Yale University School of Medicine, New Haven, Connecticut, USA. ⁴¹Howard Hughes Medical Institute, Chevy Chase, Maryland, USA. ⁴²Institut National de la Sante et de la Recherche Medicale, Unite Mixte de Recherche 1163, Laboratory of Epithelial Biology and Disease, Paris, France. ⁴³Department of Genetics, Necker Hospital, Assistance Publique . Hopitaux de Paris, Paris, France.

Address correspondence to: Friedhelm Hildebrandt, Boston Children’s Hospital, Enders 561, Harvard Medical School, 300 Longwood Avenue, Boston, Massachusetts 02115, USA. Or to: Corinne Antignac, Imagine Institute, Inserm U1163, 24 Bd du Montparnasse, 75015 Paris, France. Or to: Julie Saba, UCSF Benioff Children’s Hospital Oakland, Children’s Hospital Oakland Research Institute, 5700 Martin Luther King Jr. Way, Oakland, California 94609, USA.

Authorship note: S. Lovric, S. Goncalves, and H.Y. Gee contributed equally to this work.

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.