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

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Abstract

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 pyridoxal 5′-phosphate (PLP)-dependent enzyme needed to degrade the bioactive sphingolipid sphingosine-1-phosphate (S1P). Supplementation with the PLP precursor pyridoxine benefits some individuals with PLP-dependent enzymopathies. We investigated whether pyridoxine has therapeutic activity in SPLIS. Neurological improvement, plasma S1P normalization, and increased SPL activity in patient-derived fibroblasts were observed after pyridoxine supplementation in a patient with R222Q-variant SPLIS. Additionally, PLP dose-dependently augmented recombinant R222Q-variant SPL activity. 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. Running Title: Cofactor supplementation in R222Q-variant SPLIS

Authors

Ranjha Khan, Maria L. Allende, Ehtesham Khalid, Joanna Y. Lee, Everett Stone, Max Rodnick-Smith, Audrey Izuhara, Vadym Buncha, Georgina Gyarmati, Janos Peti-Peterdi, Ranya Al-Khaledy, Jeffrey B. Hodgin, Gizachew Tassew, Babak Oskouian, Alina Chen, Yu-Tang Chang, Rachel Zhang, Richard L. Proia, Julie D. Saba