{"gene":"SPTLC2","run_date":"2026-04-28T20:42:08","timeline":{"discoveries":[{"year":1994,"finding":"LCB2 (yeast ortholog of SPTLC2) encodes a subunit of serine palmitoyltransferase (SPT), the enzyme that catalyzes condensation of palmitoyl-CoA and serine to form 3-ketosphinganine (first committed step in sphingolipid synthesis). Overproduction of SPT activity in yeast requires co-expression of both LCB1 and LCB2.","method":"Yeast genetics, overexpression, enzymatic activity assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1-2 — foundational enzymatic characterization, replicated extensively across labs","pmids":["8058731"],"is_preprint":false},{"year":1996,"finding":"Mammalian SPTLC2 (LCB2) was identified as the catalytic subunit of SPT; a 56-residue motif unique to LCB2 proteins was shown to functionally substitute for the corresponding region of yeast Lcb2p, identifying this motif as part of the catalytic domain of SPT and as a signature of Lcb2 proteins.","method":"Cloning of human and mouse LCB2 cDNAs, functional complementation in yeast, sequence analysis","journal":"Gene","confidence":"High","confidence_rationale":"Tier 1 — functional complementation and mutational mapping of catalytic domain, multiple orthogonal methods","pmids":["8921873"],"is_preprint":false},{"year":1998,"finding":"SPTLC2 (LCB2) forms a heterodimeric complex with SPTLC1 (LCB1) to constitute the functional SPT enzyme; both subunits are required for serine palmitoyltransferase activity. Co-immunoprecipitation with anti-LCB2 antibody pulled down both SPT activity and LCB1 protein; affinity-tagged LCB1 co-purified endogenous LCB2.","method":"Co-immunoprecipitation, affinity pulldown, SPT activity assay in CHO cell mutants with LCB1 cDNA rescue","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — reciprocal co-IP plus activity assay, replicated in multiple cell systems","pmids":["9837968"],"is_preprint":false},{"year":2002,"finding":"SPT is an LCB1·LCB2 heterodimer with a single active site at the subunit interface. The PLP cofactor forms a Schiff base with a lysine in LCB2 (yeast Lcb2p); mutations of this lysine and a histidine predicted to be important for PLP binding dominantly inactivate SPT. HSAN1-like mutations in LCB1 reside near this PLP-binding lysine of LCB2.","method":"Site-directed mutagenesis of yeast LCB1 and LCB2, co-expression, SPT activity assay, structural modeling","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — active-site mutagenesis with activity assays and structural modeling, mechanistically rigorous","pmids":["11781309"],"is_preprint":false},{"year":2010,"finding":"Heterozygous missense mutations in SPTLC2 (V359M, G382V, I504F) cause HSAN-I by producing partial to complete loss of canonical SPT activity and promoting alternative substrate usage with alanine, resulting in accumulation of the neurotoxic 1-deoxy-sphinganine metabolite.","method":"In vitro cell-free and cell-based SPT activity assays, metabolite profiling, patient genetics","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 1-2 — in vitro enzymatic assays combined with in vivo metabolite profiling and patient variant studies","pmids":["20920666"],"is_preprint":false},{"year":2010,"finding":"LPS-induced upregulation of Sptlc2 in macrophages is mediated by NF-κB: NF-κB binding sites are present in the Sptlc2 promoter, pharmacological NF-κB inhibition prevents LPS-induced Sptlc2 upregulation, and p65 overexpression upregulates Sptlc2 and increases ceramide levels. MAP kinases are not involved.","method":"Promoter analysis, ChIP assay, pharmacological inhibition of NF-κB, p65 transfection, ceramide measurement","journal":"Prostaglandins & other lipid mediators","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP plus functional promoter analysis and genetic/pharmacological validation in one lab","pmids":["21167294"],"is_preprint":false},{"year":2013,"finding":"HSAN1-associated SPTLC2 mutations (V359M, G382V, I504F) map to the PLP-binding region of the enzyme; structural analysis using the bacterial SPT mimic shows these mutations perturb PLP cofactor binding, reduce affinity for both substrates (serine and palmitoyl-CoA), and decrease enzymatic activity. Small subunits ssSPTa/b modulate mutant activity.","method":"Bacterial SPT mimic mutagenesis, enzymatic activity assays with and without small subunits, structural mapping","journal":"BioMed research international","confidence":"Medium","confidence_rationale":"Tier 1 — structural mapping and in vitro enzymatic assays with mutagenesis, single lab","pmids":["24175284"],"is_preprint":false},{"year":2013,"finding":"A novel SPTLC2 mutation (A182P) causes HSAN-I by reducing canonical SPT activity while increasing alternative activity using alanine as substrate, leading to strongly elevated 1-deoxysphingolipid levels; this confirms substrate promiscuity as the common pathomechanism for SPTLC2 HSAN-I mutations.","method":"Cell-free and cell-based SPT activity assays, LC-MS sphingolipid profiling","journal":"Neurology","confidence":"Medium","confidence_rationale":"Tier 2 — enzymatic assay plus metabolite measurement, single lab","pmids":["23658386"],"is_preprint":false},{"year":2015,"finding":"SPTLC2 variant p.(Arg183Trp) shifts SPT substrate specificity, resulting in elevated 1-deoxysphingolipid production in vitro (HEK293 cell-based assay) and elevated serum 1-deoxysphingolipids in patients.","method":"Cell-based SPT activity assay, LC-MS plasma sphingolipid profiling","journal":"Neuromolecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 — in vitro and in vivo metabolite profiling, single lab","pmids":["26573920"],"is_preprint":false},{"year":2019,"finding":"SPTLC2 deficiency in T cells reduces sphingolipid biosynthetic flux, leading to prolonged mTORC1 activation, ER stress, and CD8+ T cell death. Antigen stimulation induces SPTLC2 expression, and T-cell-specific Sptlc2 knockout impairs antiviral T-cell expansion and effector function; these defects are rescued by exogenous sphingolipids or pharmacological ER stress inhibition.","method":"T-cell-specific conditional knockout mice, viral infection model, mTORC1 signaling assays, ER stress markers, patient PBMC studies, sphingolipid supplementation rescue","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 2 — clean conditional KO with defined cellular phenotype plus pharmacological/metabolic rescue, replicated in human and mouse","pmids":["30952607"],"is_preprint":false},{"year":2019,"finding":"SPTLC2 variant N177D causes HSAN1 by increasing de novo 1-deoxysphingolipid formation and also elevating canonical SPT activity and C20 sphingoid base production, as demonstrated in HEK293 cells.","method":"Cell-based SPT activity assay, LC-MS sphingolipid profiling","journal":"Neuromolecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 — in vitro functional assay with metabolite profiling, single lab","pmids":["30955194"],"is_preprint":false},{"year":2022,"finding":"ER stress transcriptionally activates Sptlc2 via the spliced form of XBP1 (sXBP1), increasing de novo ceramide synthesis. Liver-specific Sptlc2 transgenic mice show elevated ceramide, elevated fasting glucose, and reduced insulin receptor β phosphorylation, establishing a mechanistic link between ER stress → sXBP1 → Sptlc2 upregulation → ceramide accumulation → hepatic insulin resistance.","method":"Sptlc2 promoter analysis, Sptlc2 liver-specific transgenic mice, insulin signaling assays, ceramide measurement in primary hepatocytes and HepG2 cells","journal":"Experimental & molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 — promoter analysis with transgenic mouse model and functional insulin signaling readout, single lab","pmids":["35513574"],"is_preprint":false},{"year":2024,"finding":"A recurrent de novo SPTLC2 variant (p.Glu260Lys; c.778G>A) causes gain-of-function excess canonical sphingolipid biosynthesis (elevated ceramides) in patient plasma and HEK cells, presenting as juvenile ALS. The variant lies within the transmembrane domain near the ORMDL3-interaction region, suggesting it renders SPT insensitive to ORMDL3-mediated feedback inhibition.","method":"Whole-genome/exome sequencing, sphingolipidomics (LC-MS), mutant HEK cell expression assays","journal":"Journal of neurology, neurosurgery, and psychiatry","confidence":"Medium","confidence_rationale":"Tier 2 — sphingolipidomics in patient and mutant cells, mechanistic hypothesis supported by domain localization","pmids":["38041684"],"is_preprint":false},{"year":2024,"finding":"SPTLC2 p.Glu260Lys variant (recurrent in juvenile ALS) causes unrestrained SPT activity and elevated sphingolipid production distinct from the substrate-shift mechanism of HSAN-associated SPTLC2 variants, confirmed in plasma and fibroblasts of patients; serine supplementation (beneficial in HSAN) is predicted to exacerbate ALS pathogenesis.","method":"Biochemical investigation in patient plasma and fibroblasts, ceramide/sphingolipid measurement by LC-MS/MS, clinical/genetic characterization","journal":"Journal of neurology, neurosurgery, and psychiatry","confidence":"Medium","confidence_rationale":"Tier 2 — patient plasma and fibroblast metabolomics, multiple patients across multiple families","pmids":["38041679"],"is_preprint":false},{"year":2024,"finding":"SPTLC2 variants in early-onset ALS (located in a region adjacent to ORMDL3-interaction domain) cause elevated SPT activity and sphingolipid overproduction, as shown by elevated plasma ceramide levels in patients.","method":"Whole-exome sequencing, sphingolipidomics (LC-MS), protein structure analysis","journal":"Annals of clinical and translational neurology","confidence":"Medium","confidence_rationale":"Tier 2 — patient metabolomics plus structural analysis, single lab","pmids":["38316966"],"is_preprint":false},{"year":2025,"finding":"Novel SPTLC2 variant p.T66R (transmembrane domain) reduces ORMDL3-mediated inhibitory regulation of SPT, leading to unrestrained SPT activity and excess sphingolipid production; functional studies in mutant cell lines demonstrated elevated specific sphingolipid levels.","method":"Mutant cell line functional studies, UPLC-MS/MS sphingolipid profiling, whole-exome sequencing","journal":"Journal of neuromuscular diseases","confidence":"Medium","confidence_rationale":"Tier 2 — cell-line functional assay with metabolite profiling, single lab","pmids":["40849231"],"is_preprint":false},{"year":2025,"finding":"SPTLC2 binds EGFR and drives an EGFR-FAK-HBEGF signaling axis in ovarian cancer cells; the SPT enzymatic activity of SPTLC2 is required for this signaling function, as catalytically inactive SPTLC2 fails to activate the axis.","method":"Co-immunoprecipitation (SPTLC2-EGFR interaction), SPTLC2 knockdown/overexpression, xenograft metastasis model, clonogenic and migration assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 3 — single Co-IP plus loss/gain-of-function with phenotype, enzymatic activity requirement established","pmids":["39645550"],"is_preprint":false},{"year":2025,"finding":"β-cell-specific deletion of Sptlc2 in mice causes marked reduction in ceramide and sphingomyelin levels, drastic (~80%) loss of β-cell mass, and profound impairment of glucose-regulated insulin secretion and glucose tolerance, demonstrating that de novo ceramide synthesis via SPTLC2 is required for normal β-cell survival and function.","method":"Cre/lox conditional knockout (Ins1-Cre), metabolic phenotyping, ceramide/sphingomyelin measurement, histology, transcriptomics","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 — clean conditional KO with defined cellular phenotype and metabolite validation, preprint","pmids":["bio_10.1101_2025.05.14.653935"],"is_preprint":true}],"current_model":"SPTLC2 is the catalytic LCB2 subunit of the heterodimeric serine palmitoyltransferase (SPT) complex (with SPTLC1/LCB1), where it contributes the PLP-binding lysine at the active site at the subunit interface to catalyze the first and rate-limiting condensation of serine and palmitoyl-CoA in de novo sphingolipid biosynthesis; HSAN-I-associated missense mutations shift substrate specificity toward alanine, producing neurotoxic 1-deoxysphingolipids, while juvenile ALS-associated gain-of-function variants in the transmembrane domain impair ORMDL3-mediated feedback inhibition, causing unrestrained sphingolipid overproduction; upstream, Sptlc2 transcription is induced by NF-κB (in response to LPS) and by sXBP1 (in response to ER stress), and SPTLC2 is required for T-cell metabolic fitness, β-cell survival, and has been shown to physically interact with EGFR to drive oncogenic signaling."},"narrative":{"teleology":[{"year":1994,"claim":"Establishing that LCB2 encodes a required subunit of SPT resolved the gene identity behind the first committed step of sphingolipid biosynthesis, showing that both LCB1 and LCB2 are needed for activity.","evidence":"Yeast genetics with LCB1/LCB2 co-expression and enzymatic activity assays","pmids":["8058731"],"confidence":"High","gaps":["Mammalian ortholog not yet characterized","Subunit stoichiometry unknown","Active-site architecture unresolved"]},{"year":1998,"claim":"Demonstrating that SPTLC2 and SPTLC1 form a physical heterodimer essential for SPT activity in mammalian cells established the minimal enzyme composition and confirmed the yeast paradigm in mammals.","evidence":"Reciprocal co-immunoprecipitation and SPT activity assays in CHO cell mutants with cDNA rescue","pmids":["9837968"],"confidence":"High","gaps":["No structural information on the heterodimer","Contribution of each subunit to catalysis not resolved"]},{"year":2002,"claim":"Mapping the PLP cofactor Schiff-base linkage to a specific lysine in LCB2 and showing that HSAN1-like mutations cluster near this residue resolved how the active site spans the subunit interface and identified the catalytic residues.","evidence":"Site-directed mutagenesis of yeast LCB1/LCB2 with SPT activity assays and structural modeling","pmids":["11781309"],"confidence":"High","gaps":["No high-resolution crystal structure of mammalian SPT","Substrate-binding determinants for serine vs. alternative amino acids unknown"]},{"year":2010,"claim":"Identification of SPTLC2 missense mutations (V359M, G382V, I504F) as the cause of HSAN-I, with demonstration that these mutations shift substrate specificity toward alanine to produce neurotoxic 1-deoxysphingolipids, established a gain-of-aberrant-function pathomechanism distinct from simple loss of activity.","evidence":"Patient genetics combined with cell-free and cell-based SPT activity assays and LC-MS metabolite profiling","pmids":["20920666"],"confidence":"High","gaps":["Structural basis of altered substrate selectivity not determined","Mechanism of 1-deoxysphingolipid neurotoxicity not established"]},{"year":2010,"claim":"Showing that NF-κB directly activates the Sptlc2 promoter in response to LPS established a transcriptional mechanism linking innate immune activation to de novo sphingolipid biosynthesis.","evidence":"ChIP, promoter analysis, pharmacological NF-κB inhibition, and p65 overexpression in macrophages","pmids":["21167294"],"confidence":"Medium","gaps":["Relevance to in vivo inflammatory sphingolipid accumulation not tested","Other transcription factors potentially involved not examined"]},{"year":2013,"claim":"Structural mapping of HSAN-I mutations to the PLP-binding pocket using a bacterial SPT mimic, and identification of additional HSAN-I mutations (A182P, R183W) that recapitulate the substrate-shift mechanism, consolidated the shared pathomechanism across multiple SPTLC2 HSAN-I variants.","evidence":"Bacterial SPT mimic mutagenesis with enzymatic assays; cell-based assays and LC-MS sphingolipid profiling for new variants","pmids":["24175284","23658386"],"confidence":"Medium","gaps":["Role of small subunits ssSPTa/b in modulating mutant phenotype incompletely defined","No mammalian SPT crystal structure to validate modeling"]},{"year":2019,"claim":"Conditional T-cell knockout of Sptlc2 revealed that de novo sphingolipid synthesis is required for CD8+ T-cell survival by restraining mTORC1 hyperactivation and ER stress, establishing a cell-autonomous metabolic requirement for SPTLC2 in adaptive immunity.","evidence":"T-cell-specific Sptlc2 conditional knockout mice, viral infection model, mTORC1/ER stress readouts, sphingolipid rescue experiments","pmids":["30952607"],"confidence":"High","gaps":["Specific sphingolipid species responsible not identified","Role in other lymphocyte lineages not tested"]},{"year":2022,"claim":"Demonstrating that sXBP1 transactivates the Sptlc2 promoter during ER stress, linking ceramide overproduction to hepatic insulin resistance in transgenic mice, established a second transcriptional induction axis and a metabolic disease consequence.","evidence":"Sptlc2 promoter analysis, liver-specific Sptlc2 transgenic mice, insulin signaling assays, ceramide measurements","pmids":["35513574"],"confidence":"Medium","gaps":["Relative contribution of sXBP1 vs. NF-κB to Sptlc2 induction in different tissues unknown","Causal role of specific ceramide species in insulin resistance not delineated"]},{"year":2024,"claim":"Discovery that the recurrent SPTLC2 p.Glu260Lys variant causes juvenile ALS through unrestrained SPT activity—mechanistically distinct from HSAN-I substrate shifts—by impairing ORMDL3-mediated feedback inhibition revealed a second, gain-of-function disease mechanism operating through the SPT regulatory interface.","evidence":"Whole-genome/exome sequencing, sphingolipidomics in patient plasma and fibroblasts, mutant HEK cell expression assays across multiple families","pmids":["38041684","38041679","38316966"],"confidence":"Medium","gaps":["Direct biophysical evidence that ORMDL3 binding is disrupted by E260K not shown","Downstream pathway from excess sphingolipids to motor neuron death not elucidated"]},{"year":2025,"claim":"Additional transmembrane-domain variants (T66R) confirmed the ORMDL3-derepression mechanism, while binding of SPTLC2 to EGFR and requirement of SPT catalytic activity for EGFR-FAK-HBEGF oncogenic signaling revealed an unexpected role in receptor tyrosine kinase signaling.","evidence":"Mutant cell-line sphingolipid profiling for T66R; co-immunoprecipitation and knockdown/overexpression with xenograft model for EGFR interaction","pmids":["40849231","39645550"],"confidence":"Medium","gaps":["SPTLC2-EGFR interaction demonstrated by single Co-IP without reciprocal validation or domain mapping","Generality of EGFR interaction beyond ovarian cancer unknown","Mechanism by which sphingolipid products activate FAK-HBEGF axis not defined"]},{"year":null,"claim":"A high-resolution structure of the mammalian SPT heterodimer (with ORMDL3) explaining both HSAN-I substrate-shift mutations and ALS-associated derepression mutations, and the identity of specific sphingolipid species mediating T-cell fitness, β-cell survival, and motor neuron toxicity, remain to be determined.","evidence":"","pmids":[],"confidence":"High","gaps":["No published mammalian SPT-ORMDL3 co-structure defining the regulatory interface","Specific sphingolipid species mediating downstream cellular phenotypes not identified","Relative contribution of canonical vs. deoxy-sphingolipid toxicity to ALS pathogenesis unresolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,1,3,4]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[3]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[9,11]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[0,1,2,3,4,9,11]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[4,7,12,13]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[9]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[16]}],"complexes":["SPT (serine palmitoyltransferase heterodimer with SPTLC1)"],"partners":["SPTLC1","ORMDL3","EGFR","SSSPTA","SSSPTB"],"other_free_text":[]},"mechanistic_narrative":"SPTLC2 is the PLP-binding catalytic subunit of serine palmitoyltransferase (SPT), the heterodimeric enzyme that catalyzes the rate-limiting condensation of serine and palmitoyl-CoA to 3-ketosphinganine in de novo sphingolipid biosynthesis. SPTLC2 forms an obligate heterodimer with SPTLC1, with the active site residing at the subunit interface where a conserved lysine in SPTLC2 forms a Schiff base with the PLP cofactor [PMID:8058731, PMID:9837968, PMID:11781309]. Missense mutations in the PLP-binding region of SPTLC2 cause hereditary sensory and autonomic neuropathy type I (HSAN-I) by shifting substrate specificity from serine toward alanine, resulting in accumulation of neurotoxic 1-deoxysphingolipids, whereas gain-of-function variants in the transmembrane domain near the ORMDL3-interaction region cause juvenile ALS through unrestrained sphingolipid overproduction due to loss of ORMDL3-mediated feedback inhibition [PMID:20920666, PMID:38041684, PMID:40849231]. SPTLC2 transcription is induced by NF-κB during inflammation and by sXBP1 during ER stress, and SPTLC2-dependent sphingolipid synthesis is required for CD8+ T-cell metabolic fitness and pancreatic β-cell survival [PMID:21167294, PMID:35513574, PMID:30952607]."},"prefetch_data":{"uniprot":{"accession":"O15270","full_name":"Serine palmitoyltransferase 2","aliases":["Long chain base biosynthesis protein 2","LCB 2","Long chain base biosynthesis protein 2a","LCB2a","Serine-palmitoyl-CoA transferase 2","SPT 2"],"length_aa":562,"mass_kda":62.9,"function":"Component of the serine palmitoyltransferase multisubunit enzyme (SPT) that catalyzes the initial and rate-limiting step in sphingolipid biosynthesis by condensing L-serine and activated acyl-CoA (most commonly palmitoyl-CoA) to form long-chain bases (PubMed:19416851, PubMed:19648650, PubMed:20504773, PubMed:20920666). The SPT complex is composed of SPTLC1, SPTLC2 or SPTLC3 and SPTSSA or SPTSSB. Within this complex, the heterodimer consisting of SPTLC1 and SPTLC2/SPTLC3 forms the catalytic core (PubMed:19416851). The composition of the serine palmitoyltransferase (SPT) complex determines the substrate preference (PubMed:19416851). The SPTLC1-SPTLC2-SPTSSA complex shows a strong preference for C16-CoA substrate, while the SPTLC1-SPTLC3-SPTSSA isozyme uses both C14-CoA and C16-CoA as substrates, with a slight preference for C14-CoA (PubMed:19416851, PubMed:19648650). The SPTLC1-SPTLC2-SPTSSB complex shows a strong preference for C18-CoA substrate, while the SPTLC1-SPTLC3-SPTSSB isozyme displays an ability to use a broader range of acyl-CoAs, without apparent preference (PubMed:19416851, PubMed:19648650). Crucial for adipogenesis (By similarity)","subcellular_location":"Endoplasmic reticulum membrane","url":"https://www.uniprot.org/uniprotkb/O15270/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SPTLC2","classification":"Not Classified","n_dependent_lines":140,"n_total_lines":1208,"dependency_fraction":0.11589403973509933},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000100596","cell_line_id":"CID000293","localizations":[{"compartment":"er","grade":3}],"interactors":[{"gene":"SPTLC1","stoichiometry":10.0},{"gene":"ALDH3A2","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000293","total_profiled":1310},"omim":[{"mim_id":"613640","title":"NEUROPATHY, HEREDITARY SENSORY AND AUTONOMIC, TYPE IC; HSAN1C","url":"https://www.omim.org/entry/613640"},{"mim_id":"613540","title":"SERINE PALMITOYLTRANSFERASE, SMALL SUBUNIT, A; SPTSSA","url":"https://www.omim.org/entry/613540"},{"mim_id":"611120","title":"SERINE PALMITOYLTRANSFERASE, LONG-CHAIN BASE SUBUNIT 3; SPTLC3","url":"https://www.omim.org/entry/611120"},{"mim_id":"610412","title":"SERINE PALMITOYLTRANSFERASE, SMALL SUBUNIT, B; SPTSSB","url":"https://www.omim.org/entry/610412"},{"mim_id":"605713","title":"SERINE PALMITOYLTRANSFERASE, LONG-CHAIN BASE SUBUNIT 2; SPTLC2","url":"https://www.omim.org/entry/605713"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Plasma membrane","reliability":"Approved"},{"location":"Cell Junctions","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SPTLC2"},"hgnc":{"alias_symbol":["KIAA0526","LCB2","LCB2A","hLCB2a"],"prev_symbol":[]},"alphafold":{"accession":"O15270","domains":[{"cath_id":"3.90.1150.10","chopping":"67-173_435-543","consensus_level":"medium","plddt":91.9748,"start":67,"end":543},{"cath_id":"3.40.640.10","chopping":"188-428","consensus_level":"high","plddt":96.4188,"start":188,"end":428}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O15270","model_url":"https://alphafold.ebi.ac.uk/files/AF-O15270-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O15270-F1-predicted_aligned_error_v6.png","plddt_mean":86.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SPTLC2","jax_strain_url":"https://www.jax.org/strain/search?query=SPTLC2"},"sequence":{"accession":"O15270","fasta_url":"https://rest.uniprot.org/uniprotkb/O15270.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O15270/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O15270"}},"corpus_meta":[{"pmid":"8058731","id":"PMC_8058731","title":"The LCB2 gene of Saccharomyces and the related LCB1 gene encode subunits of serine palmitoyltransferase, the initial enzyme in sphingolipid synthesis.","date":"1994","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/8058731","citation_count":187,"is_preprint":false},{"pmid":"9837968","id":"PMC_9837968","title":"Mammalian cell mutants resistant to a sphingomyelin-directed cytolysin. Genetic and biochemical evidence for complex formation of the LCB1 protein with the LCB2 protein for serine palmitoyltransferase.","date":"1998","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/9837968","citation_count":165,"is_preprint":false},{"pmid":"20920666","id":"PMC_20920666","title":"Mutations in the SPTLC2 subunit of serine palmitoyltransferase cause hereditary sensory and autonomic neuropathy type I.","date":"2010","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/20920666","citation_count":153,"is_preprint":false},{"pmid":"21534970","id":"PMC_21534970","title":"MPK6, sphinganine and the LCB2a gene from serine palmitoyltransferase are required in the signaling pathway that mediates cell death induced by long chain bases in Arabidopsis.","date":"2011","source":"The New 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neurology","url":"https://pubmed.ncbi.nlm.nih.gov/38316966","citation_count":8,"is_preprint":false},{"pmid":"34090020","id":"PMC_34090020","title":"Rare mutations in ATL3, SPTLC2 and SCN9A explaining hereditary sensory neuropathy and congenital insensitivity to pain in a Brazilian cohort.","date":"2021","source":"Journal of the neurological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/34090020","citation_count":8,"is_preprint":false},{"pmid":"31372925","id":"PMC_31372925","title":"The Effect of SPTLC2 on Promoting Neuronal Apoptosis is Alleviated by MiR-124-3p Through TLR4 Signalling Pathway.","date":"2019","source":"Neurochemical research","url":"https://pubmed.ncbi.nlm.nih.gov/31372925","citation_count":7,"is_preprint":false},{"pmid":"39645550","id":"PMC_39645550","title":"SPTLC2 drives an EGFR-FAK-HBEGF signaling axis to promote ovarian cancer 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(Coccolithovirus).","date":"2012","source":"Acta oceanologica Sinica = Hai yang xue bao","url":"https://pubmed.ncbi.nlm.nih.gov/32226188","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.05.14.653935","title":"Serine palmitoyltransferase-mediated de novo sphingolipid biosynthesis is required for normal insulin production and glucose tolerance","date":"2025-05-17","source":"bioRxiv","url":"https://doi.org/10.1101/2025.05.14.653935","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":22289,"output_tokens":4346,"usd":0.066029},"stage2":{"model":"claude-opus-4-6","input_tokens":7854,"output_tokens":2897,"usd":0.167543},"total_usd":0.233572,"stage1_batch_id":"msgbatch_011rkcQdVV1RaFq9XhcG6df6","stage2_batch_id":"msgbatch_01RzgrJafdF4EWHhj5mNi6dh","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1994,\n      \"finding\": \"LCB2 (yeast ortholog of SPTLC2) encodes a subunit of serine palmitoyltransferase (SPT), the enzyme that catalyzes condensation of palmitoyl-CoA and serine to form 3-ketosphinganine (first committed step in sphingolipid synthesis). Overproduction of SPT activity in yeast requires co-expression of both LCB1 and LCB2.\",\n      \"method\": \"Yeast genetics, overexpression, enzymatic activity assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — foundational enzymatic characterization, replicated extensively across labs\",\n      \"pmids\": [\"8058731\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"Mammalian SPTLC2 (LCB2) was identified as the catalytic subunit of SPT; a 56-residue motif unique to LCB2 proteins was shown to functionally substitute for the corresponding region of yeast Lcb2p, identifying this motif as part of the catalytic domain of SPT and as a signature of Lcb2 proteins.\",\n      \"method\": \"Cloning of human and mouse LCB2 cDNAs, functional complementation in yeast, sequence analysis\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — functional complementation and mutational mapping of catalytic domain, multiple orthogonal methods\",\n      \"pmids\": [\"8921873\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"SPTLC2 (LCB2) forms a heterodimeric complex with SPTLC1 (LCB1) to constitute the functional SPT enzyme; both subunits are required for serine palmitoyltransferase activity. Co-immunoprecipitation with anti-LCB2 antibody pulled down both SPT activity and LCB1 protein; affinity-tagged LCB1 co-purified endogenous LCB2.\",\n      \"method\": \"Co-immunoprecipitation, affinity pulldown, SPT activity assay in CHO cell mutants with LCB1 cDNA rescue\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — reciprocal co-IP plus activity assay, replicated in multiple cell systems\",\n      \"pmids\": [\"9837968\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"SPT is an LCB1·LCB2 heterodimer with a single active site at the subunit interface. The PLP cofactor forms a Schiff base with a lysine in LCB2 (yeast Lcb2p); mutations of this lysine and a histidine predicted to be important for PLP binding dominantly inactivate SPT. HSAN1-like mutations in LCB1 reside near this PLP-binding lysine of LCB2.\",\n      \"method\": \"Site-directed mutagenesis of yeast LCB1 and LCB2, co-expression, SPT activity assay, structural modeling\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — active-site mutagenesis with activity assays and structural modeling, mechanistically rigorous\",\n      \"pmids\": [\"11781309\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Heterozygous missense mutations in SPTLC2 (V359M, G382V, I504F) cause HSAN-I by producing partial to complete loss of canonical SPT activity and promoting alternative substrate usage with alanine, resulting in accumulation of the neurotoxic 1-deoxy-sphinganine metabolite.\",\n      \"method\": \"In vitro cell-free and cell-based SPT activity assays, metabolite profiling, patient genetics\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro enzymatic assays combined with in vivo metabolite profiling and patient variant studies\",\n      \"pmids\": [\"20920666\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"LPS-induced upregulation of Sptlc2 in macrophages is mediated by NF-κB: NF-κB binding sites are present in the Sptlc2 promoter, pharmacological NF-κB inhibition prevents LPS-induced Sptlc2 upregulation, and p65 overexpression upregulates Sptlc2 and increases ceramide levels. MAP kinases are not involved.\",\n      \"method\": \"Promoter analysis, ChIP assay, pharmacological inhibition of NF-κB, p65 transfection, ceramide measurement\",\n      \"journal\": \"Prostaglandins & other lipid mediators\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP plus functional promoter analysis and genetic/pharmacological validation in one lab\",\n      \"pmids\": [\"21167294\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"HSAN1-associated SPTLC2 mutations (V359M, G382V, I504F) map to the PLP-binding region of the enzyme; structural analysis using the bacterial SPT mimic shows these mutations perturb PLP cofactor binding, reduce affinity for both substrates (serine and palmitoyl-CoA), and decrease enzymatic activity. Small subunits ssSPTa/b modulate mutant activity.\",\n      \"method\": \"Bacterial SPT mimic mutagenesis, enzymatic activity assays with and without small subunits, structural mapping\",\n      \"journal\": \"BioMed research international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — structural mapping and in vitro enzymatic assays with mutagenesis, single lab\",\n      \"pmids\": [\"24175284\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"A novel SPTLC2 mutation (A182P) causes HSAN-I by reducing canonical SPT activity while increasing alternative activity using alanine as substrate, leading to strongly elevated 1-deoxysphingolipid levels; this confirms substrate promiscuity as the common pathomechanism for SPTLC2 HSAN-I mutations.\",\n      \"method\": \"Cell-free and cell-based SPT activity assays, LC-MS sphingolipid profiling\",\n      \"journal\": \"Neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — enzymatic assay plus metabolite measurement, single lab\",\n      \"pmids\": [\"23658386\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"SPTLC2 variant p.(Arg183Trp) shifts SPT substrate specificity, resulting in elevated 1-deoxysphingolipid production in vitro (HEK293 cell-based assay) and elevated serum 1-deoxysphingolipids in patients.\",\n      \"method\": \"Cell-based SPT activity assay, LC-MS plasma sphingolipid profiling\",\n      \"journal\": \"Neuromolecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vitro and in vivo metabolite profiling, single lab\",\n      \"pmids\": [\"26573920\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SPTLC2 deficiency in T cells reduces sphingolipid biosynthetic flux, leading to prolonged mTORC1 activation, ER stress, and CD8+ T cell death. Antigen stimulation induces SPTLC2 expression, and T-cell-specific Sptlc2 knockout impairs antiviral T-cell expansion and effector function; these defects are rescued by exogenous sphingolipids or pharmacological ER stress inhibition.\",\n      \"method\": \"T-cell-specific conditional knockout mice, viral infection model, mTORC1 signaling assays, ER stress markers, patient PBMC studies, sphingolipid supplementation rescue\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean conditional KO with defined cellular phenotype plus pharmacological/metabolic rescue, replicated in human and mouse\",\n      \"pmids\": [\"30952607\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SPTLC2 variant N177D causes HSAN1 by increasing de novo 1-deoxysphingolipid formation and also elevating canonical SPT activity and C20 sphingoid base production, as demonstrated in HEK293 cells.\",\n      \"method\": \"Cell-based SPT activity assay, LC-MS sphingolipid profiling\",\n      \"journal\": \"Neuromolecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vitro functional assay with metabolite profiling, single lab\",\n      \"pmids\": [\"30955194\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ER stress transcriptionally activates Sptlc2 via the spliced form of XBP1 (sXBP1), increasing de novo ceramide synthesis. Liver-specific Sptlc2 transgenic mice show elevated ceramide, elevated fasting glucose, and reduced insulin receptor β phosphorylation, establishing a mechanistic link between ER stress → sXBP1 → Sptlc2 upregulation → ceramide accumulation → hepatic insulin resistance.\",\n      \"method\": \"Sptlc2 promoter analysis, Sptlc2 liver-specific transgenic mice, insulin signaling assays, ceramide measurement in primary hepatocytes and HepG2 cells\",\n      \"journal\": \"Experimental & molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — promoter analysis with transgenic mouse model and functional insulin signaling readout, single lab\",\n      \"pmids\": [\"35513574\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"A recurrent de novo SPTLC2 variant (p.Glu260Lys; c.778G>A) causes gain-of-function excess canonical sphingolipid biosynthesis (elevated ceramides) in patient plasma and HEK cells, presenting as juvenile ALS. The variant lies within the transmembrane domain near the ORMDL3-interaction region, suggesting it renders SPT insensitive to ORMDL3-mediated feedback inhibition.\",\n      \"method\": \"Whole-genome/exome sequencing, sphingolipidomics (LC-MS), mutant HEK cell expression assays\",\n      \"journal\": \"Journal of neurology, neurosurgery, and psychiatry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — sphingolipidomics in patient and mutant cells, mechanistic hypothesis supported by domain localization\",\n      \"pmids\": [\"38041684\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SPTLC2 p.Glu260Lys variant (recurrent in juvenile ALS) causes unrestrained SPT activity and elevated sphingolipid production distinct from the substrate-shift mechanism of HSAN-associated SPTLC2 variants, confirmed in plasma and fibroblasts of patients; serine supplementation (beneficial in HSAN) is predicted to exacerbate ALS pathogenesis.\",\n      \"method\": \"Biochemical investigation in patient plasma and fibroblasts, ceramide/sphingolipid measurement by LC-MS/MS, clinical/genetic characterization\",\n      \"journal\": \"Journal of neurology, neurosurgery, and psychiatry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — patient plasma and fibroblast metabolomics, multiple patients across multiple families\",\n      \"pmids\": [\"38041679\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SPTLC2 variants in early-onset ALS (located in a region adjacent to ORMDL3-interaction domain) cause elevated SPT activity and sphingolipid overproduction, as shown by elevated plasma ceramide levels in patients.\",\n      \"method\": \"Whole-exome sequencing, sphingolipidomics (LC-MS), protein structure analysis\",\n      \"journal\": \"Annals of clinical and translational neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — patient metabolomics plus structural analysis, single lab\",\n      \"pmids\": [\"38316966\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Novel SPTLC2 variant p.T66R (transmembrane domain) reduces ORMDL3-mediated inhibitory regulation of SPT, leading to unrestrained SPT activity and excess sphingolipid production; functional studies in mutant cell lines demonstrated elevated specific sphingolipid levels.\",\n      \"method\": \"Mutant cell line functional studies, UPLC-MS/MS sphingolipid profiling, whole-exome sequencing\",\n      \"journal\": \"Journal of neuromuscular diseases\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — cell-line functional assay with metabolite profiling, single lab\",\n      \"pmids\": [\"40849231\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SPTLC2 binds EGFR and drives an EGFR-FAK-HBEGF signaling axis in ovarian cancer cells; the SPT enzymatic activity of SPTLC2 is required for this signaling function, as catalytically inactive SPTLC2 fails to activate the axis.\",\n      \"method\": \"Co-immunoprecipitation (SPTLC2-EGFR interaction), SPTLC2 knockdown/overexpression, xenograft metastasis model, clonogenic and migration assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single Co-IP plus loss/gain-of-function with phenotype, enzymatic activity requirement established\",\n      \"pmids\": [\"39645550\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"β-cell-specific deletion of Sptlc2 in mice causes marked reduction in ceramide and sphingomyelin levels, drastic (~80%) loss of β-cell mass, and profound impairment of glucose-regulated insulin secretion and glucose tolerance, demonstrating that de novo ceramide synthesis via SPTLC2 is required for normal β-cell survival and function.\",\n      \"method\": \"Cre/lox conditional knockout (Ins1-Cre), metabolic phenotyping, ceramide/sphingomyelin measurement, histology, transcriptomics\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean conditional KO with defined cellular phenotype and metabolite validation, preprint\",\n      \"pmids\": [\"bio_10.1101_2025.05.14.653935\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"SPTLC2 is the catalytic LCB2 subunit of the heterodimeric serine palmitoyltransferase (SPT) complex (with SPTLC1/LCB1), where it contributes the PLP-binding lysine at the active site at the subunit interface to catalyze the first and rate-limiting condensation of serine and palmitoyl-CoA in de novo sphingolipid biosynthesis; HSAN-I-associated missense mutations shift substrate specificity toward alanine, producing neurotoxic 1-deoxysphingolipids, while juvenile ALS-associated gain-of-function variants in the transmembrane domain impair ORMDL3-mediated feedback inhibition, causing unrestrained sphingolipid overproduction; upstream, Sptlc2 transcription is induced by NF-κB (in response to LPS) and by sXBP1 (in response to ER stress), and SPTLC2 is required for T-cell metabolic fitness, β-cell survival, and has been shown to physically interact with EGFR to drive oncogenic signaling.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"SPTLC2 is the PLP-binding catalytic subunit of serine palmitoyltransferase (SPT), the heterodimeric enzyme that catalyzes the rate-limiting condensation of serine and palmitoyl-CoA to 3-ketosphinganine in de novo sphingolipid biosynthesis. SPTLC2 forms an obligate heterodimer with SPTLC1, with the active site residing at the subunit interface where a conserved lysine in SPTLC2 forms a Schiff base with the PLP cofactor [PMID:8058731, PMID:9837968, PMID:11781309]. Missense mutations in the PLP-binding region of SPTLC2 cause hereditary sensory and autonomic neuropathy type I (HSAN-I) by shifting substrate specificity from serine toward alanine, resulting in accumulation of neurotoxic 1-deoxysphingolipids, whereas gain-of-function variants in the transmembrane domain near the ORMDL3-interaction region cause juvenile ALS through unrestrained sphingolipid overproduction due to loss of ORMDL3-mediated feedback inhibition [PMID:20920666, PMID:38041684, PMID:40849231]. SPTLC2 transcription is induced by NF-κB during inflammation and by sXBP1 during ER stress, and SPTLC2-dependent sphingolipid synthesis is required for CD8+ T-cell metabolic fitness and pancreatic β-cell survival [PMID:21167294, PMID:35513574, PMID:30952607].\",\n  \"teleology\": [\n    {\n      \"year\": 1994,\n      \"claim\": \"Establishing that LCB2 encodes a required subunit of SPT resolved the gene identity behind the first committed step of sphingolipid biosynthesis, showing that both LCB1 and LCB2 are needed for activity.\",\n      \"evidence\": \"Yeast genetics with LCB1/LCB2 co-expression and enzymatic activity assays\",\n      \"pmids\": [\"8058731\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mammalian ortholog not yet characterized\", \"Subunit stoichiometry unknown\", \"Active-site architecture unresolved\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Demonstrating that SPTLC2 and SPTLC1 form a physical heterodimer essential for SPT activity in mammalian cells established the minimal enzyme composition and confirmed the yeast paradigm in mammals.\",\n      \"evidence\": \"Reciprocal co-immunoprecipitation and SPT activity assays in CHO cell mutants with cDNA rescue\",\n      \"pmids\": [\"9837968\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structural information on the heterodimer\", \"Contribution of each subunit to catalysis not resolved\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Mapping the PLP cofactor Schiff-base linkage to a specific lysine in LCB2 and showing that HSAN1-like mutations cluster near this residue resolved how the active site spans the subunit interface and identified the catalytic residues.\",\n      \"evidence\": \"Site-directed mutagenesis of yeast LCB1/LCB2 with SPT activity assays and structural modeling\",\n      \"pmids\": [\"11781309\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No high-resolution crystal structure of mammalian SPT\", \"Substrate-binding determinants for serine vs. alternative amino acids unknown\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Identification of SPTLC2 missense mutations (V359M, G382V, I504F) as the cause of HSAN-I, with demonstration that these mutations shift substrate specificity toward alanine to produce neurotoxic 1-deoxysphingolipids, established a gain-of-aberrant-function pathomechanism distinct from simple loss of activity.\",\n      \"evidence\": \"Patient genetics combined with cell-free and cell-based SPT activity assays and LC-MS metabolite profiling\",\n      \"pmids\": [\"20920666\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of altered substrate selectivity not determined\", \"Mechanism of 1-deoxysphingolipid neurotoxicity not established\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Showing that NF-κB directly activates the Sptlc2 promoter in response to LPS established a transcriptional mechanism linking innate immune activation to de novo sphingolipid biosynthesis.\",\n      \"evidence\": \"ChIP, promoter analysis, pharmacological NF-κB inhibition, and p65 overexpression in macrophages\",\n      \"pmids\": [\"21167294\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relevance to in vivo inflammatory sphingolipid accumulation not tested\", \"Other transcription factors potentially involved not examined\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Structural mapping of HSAN-I mutations to the PLP-binding pocket using a bacterial SPT mimic, and identification of additional HSAN-I mutations (A182P, R183W) that recapitulate the substrate-shift mechanism, consolidated the shared pathomechanism across multiple SPTLC2 HSAN-I variants.\",\n      \"evidence\": \"Bacterial SPT mimic mutagenesis with enzymatic assays; cell-based assays and LC-MS sphingolipid profiling for new variants\",\n      \"pmids\": [\"24175284\", \"23658386\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Role of small subunits ssSPTa/b in modulating mutant phenotype incompletely defined\", \"No mammalian SPT crystal structure to validate modeling\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Conditional T-cell knockout of Sptlc2 revealed that de novo sphingolipid synthesis is required for CD8+ T-cell survival by restraining mTORC1 hyperactivation and ER stress, establishing a cell-autonomous metabolic requirement for SPTLC2 in adaptive immunity.\",\n      \"evidence\": \"T-cell-specific Sptlc2 conditional knockout mice, viral infection model, mTORC1/ER stress readouts, sphingolipid rescue experiments\",\n      \"pmids\": [\"30952607\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific sphingolipid species responsible not identified\", \"Role in other lymphocyte lineages not tested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Demonstrating that sXBP1 transactivates the Sptlc2 promoter during ER stress, linking ceramide overproduction to hepatic insulin resistance in transgenic mice, established a second transcriptional induction axis and a metabolic disease consequence.\",\n      \"evidence\": \"Sptlc2 promoter analysis, liver-specific Sptlc2 transgenic mice, insulin signaling assays, ceramide measurements\",\n      \"pmids\": [\"35513574\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relative contribution of sXBP1 vs. NF-κB to Sptlc2 induction in different tissues unknown\", \"Causal role of specific ceramide species in insulin resistance not delineated\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Discovery that the recurrent SPTLC2 p.Glu260Lys variant causes juvenile ALS through unrestrained SPT activity—mechanistically distinct from HSAN-I substrate shifts—by impairing ORMDL3-mediated feedback inhibition revealed a second, gain-of-function disease mechanism operating through the SPT regulatory interface.\",\n      \"evidence\": \"Whole-genome/exome sequencing, sphingolipidomics in patient plasma and fibroblasts, mutant HEK cell expression assays across multiple families\",\n      \"pmids\": [\"38041684\", \"38041679\", \"38316966\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct biophysical evidence that ORMDL3 binding is disrupted by E260K not shown\", \"Downstream pathway from excess sphingolipids to motor neuron death not elucidated\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Additional transmembrane-domain variants (T66R) confirmed the ORMDL3-derepression mechanism, while binding of SPTLC2 to EGFR and requirement of SPT catalytic activity for EGFR-FAK-HBEGF oncogenic signaling revealed an unexpected role in receptor tyrosine kinase signaling.\",\n      \"evidence\": \"Mutant cell-line sphingolipid profiling for T66R; co-immunoprecipitation and knockdown/overexpression with xenograft model for EGFR interaction\",\n      \"pmids\": [\"40849231\", \"39645550\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"SPTLC2-EGFR interaction demonstrated by single Co-IP without reciprocal validation or domain mapping\", \"Generality of EGFR interaction beyond ovarian cancer unknown\", \"Mechanism by which sphingolipid products activate FAK-HBEGF axis not defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"A high-resolution structure of the mammalian SPT heterodimer (with ORMDL3) explaining both HSAN-I substrate-shift mutations and ALS-associated derepression mutations, and the identity of specific sphingolipid species mediating T-cell fitness, β-cell survival, and motor neuron toxicity, remain to be determined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No published mammalian SPT-ORMDL3 co-structure defining the regulatory interface\", \"Specific sphingolipid species mediating downstream cellular phenotypes not identified\", \"Relative contribution of canonical vs. deoxy-sphingolipid toxicity to ALS pathogenesis unresolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 1, 3, 4]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [9, 11]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0, 1, 2, 3, 4, 9, 11]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [4, 7, 12, 13]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [9]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [16]}\n    ],\n    \"complexes\": [\n      \"SPT (serine palmitoyltransferase heterodimer with SPTLC1)\"\n    ],\n    \"partners\": [\n      \"SPTLC1\",\n      \"ORMDL3\",\n      \"EGFR\",\n      \"ssSPTa\",\n      \"ssSPTb\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}