Pyridoxine supplementation amelioratesSGPL1 R222Q variant sphingosine phosphate lyase insufficiency syndrome in mice.

Sphingosine-1-phosphate lyase insufficiency syndrome (SPLIS) is a rare condition causing nephrotic syndrome, neuropathy, and other manifestations. SPLIS is caused by mutations in SGPL1, which encodes sphingosine-1-phosphate lyase (SPL), a vitamin B6-dependent enzyme needed to degrade the bioactive sphingolipid sphingosine-1-phosphate (S1P). Supplementation with pyridoxine, a form of vitamin B6, benefits some individuals with other diseases caused by defects of B6-dependent enzymes. We investigated whether pyridoxine has therapeutic activity in SPLIS. Neurological improvement, plasma S1P normalization, and increased SPL activity in patient-derived skin cells were observed after pyridoxine supplementation in a patient with R222Q-variant SPLIS. Additionally, B6 dose-dependently increased disease-associated SPL mutant enzyme activity in vitro. To further explore pyridoxine's effects, gene editing was employed to create an R222Q-variant SPLIS mouse model. SPLR222Q mice fed pyridoxine-enriched chow lacked obvious phenotypes. However, SPL inactivation, S1P accumulation, proteinuria, and kidney fibrosis developed in SPL R222Q but not WT mice fed chow with reduced pyridoxine. Super-resolution microscopy showed injury and loss of podocytes, the key cells implicated in nephrotic syndrome. Comparison of the gene expression patterns of the kidneys of SPLIS mice and controls revealed changes consistent with inflammation and scar formation (fibrosis) in the SPLIS kidneys at an early point. Inhibiting S1P production or signaling prevented the development of kidney disease in SPLIS mice fed chow lacking pyridoxine. Our findings establish a SPLIS mouse model that recapitulates R222Q-variant SPLIS, demonstrates its responsiveness to pyridoxine, and implicates a S1P/RhoA/ROCK signaling pathway as an underlying cause of the disease.