Sphingosine phosphate lyase insufficiency syndrome (SPLIS): A novel inborn error of sphingolipid metabolism

Abstract

Sphingosine-1-phosphate lyase (SPL) is an intracellular enzyme that controls the final step in the sphingolipid degradative pathway, the only biochemical pathway for removal of sphingolipids. Specifically, SPL catalyzes the cleavage of sphingosine 1-phosphate (S1P) at the C2-3 carbon bond, resulting in its irreversible degradation to phosphoethanolamine (PE) and hexadecenal. The substrate of the reaction, S1P, is a bioactive sphingolipid metabolite that signals through a family of five G protein-coupled S1P receptors (S1PRs) to mediate biological activities including cell migration, cell survival/death/proliferation and cell extrusion, thereby contributing to development, physiological functions and - when improperly regulated - the pathophysiology of disease. In 2017, several groups including ours reported a novel childhood syndrome that featured a wide range of presentations including fetal hydrops, steroid-resistant nephrotic syndrome (SRNS), primary adrenal insufficiency (PAI), rapid or insidious neurological deterioration, immunodeficiency, acanthosis and endocrine abnormalities. In all cases, the disease was attributed to recessive mutations in the human SPL gene, SGPL1. We now refer to this condition as SPL Insufficiency Syndrome, or SPLIS. Some features of this new sphingolipidosis were predicted by the reported phenotypes of Sgpl1 homozygous null mice that serve as vertebrate SPLIS disease models. However, other SPLIS features reveal previously unrecognized roles for SPL in human physiology. In this review, we briefly summarize the biochemistry, functions and regulation of SPL, the main clinical and biochemical features of SPLIS and what is known about the pathophysiology of this condition from murine and cell models. Lastly, we consider potential therapeutic strategies for the treatment of SPLIS patients.

Keywords: Charcot Marie Tooth disease; Focal segmental glomerulosclerosis; Immunodeficiency; Lymphopenia; NPHS14; Nephrotic syndrome; Neuropathy; SGPL1; Sphingolipid; Sphingosine phosphate lyase; Sphingosine-1-phosphate.

Figure 1.. Basic structures of sphingolipids.

Sphingolipids contain a long chain amino base, also known as a sphingoid base. Sphingosine is the most common sphingoid base in mammals. Ceramides contain sphingosine in amide linkage with a fatty acid of variable chain length and saturation. Sphingosine can be phosphorylated, giving rise to the bioactive signaling molecule, sphingosine-1-phosphate (S1P). Sphingomyelin is formed when a phosphocholine head group is added to the hydroxyl group at the C1 position of ceramide.

Figure 2.. Sphingolipid metabolic pathway.

Enzymes catalyzing the conversion steps are listed numerically. Of note, serine palmitoyltransferase (SPT) catalyzes the condensation reaction between serine and palmitoyl-CoA, the rate limiting induction step in sphingolipid biosynthesis. Sphingosine phosphate lyase (SPL) catalyzes the irreversible cleavage of sphingosine-1-phosphate (S1P), the final and essential step in sphingolipid catabolism.

Figure 3.. Sites of all identified SGPL1 mutations in exon and protein structures.

SGPL1 cDNA contains 15 exons, and the coding sequence is 568 amino acids long. Pyridoxal-dependent decarboxylase conserved domain (PDCD) contains active site residue K353 whichbinds to pyridoxal 5′-phosphate (PLP). ELD, Endoplasmic lumenal domain; T, Transmembrane domain; Cytoplasmic domain in green.