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

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

Authors :
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
Source :
The Journal of clinical investigation [J Clin Invest] 2017 Mar 01; Vol. 127 (3), pp. 912-928. Date of Electronic Publication: 2017 Feb 06.
Publication Year :
2017

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.

Details

Language :
English
ISSN :
1558-8238
Volume :
127
Issue :
3
Database :
MEDLINE
Journal :
The Journal of clinical investigation
Publication Type :
Academic Journal
Accession number :
28165339
Full Text :
https://doi.org/10.1172/JCI89626