Pyridoxine supplementation ameliorates SGPL1 R222Q variant sphingosine phosphate lyase insufficiency syndrome in mice

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 glomerulosclerosis developed in SPLR222Q but not WT mice fed chow with reduced pyridoxine.

Ultrastructural analysis and super-resolution microscopy showed podocyte loss and foot process effacement. Transcriptional profiling revealed patterns of cytokine upregulation and extracellular matrix remodeling. Inhibiting S1P production or RhoA/ROCK signaling prevented nephrosis in SPLR222Q 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 pathway in its pathophysiology.