Back to Search
Start Over
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.
- 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.
- Subjects :
- Animals
Cell Line
Drosophila Proteins genetics
Drosophila Proteins metabolism
Drosophila melanogaster
Female
Humans
Male
Mesangial Cells pathology
Mice
Mice, Knockout
Protein Transport genetics
Rats
Aldehyde-Lyases genetics
Aldehyde-Lyases metabolism
Cell Movement genetics
Ichthyosis, Lamellar enzymology
Ichthyosis, Lamellar genetics
Ichthyosis, Lamellar pathology
Mesangial Cells enzymology
Mutation
Nephrotic Syndrome enzymology
Nephrotic Syndrome genetics
Nephrotic Syndrome pathology
Subjects
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