Srinivas, Honnappa and Wilcken, Rainer (2017) Manuscript: SGPL1 mutations cause nephrosis with ichthyosis and adrenal insufficiency. Note: Details of NIBR contribution to manuscript: The results of Mutational analysis of SGPL1: In silico modelling ( were approved in OAK before-ref link https://oak-intra.novartis.com/25460/). Mutational analysis of SGPL1: In silico modelling results were shared with Prof. Friedhelm Hildebrandt, Harvard medical school, Division of Nephrology Boston Children's Hospital. These results, that were shared with Prof. Friedhelm Hildebrandt is now a part of full manuscript for publication with Prof. Friedhelm Hildebrandt as corresponding author . Honnappa Srinivas and Rainer Wilcken are the co-authors from NIBR. Please find attached the full manuscript. The Journal of clinical investigation : JCI, 127. pp. 912-928. ISSN 1558-8238

Abstract

ABSTRACT
Steroid-resistant nephrotic syndrome (SRNS) causes 15% of chronic kidney disease. A mutation in one of >40 different monogenic genes can be detected in ~30% of individuals with SRNS who manifest before 25 years of age. However, in many patients the genetic etiology remains unknown.
We performed whole exome sequencing (WES) to identify novel recessive causes of SRNS. In 7 families with a new syndrome of SRNS and facultative ichthyosis, adrenal insufficiency, immunodeficiency and neurological defects, we identified 9 different recessive mutations in SGPL1 encoding sphingosine-1-phosphate lyase. All mutations resulted in reduced or absent SGPL1 protein and/or enzyme activity. Overexpression of cDNA representing mutations of SRNS patients 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 variant proteins did not. Immunofluorescence revealed SGPL1 expression in mouse podocytes and mesangial cells. Knockdown of SGPL1 in rat mesangial cells (RMC) inhibited cell migration, which was partially rescued by VPC23109, an S1P receptor antagonist. Knockdown of SGPL1 in RMC resulted in a decrease of active RAC1 and CDC42, consistent with previously noted podocytic imbalance of active RAC1 in the pathogenesis of SRNS. In Drosophila Sply mutants, which lack SGPL1, a phenotype reminiscent of nephrotic syndrome was observed in ‘nephrocytes’ and was rescued by WT Sply but not by the disease-associated variants.
We here discover SGPL1 mutations as a new syndromic form of SRNS. Its pathogenesis entails mesangial cell dysfunction and decrease of active RAC1, which was partially mitigated by S1P receptor inhibition.

Item Type:	Article
Date Deposited:	23 Mar 2017 00:45
Last Modified:	23 Mar 2017 00:45
URI:	https://oak.novartis.com/id/eprint/30139