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

Svjetlana Lovric; Sara Goncalves; Heon Yung Gee; Babak Oskouian; Honnappa Srinivas; Won Il Choi; Shirlee Shril; Shazia Ashraf; Weizhen Tan; Jia Rao; Merlin Airik; David Schapiro; Daniela A. Braun; Carolin E. Sadowski; Eugen Widmeier; Tilman Jobst-Schwan; Johanna Magdalena Schmidt; Vladimir Girik; Guido Capitani; Jung H. Suh; Noëlle Lachaussée; Christelle Arrondel; Julie Patat; Olivier Gribouval; Monica Furlano; Olivia Boyer; Alain Schmitt; Vincent Vuiblet; Seema Hashmi; Rainer Wilcken; Francois P. Bernier; A. Micheil Innes; Jillian S. Parboosingh; Ryan E. Lamont; Julian P. Midgley; Nicola Wright; Jacek Majewski; Martin Zenker; Franz Schaefer; Navina Kuss; Johann Greil; Thomas Giese; Klaus Schwarz; Vilain Catheline; Denny Schanze; Ingolf Franke; Yves Sznajer; Anne S. Truant; Brigitte Adams; Julie Désir; Ronald Biemann; York Pei; Elisabet Ars; Nuria Lloberas; Alvaro Madrid; Vikas R. Dharnidharka; Anne M. Connolly; Marcia C. Willing; Megan A. Cooper; Richard P. Lifton; Matias Simons; Howard Riezman; Corinne Antignac; Julie D. Saba; Friedhelm Hildebrandt

doi:10.1172/JCI89626

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

Svjetlana Lovric, Sara Goncalves, Heon Yung Gee, Babak Oskouian, Honnappa Srinivas, Won Il Choi, Shirlee Shril, Shazia Ashraf, Weizhen Tan, Jia Rao, Merlin Airik, David Schapiro, Daniela A. Braun, Carolin E. Sadowski, Eugen Widmeier, Tilman Jobst-Schwan, Johanna Magdalena Schmidt, Vladimir Girik, Guido Capitani, Jung H. SuhNoëlle Lachaussée, Christelle Arrondel, Julie Patat, Olivier Gribouval, Monica Furlano, Olivia Boyer, Alain Schmitt, Vincent Vuiblet, Seema Hashmi, Rainer Wilcken, Francois P. Bernier, A. Micheil Innes, Jillian S. Parboosingh, Ryan E. Lamont, Julian P. Midgley, Nicola Wright, Jacek Majewski, Martin Zenker, Franz Schaefer, Navina Kuss, Johann Greil, Thomas Giese, Klaus Schwarz, Vilain Catheline, Denny Schanze, Ingolf Franke, Yves Sznajer, Anne S. Truant, Brigitte Adams, Julie Désir, Ronald Biemann, York Pei, Elisabet Ars, Nuria Lloberas, Alvaro Madrid, Vikas R. Dharnidharka, Anne M. Connolly, Marcia C. Willing, Megan A. Cooper, Richard P. Lifton, Matias Simons, Howard Riezman, Corinne Antignac, Julie D. Saba, Friedhelm Hildebrandt

Department of Pharmacology

Research output: Contribution to journal › Article › peer-review

115 Citations (Scopus)

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 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.

Original language	English
Pages (from-to)	912-928
Number of pages	17
Journal	Journal of Clinical Investigation
Volume	127
Issue number	3
DOIs	https://doi.org/10.1172/JCI89626
Publication status	Published - 2017 Mar 1

Bibliographical note

Funding 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 Médicale (DEQ20150331682), and the ''Investments for the Future'' program (ANR-10-IAHU-01). SG was supported by the Program Santé-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 füur 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 Génome Québec Innovation Centre, Montréal, Canada. The names of Care4Rare Canada steering committee members appear in the Supplemental Acknowledgments.

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Medicine(all)

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10.1172/JCI89626

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Lovric, S., Goncalves, S., Gee, H. Y., Oskouian, B., Srinivas, H., Choi, W. I., Shril, S., Ashraf, S., Tan, W., Rao, J., Airik, M., Schapiro, D., Braun, D. A., Sadowski, C. E., Widmeier, E., Jobst-Schwan, T., Schmidt, J. M., Girik, V., Capitani, G., ... Hildebrandt, F. (2017). Mutations in sphingosine-1-phosphate lyase cause nephrosis with ichthyosis and adrenal insufficiency. Journal of Clinical Investigation, 127(3), 912-928. https://doi.org/10.1172/JCI89626

@article{267b82555bdc481d98de96266433f4ae,

title = "Mutations in sphingosine-1-phosphate lyase cause nephrosis with ichthyosis and adrenal insufficiency",

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 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.",

author = "Svjetlana Lovric and Sara Goncalves and Gee, {Heon Yung} and Babak Oskouian and Honnappa Srinivas and Choi, {Won Il} and Shirlee Shril and Shazia Ashraf and Weizhen Tan and Jia Rao and Merlin Airik and David Schapiro and Braun, {Daniela A.} and Sadowski, {Carolin E.} and Eugen Widmeier and Tilman Jobst-Schwan and Schmidt, {Johanna Magdalena} and Vladimir Girik and Guido Capitani and Suh, {Jung H.} and No{\"e}lle Lachauss{\'e}e and Christelle Arrondel and Julie Patat and Olivier Gribouval and Monica Furlano and Olivia Boyer and Alain Schmitt and Vincent Vuiblet and Seema Hashmi and Rainer Wilcken and Bernier, {Francois P.} and Innes, {A. Micheil} and Parboosingh, {Jillian S.} and Lamont, {Ryan E.} and Midgley, {Julian P.} and Nicola Wright and Jacek Majewski and Martin Zenker and Franz Schaefer and Navina Kuss and Johann Greil and Thomas Giese and Klaus Schwarz and Vilain Catheline and Denny Schanze and Ingolf Franke and Yves Sznajer and Truant, {Anne S.} and Brigitte Adams and Julie D{\'e}sir and Ronald Biemann and York Pei and Elisabet Ars and Nuria Lloberas and Alvaro Madrid and Dharnidharka, {Vikas R.} and Connolly, {Anne M.} and Willing, {Marcia C.} and Cooper, {Megan A.} and Lifton, {Richard P.} and Matias Simons and Howard Riezman and Corinne Antignac and Saba, {Julie D.} and Friedhelm Hildebrandt",

note = "Funding 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{\'e}dicale (DEQ20150331682), and the ''Investments for the Future'' program (ANR-10-IAHU-01). SG was supported by the Program Sant{\'e}-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{\"u}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{\'e}nome Qu{\'e}bec Innovation Centre, Montr{\'e}al, Canada. The names of Care4Rare Canada steering committee members appear in the Supplemental Acknowledgments.",

year = "2017",

month = mar,

day = "1",

doi = "10.1172/JCI89626",

language = "English",

volume = "127",

pages = "912--928",

journal = "Journal of Clinical Investigation",

issn = "0021-9738",

publisher = "The American Society for Clinical Investigation",

number = "3",

}

Lovric, S, Goncalves, S, Gee, HY, Oskouian, B, Srinivas, H, Choi, WI, Shril, S, Ashraf, S, Tan, W, Rao, J, Airik, M, Schapiro, D, Braun, DA, Sadowski, CE, Widmeier, E, Jobst-Schwan, T, Schmidt, JM, Girik, V, Capitani, G, Suh, JH, Lachaussée, N, Arrondel, C, Patat, J, Gribouval, O, Furlano, M, Boyer, O, Schmitt, A, Vuiblet, V, Hashmi, S, Wilcken, R, Bernier, FP, Innes, AM, Parboosingh, JS, Lamont, RE, Midgley, JP, Wright, N, Majewski, J, Zenker, M, Schaefer, F, Kuss, N, Greil, J, Giese, T, Schwarz, K, Catheline, V, Schanze, D, Franke, I, Sznajer, Y, Truant, AS, Adams, B, Désir, J, Biemann, R, Pei, Y, Ars, E, Lloberas, N, Madrid, A, Dharnidharka, VR, Connolly, AM, Willing, MC, Cooper, MA, Lifton, RP, Simons, M, Riezman, H, Antignac, C, Saba, JD & Hildebrandt, F 2017, 'Mutations in sphingosine-1-phosphate lyase cause nephrosis with ichthyosis and adrenal insufficiency', Journal of Clinical Investigation, vol. 127, no. 3, pp. 912-928. https://doi.org/10.1172/JCI89626

TY - JOUR

T1 - Mutations in sphingosine-1-phosphate lyase cause nephrosis with ichthyosis and adrenal insufficiency

AU - Lovric, Svjetlana

AU - Goncalves, Sara

AU - Gee, Heon Yung

AU - Oskouian, Babak

AU - Srinivas, Honnappa

AU - Choi, Won Il

AU - Shril, Shirlee

AU - Ashraf, Shazia

AU - Tan, Weizhen

AU - Rao, Jia

AU - Airik, Merlin

AU - Schapiro, David

AU - Braun, Daniela A.

AU - Sadowski, Carolin E.

AU - Widmeier, Eugen

AU - Jobst-Schwan, Tilman

AU - Schmidt, Johanna Magdalena

AU - Girik, Vladimir

AU - Capitani, Guido

AU - Suh, Jung H.

AU - Lachaussée, Noëlle

AU - Arrondel, Christelle

AU - Patat, Julie

AU - Gribouval, Olivier

AU - Furlano, Monica

AU - Boyer, Olivia

AU - Schmitt, Alain

AU - Vuiblet, Vincent

AU - Hashmi, Seema

AU - Wilcken, Rainer

AU - Bernier, Francois P.

AU - Innes, A. Micheil

AU - Parboosingh, Jillian S.

AU - Lamont, Ryan E.

AU - Midgley, Julian P.

AU - Wright, Nicola

AU - Majewski, Jacek

AU - Zenker, Martin

AU - Schaefer, Franz

AU - Kuss, Navina

AU - Greil, Johann

AU - Giese, Thomas

AU - Schwarz, Klaus

AU - Catheline, Vilain

AU - Schanze, Denny

AU - Franke, Ingolf

AU - Sznajer, Yves

AU - Truant, Anne S.

AU - Adams, Brigitte

AU - Désir, Julie

AU - Biemann, Ronald

AU - Pei, York

AU - Ars, Elisabet

AU - Lloberas, Nuria

AU - Madrid, Alvaro

AU - Dharnidharka, Vikas R.

AU - Connolly, Anne M.

AU - Willing, Marcia C.

AU - Cooper, Megan A.

AU - Lifton, Richard P.

AU - Simons, Matias

AU - Riezman, Howard

AU - Antignac, Corinne

AU - Saba, Julie D.

AU - Hildebrandt, Friedhelm

N1 - Funding 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 Médicale (DEQ20150331682), and the ''Investments for the Future'' program (ANR-10-IAHU-01). SG was supported by the Program Santé-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 füur 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 Génome Québec Innovation Centre, Montréal, Canada. The names of Care4Rare Canada steering committee members appear in the Supplemental Acknowledgments.

PY - 2017/3/1

Y1 - 2017/3/1

N2 - 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.

AB - 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.

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U2 - 10.1172/JCI89626

DO - 10.1172/JCI89626

M3 - Article

C2 - 28165339

AN - SCOPUS:85015884455

SN - 0021-9738

VL - 127

SP - 912

EP - 928

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

IS - 3

ER -

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

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