{"database":"GEO","file_versions":[{"headers":{"Content-Type":["application/json"]},"body":{"files":{"Other":["ftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE345nnn/GSE345689/"]},"type":"primary"},"statusCode":"OK","statusCodeValue":200}],"scores":null,"additional":{"omics_type":["Transcriptomics"],"species":["Mus musculus"],"gds_type":["Expression profiling by high throughput sequencing"],"full_dataset_link":["https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE345689"],"repository":["GEO"],"entry_type":["GSE"],"additional_accession":[]},"is_claimable":false,"name":"Pyridoxine supplementation ameliorates SGPL1 R222Q variant sphingosine phosphate lyase insufficiency syndrome in mice","description":"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.","dates":{"publication":"2026/09/02"},"accession":"GSE345689","cross_references":{"GSM":["GSM10013095","GSM10013096","GSM10013093","GSM10013094","GSM10013088","GSM10013089","GSM10013086","GSM10013097","GSM10013087","GSM10013091","GSM10013092","GSM10013090"],"GPL":["24247"],"GSE":["345689"],"taxon":["Mus musculus"]}}