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

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Lovric, Svjetlana Goncalves, Sara Gee, Heon Yung Oskouian, Babak Srinivas, Honnappa Sznajer, Yves [UCL] Truant, Anne-Sophie [UCL] Hildebrandt, Friedhelm

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.

Document type Article de périodique (Journal article) – Article de recherche
Access type Accès libre
Publication date 2017
Language Anglais
Journal information "Journal of Clinical Investigation" - Vol. 127, no.3, p. 912-928 (2017)
Peer reviewed yes
Publisher American Society for Clinical Investigation ((United States) Ann Arbor, MI)
issn 0021-9738
e-issn 1558-8238
Publication status Publié
Affiliations UCL - SSS/IREC/SLUC - Pôle St.-Luc
UCL - (SLuc) Centre de génétique médicale UCL
UCL - (SLuc) Service de néonatologie
MESH Subject Aldehyde-Lyases ; Animals ; Cell Line ; Cell Movement ; Drosophila Proteins ; Drosophila melanogaster ; Female ; Humans ; Ichthyosis, Lamellar ; Male ; Mesangial Cells ; Mice ; Mice, Knockout ; Mutation ; Nephrotic Syndrome ; Protein Transport ; Rats
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Bibliographic reference Lovric, Svjetlana ; Goncalves, Sara ; Gee, Heon Yung ; Oskouian, Babak ; Srinivas, Honnappa ; et. al. Mutations in sphingosine-1-phosphate lyase cause nephrosis with ichthyosis and adrenal insufficiency.. In: Journal of Clinical Investigation, Vol. 127, no.3, p. 912-928 (2017)
Permanent URL http://hdl.handle.net/2078.1/204417