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

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 diseaseassociated 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.

Dyslipidaemia in nephrotic syndrome: mechanisms and treatment

“…Finally, the finding that a mutation in the enzyme sphingosine 1 phosphate lyase causes nephrotic syndrome 74 , together with the observation that enzymes involved in sphingolipid metabolism, such as acid sphingomyelinase-like phosphodiesterase 3b (SMPDL3b), might serve as modulators of lipid raft-dependent signalling 75 and might cause proteinuria, raises the important question of the potential role of sphingolipid modulators in causing podocyte injury in nephrotic syndrome.…”

Primary adrenal insufficiency: New genetic causes and their long‐term consequences

“…Another recent discovery is the association of PAI with steroid‐resistant nephrotic syndrome, due to homozygous or compound heterozygous variants in sphingosine‐1‐phosphate lyase‐1 (SGPL1) …”

“…Another recent discovery is the association of PAI with steroid-resistant nephrotic syndrome, due to homozygous or compound heterozygous variants in sphingosine-1-phosphate lyase-1 (SGPL1). [67][68][69] SGPL1 is an enzyme that catalyses the breakdown of sphingolipids by cleaving sphingosine-1-phosphate. 67 Figure 4B).…”

Conserved function of ether lipids and sphingolipids in the early secretory pathway

“…These bioactive lipids have been extensively studied in the last decades, revealing distinctive physico-chemical properties and connections to diseases 4, 5 . SL have been implicated in diabetes 6 , cancer 7 and inflammation 8 , and mutations in SL synthetic or metabolic enzymes are associated with severe genetic disorders 9-11 . SL species sphingosine (So) and ceramide (Cer) can permeabilize membranes 12, 13 ; Cer induces the flip-flop of neighbouring lipids 14 and can phase-separate to form membrane platforms important for signalling 15 .…”