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

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

doi:10.1172/JCI206980

¹Department of Pediatrics, UCSF School of Medicine, San Francisco, United States of America

²Genetics of Development and Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, United States of America

³Ochsner Clinical School, University of Queensland and Ochsner Health, New Orleans, United States of America

⁴Department of Molecular Biosciences, University of Texas at Austin, Austin, United States of America

⁵Department of Physiology and Neuroscience and Department of Medicine, Zilkha Neurogenetic Institute, University of Southern California, Los Angeles, United States of America

⁶Department of Pathology, University of Michigan School of Medicine, Ann Arbor, United States of America

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¹Department of Pediatrics, UCSF School of Medicine, San Francisco, United States of America

²Genetics of Development and Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, United States of America

³Ochsner Clinical School, University of Queensland and Ochsner Health, New Orleans, United States of America

⁴Department of Molecular Biosciences, University of Texas at Austin, Austin, United States of America

⁵Department of Physiology and Neuroscience and Department of Medicine, Zilkha Neurogenetic Institute, University of Southern California, Los Angeles, United States of America

⁶Department of Pathology, University of Michigan School of Medicine, Ann Arbor, United States of America

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¹Department of Pediatrics, UCSF School of Medicine, San Francisco, United States of America

²Genetics of Development and Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, United States of America

³Ochsner Clinical School, University of Queensland and Ochsner Health, New Orleans, United States of America

⁴Department of Molecular Biosciences, University of Texas at Austin, Austin, United States of America

⁵Department of Physiology and Neuroscience and Department of Medicine, Zilkha Neurogenetic Institute, University of Southern California, Los Angeles, United States of America

⁶Department of Pathology, University of Michigan School of Medicine, Ann Arbor, United States of America

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¹Department of Pediatrics, UCSF School of Medicine, San Francisco, United States of America

²Genetics of Development and Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, United States of America

³Ochsner Clinical School, University of Queensland and Ochsner Health, New Orleans, United States of America

⁴Department of Molecular Biosciences, University of Texas at Austin, Austin, United States of America

⁵Department of Physiology and Neuroscience and Department of Medicine, Zilkha Neurogenetic Institute, University of Southern California, Los Angeles, United States of America

⁶Department of Pathology, University of Michigan School of Medicine, Ann Arbor, United States of America

Find articles by Lee, J. in: PubMed | Google Scholar

¹Department of Pediatrics, UCSF School of Medicine, San Francisco, United States of America

²Genetics of Development and Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, United States of America

³Ochsner Clinical School, University of Queensland and Ochsner Health, New Orleans, United States of America

⁴Department of Molecular Biosciences, University of Texas at Austin, Austin, United States of America

⁵Department of Physiology and Neuroscience and Department of Medicine, Zilkha Neurogenetic Institute, University of Southern California, Los Angeles, United States of America

⁶Department of Pathology, University of Michigan School of Medicine, Ann Arbor, United States of America

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¹Department of Pediatrics, UCSF School of Medicine, San Francisco, United States of America

²Genetics of Development and Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, United States of America

³Ochsner Clinical School, University of Queensland and Ochsner Health, New Orleans, United States of America

⁴Department of Molecular Biosciences, University of Texas at Austin, Austin, United States of America

⁵Department of Physiology and Neuroscience and Department of Medicine, Zilkha Neurogenetic Institute, University of Southern California, Los Angeles, United States of America

⁶Department of Pathology, University of Michigan School of Medicine, Ann Arbor, United States of America

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¹Department of Pediatrics, UCSF School of Medicine, San Francisco, United States of America

²Genetics of Development and Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, United States of America

³Ochsner Clinical School, University of Queensland and Ochsner Health, New Orleans, United States of America

⁴Department of Molecular Biosciences, University of Texas at Austin, Austin, United States of America

⁵Department of Physiology and Neuroscience and Department of Medicine, Zilkha Neurogenetic Institute, University of Southern California, Los Angeles, United States of America

⁶Department of Pathology, University of Michigan School of Medicine, Ann Arbor, United States of America

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¹Department of Pediatrics, UCSF School of Medicine, San Francisco, United States of America

²Genetics of Development and Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, United States of America

³Ochsner Clinical School, University of Queensland and Ochsner Health, New Orleans, United States of America

⁴Department of Molecular Biosciences, University of Texas at Austin, Austin, United States of America

⁵Department of Physiology and Neuroscience and Department of Medicine, Zilkha Neurogenetic Institute, University of Southern California, Los Angeles, United States of America

⁶Department of Pathology, University of Michigan School of Medicine, Ann Arbor, United States of America

Find articles by Buncha, V. in: PubMed | Google Scholar

¹Department of Pediatrics, UCSF School of Medicine, San Francisco, United States of America

²Genetics of Development and Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, United States of America

³Ochsner Clinical School, University of Queensland and Ochsner Health, New Orleans, United States of America

⁴Department of Molecular Biosciences, University of Texas at Austin, Austin, United States of America

⁵Department of Physiology and Neuroscience and Department of Medicine, Zilkha Neurogenetic Institute, University of Southern California, Los Angeles, United States of America

⁶Department of Pathology, University of Michigan School of Medicine, Ann Arbor, United States of America

Find articles by Gyarmati, G. in: PubMed | Google Scholar

¹Department of Pediatrics, UCSF School of Medicine, San Francisco, United States of America

²Genetics of Development and Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, United States of America

³Ochsner Clinical School, University of Queensland and Ochsner Health, New Orleans, United States of America

⁴Department of Molecular Biosciences, University of Texas at Austin, Austin, United States of America

⁵Department of Physiology and Neuroscience and Department of Medicine, Zilkha Neurogenetic Institute, University of Southern California, Los Angeles, United States of America

⁶Department of Pathology, University of Michigan School of Medicine, Ann Arbor, United States of America

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¹Department of Pediatrics, UCSF School of Medicine, San Francisco, United States of America

²Genetics of Development and Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, United States of America

³Ochsner Clinical School, University of Queensland and Ochsner Health, New Orleans, United States of America

⁴Department of Molecular Biosciences, University of Texas at Austin, Austin, United States of America

⁵Department of Physiology and Neuroscience and Department of Medicine, Zilkha Neurogenetic Institute, University of Southern California, Los Angeles, United States of America

⁶Department of Pathology, University of Michigan School of Medicine, Ann Arbor, United States of America

Find articles by Al-Khaledy, R. in: PubMed | Google Scholar

¹Department of Pediatrics, UCSF School of Medicine, San Francisco, United States of America

²Genetics of Development and Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, United States of America

³Ochsner Clinical School, University of Queensland and Ochsner Health, New Orleans, United States of America

⁴Department of Molecular Biosciences, University of Texas at Austin, Austin, United States of America

⁵Department of Physiology and Neuroscience and Department of Medicine, Zilkha Neurogenetic Institute, University of Southern California, Los Angeles, United States of America

⁶Department of Pathology, University of Michigan School of Medicine, Ann Arbor, United States of America

Find articles by Hodgin, J. in: PubMed | Google Scholar |

¹Department of Pediatrics, UCSF School of Medicine, San Francisco, United States of America

²Genetics of Development and Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, United States of America

³Ochsner Clinical School, University of Queensland and Ochsner Health, New Orleans, United States of America

⁴Department of Molecular Biosciences, University of Texas at Austin, Austin, United States of America

⁵Department of Physiology and Neuroscience and Department of Medicine, Zilkha Neurogenetic Institute, University of Southern California, Los Angeles, United States of America

⁶Department of Pathology, University of Michigan School of Medicine, Ann Arbor, United States of America

Find articles by Tassew, G. in: PubMed | Google Scholar

¹Department of Pediatrics, UCSF School of Medicine, San Francisco, United States of America

²Genetics of Development and Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, United States of America

³Ochsner Clinical School, University of Queensland and Ochsner Health, New Orleans, United States of America

⁴Department of Molecular Biosciences, University of Texas at Austin, Austin, United States of America

⁵Department of Physiology and Neuroscience and Department of Medicine, Zilkha Neurogenetic Institute, University of Southern California, Los Angeles, United States of America

⁶Department of Pathology, University of Michigan School of Medicine, Ann Arbor, United States of America

Find articles by Oskouian, B. in: PubMed | Google Scholar

¹Department of Pediatrics, UCSF School of Medicine, San Francisco, United States of America

²Genetics of Development and Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, United States of America

³Ochsner Clinical School, University of Queensland and Ochsner Health, New Orleans, United States of America

⁴Department of Molecular Biosciences, University of Texas at Austin, Austin, United States of America

⁵Department of Physiology and Neuroscience and Department of Medicine, Zilkha Neurogenetic Institute, University of Southern California, Los Angeles, United States of America

⁶Department of Pathology, University of Michigan School of Medicine, Ann Arbor, United States of America

Find articles by Chen, A. in: PubMed | Google Scholar

¹Department of Pediatrics, UCSF School of Medicine, San Francisco, United States of America

²Genetics of Development and Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, United States of America

³Ochsner Clinical School, University of Queensland and Ochsner Health, New Orleans, United States of America

⁴Department of Molecular Biosciences, University of Texas at Austin, Austin, United States of America

⁵Department of Physiology and Neuroscience and Department of Medicine, Zilkha Neurogenetic Institute, University of Southern California, Los Angeles, United States of America

⁶Department of Pathology, University of Michigan School of Medicine, Ann Arbor, United States of America

Find articles by Chang, Y. in: PubMed | Google Scholar

¹Department of Pediatrics, UCSF School of Medicine, San Francisco, United States of America

²Genetics of Development and Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, United States of America

³Ochsner Clinical School, University of Queensland and Ochsner Health, New Orleans, United States of America

⁴Department of Molecular Biosciences, University of Texas at Austin, Austin, United States of America

⁵Department of Physiology and Neuroscience and Department of Medicine, Zilkha Neurogenetic Institute, University of Southern California, Los Angeles, United States of America

⁶Department of Pathology, University of Michigan School of Medicine, Ann Arbor, United States of America

Find articles by Zhang, R. in: PubMed | Google Scholar

¹Department of Pediatrics, UCSF School of Medicine, San Francisco, United States of America

²Genetics of Development and Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, United States of America

³Ochsner Clinical School, University of Queensland and Ochsner Health, New Orleans, United States of America

⁴Department of Molecular Biosciences, University of Texas at Austin, Austin, United States of America

⁵Department of Physiology and Neuroscience and Department of Medicine, Zilkha Neurogenetic Institute, University of Southern California, Los Angeles, United States of America

⁶Department of Pathology, University of Michigan School of Medicine, Ann Arbor, United States of America

Find articles by Proia, R. in: PubMed | Google Scholar |

¹Department of Pediatrics, UCSF School of Medicine, San Francisco, United States of America

²Genetics of Development and Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bethesda, United States of America

³Ochsner Clinical School, University of Queensland and Ochsner Health, New Orleans, United States of America

⁴Department of Molecular Biosciences, University of Texas at Austin, Austin, United States of America

⁵Department of Physiology and Neuroscience and Department of Medicine, Zilkha Neurogenetic Institute, University of Southern California, Los Angeles, United States of America

⁶Department of Pathology, University of Michigan School of Medicine, Ann Arbor, United States of America

Find articles by Saba, J. in: PubMed | Google Scholar

J Clin Invest. https://doi.org/10.1172/JCI206980.
Copyright © 2026, Khan et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

Published September 24, 2026 - Version history

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. SPL^R222Q mice fed pyridoxine-enriched chow lacked obvious phenotypes. However, SPL inactivation, S1P accumulation, proteinuria, and glomerulosclerosis developed in SPL^R222Q 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 SPL^R222Q 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

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

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

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