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

TitleMutations in sphingosine-1-phosphate lyase cause nephrosis with ichthyosis and adrenal insufficiency.
Publication TypeJournal Article
Year of Publication2017
AuthorsLovric, S, Goncalves, S, Gee, HYung, Oskouian, B, Srinivas, H, Choi, W-I, Shril, S, Ashraf, S, Tan, W, Rao, J, Airik, M, Schapiro, D, Braun, DA, Sadowski, CE, Widmeier, E, Jobst-Schwan, T, Schmidt, JMagdalena, 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, A Innes, M, 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
JournalJ Clin Invest
Date Published2017 Mar 01
KeywordsAldehyde-Lyases, Animals, Cell Line, Cell Movement, Drosophila melanogaster, Drosophila Proteins, Female, Humans, Ichthyosis, Lamellar, Male, Mesangial Cells, Mice, Mice, Knockout, Mutation, Nephrotic Syndrome, Protein Transport, Rats

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.

Alternate JournalJ. Clin. Invest.
PubMed ID28165339
PubMed Central IDPMC5330730
Grant ListUM1 HG006504 / HG / NHGRI NIH HHS / United States
UL1 TR001863 / TR / NCATS NIH HHS / United States
P30 DK079310 / DK / NIDDK NIH HHS / United States
F32 GM066594 / GM / NIGMS NIH HHS / United States
R01 DK076683 / DK / NIDDK NIH HHS / United States
R01 DK068306 / DK / NIDDK NIH HHS / United States
T32 DK007726 / DK / NIDDK NIH HHS / United States
S10 OD018070 / OD / NIH HHS / United States
R01 CA129438 / CA / NCI NIH HHS / United States