Sphingosine phosphate lyase insufficiency syndrome as a primary immunodeficiency state.

Sphingosine phosphate lyase insufficiency syndrome (SPLIS) is a genetic disease associated with renal, endocrine, neurological, skin and immune defects. SPLIS is caused by inactivating mutations in SGPL1, which encodes sphingosine phosphate lyase (SPL). SPL catalyzes the irreversible degradation of the bioactive sphingolipid sphingosine-1-phosphate (S1P), a key regulator of lymphocyte egress.

The fate of intracellular S1P regulates lipid droplet turnover and lipotoxicity in pancreatic beta-cells.

Lipotoxicity has been considered the main cause of pancreatic beta-cell failure during type 2 diabetes development. Lipid droplets (LD) are believed to regulate the beta-cell sensitivity to free fatty acids (FFA), but the underlying molecular mechanisms are largely unclear. Accumulating evidence points, however, to an important role of intracellular sphingosine-1-phosphate (S1P) metabolism in lipotoxicity-mediated disturbances of beta-cell function.

AF1q is a universal marker of neuroblastoma that sustains N-Myc expression and drives tumorigenesis.

Neuroblastoma is the most common extracranial malignant tumor of childhood, accounting for 15% of all pediatric cancer deaths. Despite significant advances in our understanding of neuroblastoma biology, five-year survival rates for high-risk disease remain less than 50%, highlighting the importance of identifying novel therapeutic targets to combat the disease. MYCN amplification is the most frequent and predictive molecular aberration correlating with poor outcome in neuroblastoma.

Gene therapy with AAV9-SGPL1 in an animal model of lung fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a progressive scarring disease of the lung that leads rapidly to respiratory failure. Novel approaches to treatment are urgently needed. The bioactive lipid sphingosine-1-phosphate (S1P) is increased in IPF lungs and promotes proinflammatory and profibrotic TGF-β signaling.

AAV-SPL 2.0, a Modified Adeno-Associated Virus Gene Therapy Agent for the Treatment of Sphingosine Phosphate Lyase Insufficiency Syndrome.

Sphingosine-1-phosphate lyase insufficiency syndrome (SPLIS) is an inborn error of metabolism caused by inactivating mutations in , the gene encoding sphingosine-1-phosphate lyase (SPL), an essential enzyme needed to degrade sphingolipids. SPLIS features include glomerulosclerosis, adrenal insufficiency, neurological defects, ichthyosis, and immune deficiency. Currently, there is no cure for SPLIS, and severely affected patients often die in the first years of life.

Prevalence estimate of sphingosine phosphate lyase insufficiency syndrome in worldwide and select populations.

Purpose: Sphingosine phosphate lyase insufficiency syndrome (SPLIS) is a rare, often fatal, metabolic disorder and monogenic form of steroid-resistant nephrotic syndrome. Other manifestations include primary adrenal insufficiency, ichthyosis, and neurological defects. SPLIS is caused by biallelic pathogenic variants in , encoding sphingosine-1-phosphate lyase, a pyridoxal 5'-phosphate-dependent enzyme that catalyzes the final step of sphingolipid metabolism.

Sphingosine phosphate lyase insufficiency syndrome: a systematic review.

Background: Sphingosine-1-phosphate lyase insufficiency syndrome (SPLIS) or nephrotic syndrome type-14 is caused by biallelic mutations in SGPL1. Here, we conducted a systematic review to delineate the characteristics of SPLIS patients.

Methods: A literature search was performed in PubMed, Web of Science, and Scopus databases, and eligible studies were included.

Neurological Consequences of Sphingosine Phosphate Lyase Insufficiency.

In 2017, an inborn error of metabolism caused by recessive mutations in was discovered. The disease features steroid-resistant nephrotic syndrome, adrenal insufficiency, and neurological defects. The latter can include sensorineural hearing loss, cranial nerve defects, peripheral neuropathy, abnormal brain development, seizures and/or neurodegeneration.

Sphingosine Phosphate Lyase Is Upregulated in Duchenne Muscular Dystrophy, and Its Inhibition Early in Life Attenuates Inflammation and Dystrophy in Mdx Mice.

Duchenne muscular dystrophy (DMD) is a congenital myopathy caused by mutations in the dystrophin gene. DMD pathology is marked by myositis, muscle fiber degeneration, and eventual muscle replacement by fibrosis and adipose tissue. Satellite cells (SC) are muscle stem cells critical for muscle regeneration.

Analyzing Opposing Interactions Between Sphingosine 1-Phosphate Lyase and Influenza A Virus.

Sphingosine 1-phosphate lyase (SPL) is a critical component of sphingosine 1-phosphate (S1P) metabolism. SPL has been associated with several crucial cellular functions due to its role in S1P metabolism, but its role in viral infections is poorly understood. Studies show that SPL has an antiviral function against influenza A virus (IAV) by interacting with IKKɛ, promoting the type I interferon (IFN) innate immune response to IAV infection.

Mouse Liver Compensates Loss of Sgpl1 by Secretion of Sphingolipids into Blood and Bile.

Sphingosine 1 phosphate (S1P) lyase () catalyses the irreversible cleavage of S1P and thereby the last step of sphingolipid degradation. Loss of in humans and mice leads to accumulation of sphingolipids and multiple organ injuries. Here, we addressed the role of hepatocyte for regulation of sphingolipid homoeostasis by generating mice with hepatocyte-specific deletion of ( mice).

Genotype/Phenotype Interactions and First Steps Toward Targeted Therapy for Sphingosine Phosphate Lyase Insufficiency Syndrome.

Sphingosine-1-phosphate lyase insufficiency syndrome (SPLIS) is a rare metabolic disorder caused by a deficiency in sphingosine-1-phosphate lyase (SPL), the final enzyme in the sphingolipid degradative pathway. Inactivating mutations of SGPL1-the gene encoding SPL-lead to a deficiency of its downstream products, and buildup of sphingolipid intermediates, including its bioactive substrate, sphingosine-1-phosphate (S1P), the latter causing lymphopenia, a hallmark of the disease. Other manifestations of SPLIS include nephrotic syndrome, neuronal defects, and adrenal insufficiency, but their pathogenesis remains unknown.

Efficacy of AAV9-mediated SGPL1 gene transfer in a mouse model of S1P lyase insufficiency syndrome.

Sphingosine-1-phosphate lyase insufficiency syndrome (SPLIS) is a rare metabolic disorder caused by inactivating mutations in sphingosine-1-phosphate lyase 1 (SGPL1), which is required for the final step of sphingolipid metabolism. SPLIS features include steroid-resistant nephrotic syndrome and impairment of neurological, endocrine, and hematopoietic systems. Many affected individuals die within the first 2 years.

Responsiveness of sphingosine phosphate lyase insufficiency syndrome to vitamin B6 cofactor supplementation.

Sphingosine-1-phosphate (S1P) lyase is a vitamin B6-dependent enzyme that degrades sphingosine-1-phosphate in the final step of sphingolipid metabolism. In 2017, a new inherited disorder was described caused by mutations in SGPL1, which encodes sphingosine phosphate lyase (SPL). This condition is referred to as SPL insufficiency syndrome (SPLIS) or alternatively as nephrotic syndrome type 14 (NPHS14).

Correction to: Sphingadienes show therapeutic efficacy in neuroblastoma in vitro and in vivo by targeting the AKT signaling pathway.

The authors would like to note an omission of disclosure in this paper. Author JDS is cofounder, equity-holder, and consultant of GILTRx Therapeutics.

Fifty years of lyase and a moment of truth: sphingosine phosphate lyase from discovery to disease.

Sphingosine phosphate lyase (SPL) is the final enzyme in the sphingolipid degradative pathway, catalyzing the irreversible cleavage of long-chain base phosphates (LCBPs) to yield a long-chain aldehyde and ethanolamine phosphate (EP). SPL guards the sole exit point of sphingolipid metabolism. Its inactivation causes product depletion and accumulation of upstream sphingolipid intermediates.

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

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.

Sphingosine-1-Phosphate Signaling and Metabolism Gene Signature in Pediatric Inflammatory Bowel Disease: A Matched-case Control Pilot Study.

Goal: The aim of this study was to investigate gene expression levels of proteins involved in sphingosine-1-phosphate (S1P) metabolism and signaling in a pediatric inflammatory bowel disease (IBD) patient population.

Background: IBD is a debilitating disease affecting 0.4% of the US population.

Sphingadienes show therapeutic efficacy in neuroblastoma in vitro and in vivo by targeting the AKT signaling pathway.

Neuroblastoma is a childhood malignancy that accounts for approximately 15% of childhood cancer deaths. Only 20-35% of children with metastatic neuroblastoma survive with standard therapy. Identification of more effective therapies is essential to improving the outcome of children with high-stage disease.

S1P Lyase Regulation of Thymic Egress and Oncogenic Inflammatory Signaling.

Sphingosine-1-phosphate (S1P) is a potent lipid signaling molecule that regulates pleiotropic biological functions including cell migration, survival, angiogenesis, immune cell trafficking, inflammation, and carcinogenesis. It acts as a ligand for a family of cell surface receptors. S1P concentrations are high in blood and lymph but low in tissues, especially the thymus and lymphoid organs.

Overexpression of sphingosine-1-phosphate lyase protects insulin-secreting cells against cytokine toxicity.

Increasing evidence suggests a crucial role of inflammation in cytokine-mediated β-cell dysfunction and death in type 1 diabetes mellitus, although the mechanisms are incompletely understood. Sphingosine 1-phosphate (S1P) is a multifunctional bioactive sphingolipid involved in the development of many autoimmune and inflammatory diseases. Here, we investigated the role of intracellular S1P in insulin-secreting INS1E cells by genetically manipulating the S1P-metabolizing enzyme S1P lyase (SPL).