期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 127, 期 3, 页码 912-928出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI89626
关键词
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资金
- NIH [DK076683, DK068306, GM66594, NCI CA129438]
- Basic Science Research Program through the National Research Foundation of Korea - Ministry of Education [2015R1D1A1A01056685]
- Nephcure-ASN Foundation Kidney Research Grant
- Yonsei University College of Medicine [6-2015-0175]
- Agence Nationale de la Recherche (GenPod project) [ANR-12-BSV1-0033.01]
- European Union's Seventh Framework Programme (FP7) [305608-EURenOmics]
- Fondation Recherche Medicale [DEQ20150331682]
- Investments for the Future program [ANR-10-IAHU-01]
- Program Sante-Science (MD-PhD) of Imagine Institute
- German Centre for Infectious Diseases
- John and Edna Beck Chair in Pediatric Cancer Research
- Swim Across America Foundation
- Center for Personalized Immunology - National Health and Medical Research Council of Australia [NHMRC]
- Australian National University, Canberra, Australia
- German Ministry of Education and Research (Bundesministerium fur Bildung und Forschung, project: GeNeRARe)
- Leopoldina Fellowship Program, German National Academy of Sciences Leopoldina [LPDS 2015-07]
- Deutsche Forschungsgemeinschaft (DFG) [Jo 1324/1-1]
- Spanish Society of Nephrology
- Catalan Society of Nephrology
- Swiss National Science Foundation
- SystemsX.CH
- NCCR Chemical Biology
- Genome Canada
- Canadian Institutes of Health Research
- Ontario Genomics Institute
- Ontario Research Fund
- Genome Quebec
- Children's Hospital of Eastern Ontario Research Foundation
- Agence Nationale de la Recherche (ANR) [ANR-12-BSV1-0033] Funding Source: Agence Nationale de la Recherche (ANR)
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.
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