Deficiency of the sphingosine-1-phosphate lyase SGPL1 is associated with congenital nephrotic syndrome and congenital adrenal calcifications

Abstract

We identified two unrelated consanguineous families with three children affected by the rare association of congenital nephrotic syndrome diagnosed in the first days of life, of hypogonadism, and of prenatally detected adrenal calcifications, associated with congenital adrenal insufficiency in one case. Using exome sequencing and targeted Sanger sequencing two homozygous truncating mutations, c.1513C>T (p.Arg505*) and c.934delC (p.Leu312Phefs*30), were identified in SGPL1 encoding sphingosine-1-phosphate lyase 1. SGPL1 catalyzes the irreversible degradation of endogenous and dietary sphingosine-1-phosphate (S1P), the final step of sphingolipid catabolism, and of other phosphorylated long-chain bases. S1P is an intra- and extracellular signaling molecule involved in angiogenesis, vascular maturation, and immunity. The levels of SGPL1 substrates, S1P and sphingosine were markedly increased in the patients’ blood and fibroblasts, as determined by liquid chromatography-tandem mass spectrometry. Vascular alterations were present in a patient’s renal biopsy, in line with changes seen in Sgpl1 knockout mice that are compatible with a developmental defect in vascular maturation. In conclusion, loss of SGPL1 function is associated with congenital nephrotic syndrome, adrenal calcifications, and hypogonadism.

Yeast Mpo1 Is a Novel Dioxygenase That Catalyzes the α-Oxidation of a 2-Hydroxy Fatty Acid in an Fe2+-Dependent Manner

“…This is also the case for LCB homeostasis. In humans, mutations in sphingosine 1-phosphate lyase SGPL1 (a homolog of yeast LCBP lyase DPL1), the gene involved in the first, irreversible reaction in LCB degradation pathways, cause the inherited disorders Charcot-Marie-Tooth disease and steroid-resistant nephrotic syndrome (17)(18)(19)(20). Organisms have countless sophisticated and nonwasteful metabolic pathways to convert biomolecules into other compounds, which can in turn be used as precursors of other biomolecules or as an energy source.…”

“…DHS metabolism in mammals is achieved via the same reactions as in yeast by homologous animal enzymes (SPHK1 and SPHK2, Lcb4 homologs; SGPL1, a Dpl1 homolog; ALDH3A2, an Hfd1 homolog; and ACSL1-6, FAA1/ Faa4 homologs) (8,(12)(13)(14)(15). Mutations in two of the genes encoding these enzymes are known to cause inherited diseases (SGPL1, Charcot-Marie-Tooth disease or steroidresistant nephrotic syndrome; ALDH3A2, Sjögren-Larsson syndrome) (16)(17)(18)(19)(20), illustrating the physiological and pathological importance of the LCB degradation pathway.…”

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).…”

Aberrant DEGS1 sphingolipid metabolism impairs central and peripheral nervous system function in humans

“…Mutations in the GM3 synthase gene ST3GAL5 were associated with refractory epilepsy, myoclonus, generalized tonic-clonic seizures, psychomotor delay, developmental stagnation, blindness, and deafness due to an increase in LacCer and other gangliosides (OMIM #609056) 13,14 , whereas defects in the GM2/GD2 synthase (B4GALNT1) lead to GM3 accumulation and a complex form of hereditary spastic paraplegia with cognitive impairment and seizures (OMIM #609195) 15 . Recently, mutations in SGPL1 were associated with a spectrum of disease phenotypes 16,17,18 including recessive steroid-resistant nephrotic syndrome (SRNS), ichthyosis, adrenal insufficiency, immunodeficiency and brain defects (OMIM #617575). In addition, SGPL1 mutations were found in a family with Charcot-Marie-Tooth neuropathy (CMT).…”