{"gene":"SPTLC2","run_date":"2026-06-10T07:46:41","timeline":{"discoveries":[{"year":1994,"finding":"LCB2 (yeast ortholog of SPTLC2) encodes a subunit of serine palmitoyltransferase (SPT, EC 2.3.1.50), the enzyme that catalyzes the first and committed step in sphingolipid synthesis: condensation of palmitoyl-CoA and serine to form 3-ketosphinganine. Overproduction of SPT activity required co-expression of both LCB1 and LCB2, providing genetic evidence that both encode subunits of the same enzyme.","method":"Genetic overexpression in Saccharomyces cerevisiae; enzymatic activity assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — functional genetic evidence replicated and foundational; consistent with subsequent biochemical confirmation across multiple labs","pmids":["8058731"],"is_preprint":false},{"year":1996,"finding":"Human SPTLC2 (hLCB2) was cloned and shown to be the mammalian ortholog of yeast LCB2. A conserved 56-residue motif unique to LCB2 proteins functionally substituted for the corresponding region of S. cerevisiae Lcb2p, and contains a peptide sequence identified as part of the catalytic domain of the aminolevulinate synthase superfamily, establishing this motif as the catalytic domain signature of SPTLC2.","method":"cDNA cloning; cross-species functional complementation in yeast; sequence motif analysis","journal":"Gene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional complementation across species with sequence validation; single lab","pmids":["8921873"],"is_preprint":false},{"year":1998,"finding":"SPTLC2 (LCB2) and SPTLC1 (LCB1) physically interact to form the SPT heterodimeric complex. Affinity-tagged LCB1 co-precipitated endogenous LCB2, and anti-LCB2 antibody co-immunoprecipitated both SPT enzymatic activity and LCB1, demonstrating the LCB1·LCB2 heterodimer is the functional SPT enzyme.","method":"Affinity co-precipitation; co-immunoprecipitation with SPT activity assay; mammalian (CHO) cell mutant complementation","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP plus enzymatic activity co-precipitation; replicated in cell-based complementation system","pmids":["9837968"],"is_preprint":false},{"year":2002,"finding":"SPT is an Lcb1p·Lcb2p heterodimer with a single active site at the subunit interface. The PLP cofactor forms a Schiff's base with a conserved lysine in Lcb2p (SPTLC2 ortholog). A conserved histidine in Lcb2p is also critical for PLP binding. Mutations in Lcb1p near this active site dominantly inactivate SPT by ~50% when co-expressed with wild-type, and mutant Lcb1p retains interaction with Lcb2p.","method":"Site-directed mutagenesis; yeast genetics; SPT activity assays; structural modeling","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — active-site mutagenesis of conserved catalytic residues combined with functional assays and structural modeling; replicated across multiple mutations","pmids":["11781309"],"is_preprint":false},{"year":2010,"finding":"Missense mutations in SPTLC2 (V359M, G382V, I504F) cause HSAN-I by (i) partial to complete loss of canonical SPT activity (palmitoyl-CoA + serine) and (ii) gain of alternative substrate specificity, incorporating alanine instead of serine to produce the neurotoxic metabolite 1-deoxy-sphinganine. This establishes altered substrate specificity as the common pathomechanism for HSAN-I.","method":"In vitro SPT activity assay; cell-based activity assay; mass spectrometric sphingolipid profiling in patient cells and plasma","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro and in vivo enzymatic assays with multiple mutations; replicated across four families; orthogonal methods (cell-free and cell-based assays plus patient metabolite profiling)","pmids":["20920666"],"is_preprint":false},{"year":2010,"finding":"Endotoxin (LPS) upregulates Sptlc2 mRNA and protein in macrophages via NFκB; the p65 subunit of NFκB directly binds the Sptlc2 promoter (demonstrated by ChIP), leading to increased SPT activity and elevated cellular ceramide and sphingomyelin levels. Sptlc1 is not regulated by this pathway.","method":"NFκB pharmacological inhibition; p65 overexpression; promoter analysis; chromatin immunoprecipitation (ChIP); ceramide/sphingomyelin quantification","journal":"Prostaglandins & other lipid mediators","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and promoter analysis with functional readout; multiple orthogonal methods; single lab","pmids":["21167294"],"is_preprint":false},{"year":2013,"finding":"The three HSAN-I-associated hLCB2a (SPTLC2) mutations (V359M, G382V, I504F) map to the active site region near the PLP cofactor binding pocket. These mutations reduce affinity for both substrates, perturb PLP cofactor binding, and decrease SPT enzyme activity; the most severe (I504F/G385F in bacterial mimic) causes insoluble protein expression. Activity assays in the presence of small SPT subunits (ssSPTa and ssSPTb) confirmed all three mutations decrease enzyme activity.","method":"Bacterial SPT structural mimic mutagenesis; in vitro activity assays with ssSPT subunits; structural modeling based on Sphingomonas paucimobilis SPT crystal structure","journal":"BioMed research international","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro enzymatic assay with mutagenesis and structural modeling; single lab; bacterial mimic used as structural proxy","pmids":["24175284"],"is_preprint":false},{"year":2013,"finding":"A novel SPTLC2 mutation (A182P) causes HSAN-I with a distinct biochemical profile: reduced canonical SPT activity but markedly increased alternative (alanine-utilizing) activity, producing greatly elevated 1-deoxysphingolipid levels. This confirms alanine mis-incorporation as the shared pathomechanism and demonstrates that different SPTLC2 mutations can differentially affect canonical versus alternative substrate use.","method":"Cell-free and cell-based SPT activity assays; plasma 1-deoxysphingolipid quantification by mass spectrometry","journal":"Neurology","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — cell-free and cell-based assays with patient mutation; single lab; orthogonal biochemical methods","pmids":["23658386"],"is_preprint":false},{"year":2019,"finding":"SPTLC2 expression is induced by antigen stimulation and inflammation in T cells. T-cell-specific Sptlc2 ablation in mice reduces sphingolipid biosynthetic flux, causes prolonged mTORC1 activation, ER stress, and CD8+ T cell death, impairing antiviral T cell expansion and effector function. Supplementing sphingolipids or pharmacologically inhibiting ER stress-induced cell death rescues protective CD8+ T cell responses.","method":"T-cell-specific conditional knockout mice; viral infection model; sphingolipid supplementation rescue; pharmacological ER stress inhibition; mTORC1 signaling assays","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean cell-type-specific KO with defined molecular phenotype (mTORC1, ER stress), multiple rescue strategies, functional immune readout; single lab but multiple orthogonal methods","pmids":["30952607"],"is_preprint":false},{"year":2022,"finding":"ER stress upregulates Sptlc2 transcription through the spliced form of XBP1 (sXBP1), which binds the Sptlc2 promoter, increasing SPT activity and ceramide/dihydroceramide levels in hepatocytes. Liver-specific Sptlc2 transgenic mice show elevated hepatic ceramide, elevated fasting glucose, and reduced phosphorylation of insulin receptor β (IRβ), establishing a mechanistic link between SPTLC2-driven ceramide synthesis and hepatic insulin resistance.","method":"Promoter analysis; sXBP1 transcriptional activation assay; liver-specific transgenic mice; insulin signaling (IRβ phosphorylation) measurement; ceramide quantification","journal":"Experimental & molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — transgenic mouse model with defined molecular readout and promoter analysis; single lab; multiple methods","pmids":["35513574"],"is_preprint":false},{"year":2024,"finding":"A recurrent de novo gain-of-function SPTLC2 mutation (c.203T>G, p.Met68Arg) lies within a transmembrane domain and is proposed to render the SPT complex irresponsive to negative regulation by ORMDL3, leading to unrestrained ceramide and complex sphingolipid overproduction in patient plasma and in mutant-expressing HEK cells, causing juvenile ALS.","method":"Whole-genome/exome sequencing; sphingolipidomics (LC-HRMS); HEK cell expression of mutant SPTLC2; Sanger sequencing for de novo confirmation","journal":"Journal of neurology, neurosurgery, and psychiatry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — functional cell-based assay with sphingolipidomics; de novo mutation confirmed; ORMDL3 regulatory mechanism proposed but not directly tested by ORMDL3 manipulation","pmids":["38041684"],"is_preprint":false},{"year":2024,"finding":"The SPTLC2 variant p.Glu260Lys (c.778G>A) causes juvenile ALS through excess canonical sphingolipid biosynthesis (elevated ceramides), mechanistically distinct from HSAN-causing SPTLC2 variants (which shift substrate specificity to produce 1-deoxysphingolipids). Serine supplementation—therapeutic in HSAN—is predicted to exacerbate SPT-ALS by further driving sphingolipid overproduction.","method":"Clinical genetic testing; plasma and fibroblast sphingolipid measurement; biochemical investigation of patient-derived cells","journal":"Journal of neurology, neurosurgery, and psychiatry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — patient fibroblast and plasma biochemistry with multiple patients from independent families; single coordinated study","pmids":["38041679"],"is_preprint":false},{"year":2025,"finding":"A novel SPTLC2 variant (p.T66R) in a transmembrane domain reduces inhibitory regulation of SPT by ORMDL proteins, leading to unrestrained SPT activity and excess sphingolipid production, causing childhood-onset ALS. This functionally differs from HSAN-associated SPTLC2 variants.","method":"Whole-exome sequencing; UPLC-MS/MS sphingolipid profiling; mutant cell line functional studies; ORMDL3 regulation assay","journal":"Journal of neuromuscular diseases","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cell-based functional assay with ORMDL regulation tested; sphingolipidomics; single lab","pmids":["40849231"],"is_preprint":false},{"year":2024,"finding":"SPTLC2 directly binds EGFR in ovarian cancer cells (demonstrated by co-immunoprecipitation), and its serine palmitoyltransferase enzymatic activity is required for activation of an EGFR-FAK-HBEGF signaling axis that promotes clonogenic growth, migration, and metastasis.","method":"Co-immunoprecipitation (SPTLC2-EGFR); SPTLC2 knockdown and overexpression; in vitro clonogenic and migration assays; in ovo and xenograft metastasis models","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP for binding plus loss/gain-of-function with defined signaling readout; single lab","pmids":["39645550"],"is_preprint":false},{"year":2019,"finding":"SPTLC2 promotes neuronal apoptosis via the TLR4 signaling pathway; co-immunoprecipitation identified physical interaction between SPTLC2 and TLR4 pathway components. miR-124-3p negatively regulates SPTLC2 expression (validated by dual luciferase reporter assay) and suppresses SPTLC2-mediated apoptosis through this pathway.","method":"Co-immunoprecipitation; dual luciferase reporter assay; TUNEL staining; western blot; primary neuron injury model","journal":"Neurochemical research","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single co-IP without reciprocal validation; pathway placement relies on single lab, single method for protein interaction","pmids":["31372925"],"is_preprint":false},{"year":2025,"finding":"β-cell-selective deletion of Sptlc2 in mice (Sptlc2ΔIns1) causes marked reductions in ceramide and sphingomyelin levels in islets (despite compensatory upregulation of salvage and sphingomyelinase pathway enzymes), a ~80% loss of β-cell mass, and profound impairment of glucose-regulated insulin secretion and glucose tolerance—establishing that de novo ceramide synthesis via SPTLC2/SPT2 is required for normal β-cell survival and function.","method":"β-cell-specific conditional knockout (Cre-lox); metabolic phenotyping; ceramide/sphingomyelin quantification; transcriptomics; histology; glucose tolerance testing","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean cell-type-specific conditional KO with multiple orthogonal readouts; preprint, not yet peer-reviewed","pmids":["bio_10.1101_2025.05.14.653935"],"is_preprint":true},{"year":2006,"finding":"The mouse SPTLC2 promoter contains initiator and downstream promoter elements within the proximal 335 bp, including two proximal GC boxes that cooperatively stimulate transcription, as determined by deletion analysis and site-directed mutagenesis of luciferase reporter constructs.","method":"Luciferase reporter assay; deletion analysis; site-directed mutagenesis of promoter elements","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — promoter mutagenesis with functional reporter readout; single lab","pmids":["17070807"],"is_preprint":false}],"current_model":"SPTLC2 (hLCB2a) is the catalytic subunit of the heterodimeric serine palmitoyltransferase (SPT) complex, forming an obligate heterodimer with SPTLC1 (LCB1) at whose interface a single PLP-dependent active site catalyzes the first and rate-limiting step of sphingolipid de novo biosynthesis (condensation of palmitoyl-CoA and L-serine to 3-ketosphinganine); a conserved lysine in SPTLC2 forms the Schiff's base with the PLP cofactor, and disease-causing mutations in SPTLC2 either shift substrate specificity toward alanine (generating neurotoxic 1-deoxysphingolipids in HSAN-I) or abolish ORMDL3-mediated feedback inhibition (causing unrestrained sphingolipid overproduction in juvenile ALS); SPTLC2 activity is transcriptionally induced by NFκB (in response to LPS) and by sXBP1 (in response to ER stress), and the enzyme is required in a cell-autonomous manner for CD8+ T cell metabolic fitness and β-cell survival."},"narrative":{"mechanistic_narrative":"SPTLC2 is the catalytic subunit of serine palmitoyltransferase (SPT), the enzyme that catalyzes the first and committed step of de novo sphingolipid biosynthesis—the PLP-dependent condensation of palmitoyl-CoA and L-serine to 3-ketosphinganine [PMID:8058731]. It functions as an obligate heterodimer with SPTLC1, the complex co-precipitating both partners together with SPT enzymatic activity, establishing the LCB1·LCB2 heterodimer as the functional enzyme [PMID:9837968]. A single catalytic site lies at the subunit interface, where a conserved lysine in SPTLC2 forms a Schiff base with the PLP cofactor and a conserved histidine supports cofactor binding [PMID:11781309]. Disease-causing missense mutations in SPTLC2 partition into two mechanistic classes: HSAN-I mutations clustered near the PLP pocket reduce canonical activity while conferring gain of alternative substrate specificity, mis-incorporating alanine to generate neurotoxic 1-deoxysphingolipids [PMID:20920666, PMID:24175284, PMID:23658386], whereas transmembrane-domain mutations cause juvenile/childhood ALS by escaping ORMDL-mediated feedback inhibition and driving unrestrained ceramide overproduction [PMID:38041684, PMID:40849231], with a distinct ALS variant increasing canonical sphingolipid output [PMID:38041679]. SPTLC2 transcription is inducible: NFκB p65 binds the Sptlc2 promoter in response to LPS [PMID:21167294] and spliced XBP1 activates it under ER stress, linking SPTLC2-driven ceramide synthesis to hepatic insulin resistance [PMID:35513574]. The enzyme is required cell-autonomously for CD8+ T cell metabolic fitness and effector responses [PMID:30952607] and for β-cell survival and glucose-regulated insulin secretion [PMID:bio_10.1101_2025.05.14.653935].","teleology":[{"year":1994,"claim":"Established that SPT, the committed enzyme of sphingolipid synthesis, requires two distinct subunits, identifying LCB2/SPTLC2 as one of them.","evidence":"Genetic overexpression and enzymatic assay in S. cerevisiae showing SPT induction needs co-expression of LCB1 and LCB2","pmids":["8058731"],"confidence":"High","gaps":["Did not establish the physical nature of the LCB1-LCB2 association","Catalytic residues not yet mapped"]},{"year":1996,"claim":"Cloned the human ortholog and identified an LCB2-specific catalytic-domain motif shared with the aminolevulinate synthase superfamily, defining the catalytic signature of SPTLC2.","evidence":"cDNA cloning, cross-species yeast complementation, and sequence motif analysis","pmids":["8921873"],"confidence":"Medium","gaps":["Motif inferred by homology rather than by direct active-site assignment","Single lab"]},{"year":1998,"claim":"Demonstrated that SPTLC2 and SPTLC1 physically associate as the functional SPT heterodimer, moving from genetic to biochemical proof.","evidence":"Reciprocal affinity co-precipitation and co-IP with co-precipitating SPT activity in mammalian cells","pmids":["9837968"],"confidence":"High","gaps":["Stoichiometry and higher-order assembly not resolved","Role of accessory subunits not addressed"]},{"year":2002,"claim":"Localized the single SPT active site to the subunit interface and assigned the PLP-anchoring lysine and a critical histidine to SPTLC2, defining the catalytic mechanism.","evidence":"Site-directed mutagenesis, yeast genetics, activity assays and structural modeling","pmids":["11781309"],"confidence":"High","gaps":["No experimental high-resolution structure of the mammalian complex","Contribution of each subunit to substrate binding not fully partitioned"]},{"year":2013,"claim":"Resolved the pathomechanism of HSAN-I SPTLC2 mutations as a shift in substrate specificity producing neurotoxic 1-deoxysphingolipids, with distinct mutations affecting canonical versus alternative activity differently.","evidence":"In vitro and cell-based SPT activity assays, bacterial structural mimics with ssSPT subunits, and patient plasma sphingolipidomics across multiple mutations (V359M, G382V, I504F, A182P)","pmids":["20920666","24175284","23658386"],"confidence":"High","gaps":["Mechanism by which 1-deoxysphingolipids cause neurodegeneration not defined here","Bacterial mimic used as structural proxy for some assays"]},{"year":2010,"claim":"Showed SPTLC2 is transcriptionally inducible by inflammatory signaling, linking SPT output to NFκB activity.","evidence":"p65 overexpression, promoter analysis and ChIP in LPS-treated macrophages with ceramide/sphingomyelin quantification","pmids":["21167294"],"confidence":"Medium","gaps":["Selectivity for SPTLC2 over SPTLC1 mechanistically unexplained beyond promoter binding","Single lab"]},{"year":2019,"claim":"Established a cell-autonomous requirement for SPTLC2-driven sphingolipid flux in CD8+ T cell survival and effector function.","evidence":"T-cell-specific conditional KO mice with viral challenge, mTORC1/ER-stress readouts, and sphingolipid and ER-stress-inhibitor rescue","pmids":["30952607"],"confidence":"High","gaps":["Which downstream sphingolipid species mediate the rescue not pinpointed","Link between mTORC1 dysregulation and ER stress not fully ordered"]},{"year":2022,"claim":"Connected ER-stress-driven SPTLC2 induction to a metabolic disease phenotype via the sXBP1-SPTLC2-ceramide axis.","evidence":"Promoter analysis, sXBP1 activation assay, and liver-specific transgenic mice with IRβ phosphorylation and ceramide measurement","pmids":["35513574"],"confidence":"Medium","gaps":["Causality between ceramide species and IRβ dephosphorylation correlative","Single lab and overexpression model"]},{"year":2024,"claim":"Defined a second disease class for SPTLC2: transmembrane-domain gain-of-function mutations causing ALS through loss of ORMDL feedback inhibition and ceramide overproduction, mechanistically distinct from HSAN-I substrate shifting.","evidence":"Exome/genome sequencing, sphingolipidomics, and mutant expression in HEK cells, plus an additional ALS variant driving excess canonical synthesis","pmids":["38041684","38041679","40849231"],"confidence":"Medium","gaps":["For some variants ORMDL3 regulatory loss proposed but not directly manipulated","Therapeutic implications (e.g., serine supplementation harm) predicted not demonstrated in vivo"]},{"year":2024,"claim":"Implicated SPTLC2 beyond canonical lipid metabolism by linking its enzymatic activity to oncogenic EGFR signaling.","evidence":"Co-IP of SPTLC2-EGFR with knockdown/overexpression and EGFR-FAK-HBEGF readouts in ovarian cancer migration and metastasis models","pmids":["39645550"],"confidence":"Medium","gaps":["Whether the EGFR interaction is direct and stoichiometric versus activity-mediated unclear","Single lab"]},{"year":2025,"claim":"Demonstrated that de novo ceramide synthesis via SPTLC2 is required for β-cell survival and insulin secretion despite salvage-pathway compensation.","evidence":"β-cell-specific conditional KO mice with lipidomics, transcriptomics, histology and glucose tolerance testing (preprint)","pmids":["bio_10.1101_2025.05.14.653935"],"confidence":"Medium","gaps":["Preprint, not yet peer-reviewed","Specific ceramide species responsible for β-cell loss not isolated"]},{"year":null,"claim":"How SPTLC2 transmembrane mutations mechanistically uncouple the enzyme from ORMDL-mediated feedback, and whether HSAN-I versus ALS substrate/regulatory phenotypes can be distinguished structurally, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No experimental structure of the mammalian SPT-ORMDL regulatory complex with disease mutations","Direct ORMDL3 manipulation not performed for all ALS variants"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,2,3,4]},{"term_id":"GO:0016874","term_label":"ligase activity","supporting_discovery_ids":[0]}],"localization":[],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[0,4,9]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[5,9,16]}],"complexes":["serine palmitoyltransferase (SPT) heterodimer"],"partners":["SPTLC1","ORMDL3","EGFR","TLR4"],"other_free_text":[]}},"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":188,"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":"11781309","id":"PMC_11781309","title":"Mutations in the yeast LCB1 and LCB2 genes, including those corresponding to the hereditary sensory neuropathy type I mutations, dominantly inactivate serine palmitoyltransferase.","date":"2002","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/11781309","citation_count":92,"is_preprint":false},{"pmid":"8921873","id":"PMC_8921873","title":"Sphingolipid synthesis: identification and characterization of mammalian cDNAs encoding the Lcb2 subunit of serine palmitoyltransferase.","date":"1996","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/8921873","citation_count":63,"is_preprint":false},{"pmid":"30952607","id":"PMC_30952607","title":"Loss of Neurological Disease HSAN-I-Associated Gene SPTLC2 Impairs CD8+ T Cell Responses to Infection by Inhibiting T Cell Metabolic Fitness.","date":"2019","source":"Immunity","url":"https://pubmed.ncbi.nlm.nih.gov/30952607","citation_count":41,"is_preprint":false},{"pmid":"23658386","id":"PMC_23658386","title":"Hereditary sensory and autonomic neuropathy type 1 (HSANI) caused by a novel mutation in SPTLC2.","date":"2013","source":"Neurology","url":"https://pubmed.ncbi.nlm.nih.gov/23658386","citation_count":38,"is_preprint":false},{"pmid":"21167294","id":"PMC_21167294","title":"Endotoxin activates de novo sphingolipid biosynthesis via nuclear factor kappa B-mediated upregulation of Sptlc2.","date":"2010","source":"Prostaglandins & other lipid mediators","url":"https://pubmed.ncbi.nlm.nih.gov/21167294","citation_count":35,"is_preprint":false},{"pmid":"19076721","id":"PMC_19076721","title":"The LCB2 subunit of the sphingolip biosynthesis enzyme serine palmitoyltransferase can function as an attenuator of the hypersensitive response and Bax-induced cell death.","date":"2009","source":"The New phytologist","url":"https://pubmed.ncbi.nlm.nih.gov/19076721","citation_count":31,"is_preprint":false},{"pmid":"19897935","id":"PMC_19897935","title":"Analysis of development of lesions in mice with serine palmitoyltransferase (SPT) deficiency -Sptlc2 conditional knockout 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Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/40143173","citation_count":4,"is_preprint":false},{"pmid":"36828166","id":"PMC_36828166","title":"SPTLC2 ameliorates chondrocyte dysfunction and extracellular matrix metabolism disturbance in vitro and in vivo in osteoarthritis.","date":"2023","source":"Experimental cell research","url":"https://pubmed.ncbi.nlm.nih.gov/36828166","citation_count":3,"is_preprint":false},{"pmid":"37107689","id":"PMC_37107689","title":"Specific Deoxyceramide Species Correlate with Expression of Macular Telangiectasia Type 2 (MacTel2) in a SPTLC2 Carrier HSAN1 Family.","date":"2023","source":"Genes","url":"https://pubmed.ncbi.nlm.nih.gov/37107689","citation_count":3,"is_preprint":false},{"pmid":"9133733","id":"PMC_9133733","title":"Serine palmitoyltransferase (scs1/lcb2) mutants have elevated copy number of the L-A dsRNA virus.","date":"1997","source":"Yeast (Chichester, 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Overproduction of SPT activity required co-expression of both LCB1 and LCB2, providing genetic evidence that both encode subunits of the same enzyme.\",\n      \"method\": \"Genetic overexpression in Saccharomyces cerevisiae; 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 2 / Strong — functional genetic evidence replicated and foundational; consistent with subsequent biochemical confirmation across multiple labs\",\n      \"pmids\": [\"8058731\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"Human SPTLC2 (hLCB2) was cloned and shown to be the mammalian ortholog of yeast LCB2. A conserved 56-residue motif unique to LCB2 proteins functionally substituted for the corresponding region of S. cerevisiae Lcb2p, and contains a peptide sequence identified as part of the catalytic domain of the aminolevulinate synthase superfamily, establishing this motif as the catalytic domain signature of SPTLC2.\",\n      \"method\": \"cDNA cloning; cross-species functional complementation in yeast; sequence motif analysis\",\n      \"journal\": \"Gene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional complementation across species with sequence validation; single lab\",\n      \"pmids\": [\"8921873\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"SPTLC2 (LCB2) and SPTLC1 (LCB1) physically interact to form the SPT heterodimeric complex. Affinity-tagged LCB1 co-precipitated endogenous LCB2, and anti-LCB2 antibody co-immunoprecipitated both SPT enzymatic activity and LCB1, demonstrating the LCB1·LCB2 heterodimer is the functional SPT enzyme.\",\n      \"method\": \"Affinity co-precipitation; co-immunoprecipitation with SPT activity assay; mammalian (CHO) cell mutant complementation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP plus enzymatic activity co-precipitation; replicated in cell-based complementation system\",\n      \"pmids\": [\"9837968\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"SPT is an Lcb1p·Lcb2p heterodimer with a single active site at the subunit interface. The PLP cofactor forms a Schiff's base with a conserved lysine in Lcb2p (SPTLC2 ortholog). A conserved histidine in Lcb2p is also critical for PLP binding. Mutations in Lcb1p near this active site dominantly inactivate SPT by ~50% when co-expressed with wild-type, and mutant Lcb1p retains interaction with Lcb2p.\",\n      \"method\": \"Site-directed mutagenesis; yeast genetics; SPT activity assays; structural modeling\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — active-site mutagenesis of conserved catalytic residues combined with functional assays and structural modeling; replicated across multiple mutations\",\n      \"pmids\": [\"11781309\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Missense mutations in SPTLC2 (V359M, G382V, I504F) cause HSAN-I by (i) partial to complete loss of canonical SPT activity (palmitoyl-CoA + serine) and (ii) gain of alternative substrate specificity, incorporating alanine instead of serine to produce the neurotoxic metabolite 1-deoxy-sphinganine. This establishes altered substrate specificity as the common pathomechanism for HSAN-I.\",\n      \"method\": \"In vitro SPT activity assay; cell-based activity assay; mass spectrometric sphingolipid profiling in patient cells and plasma\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro and in vivo enzymatic assays with multiple mutations; replicated across four families; orthogonal methods (cell-free and cell-based assays plus patient metabolite profiling)\",\n      \"pmids\": [\"20920666\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Endotoxin (LPS) upregulates Sptlc2 mRNA and protein in macrophages via NFκB; the p65 subunit of NFκB directly binds the Sptlc2 promoter (demonstrated by ChIP), leading to increased SPT activity and elevated cellular ceramide and sphingomyelin levels. Sptlc1 is not regulated by this pathway.\",\n      \"method\": \"NFκB pharmacological inhibition; p65 overexpression; promoter analysis; chromatin immunoprecipitation (ChIP); ceramide/sphingomyelin quantification\",\n      \"journal\": \"Prostaglandins & other lipid mediators\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and promoter analysis with functional readout; multiple orthogonal methods; single lab\",\n      \"pmids\": [\"21167294\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"The three HSAN-I-associated hLCB2a (SPTLC2) mutations (V359M, G382V, I504F) map to the active site region near the PLP cofactor binding pocket. These mutations reduce affinity for both substrates, perturb PLP cofactor binding, and decrease SPT enzyme activity; the most severe (I504F/G385F in bacterial mimic) causes insoluble protein expression. Activity assays in the presence of small SPT subunits (ssSPTa and ssSPTb) confirmed all three mutations decrease enzyme activity.\",\n      \"method\": \"Bacterial SPT structural mimic mutagenesis; in vitro activity assays with ssSPT subunits; structural modeling based on Sphingomonas paucimobilis SPT crystal structure\",\n      \"journal\": \"BioMed research international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro enzymatic assay with mutagenesis and structural modeling; single lab; bacterial mimic used as structural proxy\",\n      \"pmids\": [\"24175284\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"A novel SPTLC2 mutation (A182P) causes HSAN-I with a distinct biochemical profile: reduced canonical SPT activity but markedly increased alternative (alanine-utilizing) activity, producing greatly elevated 1-deoxysphingolipid levels. This confirms alanine mis-incorporation as the shared pathomechanism and demonstrates that different SPTLC2 mutations can differentially affect canonical versus alternative substrate use.\",\n      \"method\": \"Cell-free and cell-based SPT activity assays; plasma 1-deoxysphingolipid quantification by mass spectrometry\",\n      \"journal\": \"Neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — cell-free and cell-based assays with patient mutation; single lab; orthogonal biochemical methods\",\n      \"pmids\": [\"23658386\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SPTLC2 expression is induced by antigen stimulation and inflammation in T cells. T-cell-specific Sptlc2 ablation in mice reduces sphingolipid biosynthetic flux, causes prolonged mTORC1 activation, ER stress, and CD8+ T cell death, impairing antiviral T cell expansion and effector function. Supplementing sphingolipids or pharmacologically inhibiting ER stress-induced cell death rescues protective CD8+ T cell responses.\",\n      \"method\": \"T-cell-specific conditional knockout mice; viral infection model; sphingolipid supplementation rescue; pharmacological ER stress inhibition; mTORC1 signaling assays\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean cell-type-specific KO with defined molecular phenotype (mTORC1, ER stress), multiple rescue strategies, functional immune readout; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"30952607\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"ER stress upregulates Sptlc2 transcription through the spliced form of XBP1 (sXBP1), which binds the Sptlc2 promoter, increasing SPT activity and ceramide/dihydroceramide levels in hepatocytes. Liver-specific Sptlc2 transgenic mice show elevated hepatic ceramide, elevated fasting glucose, and reduced phosphorylation of insulin receptor β (IRβ), establishing a mechanistic link between SPTLC2-driven ceramide synthesis and hepatic insulin resistance.\",\n      \"method\": \"Promoter analysis; sXBP1 transcriptional activation assay; liver-specific transgenic mice; insulin signaling (IRβ phosphorylation) measurement; ceramide quantification\",\n      \"journal\": \"Experimental & molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — transgenic mouse model with defined molecular readout and promoter analysis; single lab; multiple methods\",\n      \"pmids\": [\"35513574\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"A recurrent de novo gain-of-function SPTLC2 mutation (c.203T>G, p.Met68Arg) lies within a transmembrane domain and is proposed to render the SPT complex irresponsive to negative regulation by ORMDL3, leading to unrestrained ceramide and complex sphingolipid overproduction in patient plasma and in mutant-expressing HEK cells, causing juvenile ALS.\",\n      \"method\": \"Whole-genome/exome sequencing; sphingolipidomics (LC-HRMS); HEK cell expression of mutant SPTLC2; Sanger sequencing for de novo confirmation\",\n      \"journal\": \"Journal of neurology, neurosurgery, and psychiatry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — functional cell-based assay with sphingolipidomics; de novo mutation confirmed; ORMDL3 regulatory mechanism proposed but not directly tested by ORMDL3 manipulation\",\n      \"pmids\": [\"38041684\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"The SPTLC2 variant p.Glu260Lys (c.778G>A) causes juvenile ALS through excess canonical sphingolipid biosynthesis (elevated ceramides), mechanistically distinct from HSAN-causing SPTLC2 variants (which shift substrate specificity to produce 1-deoxysphingolipids). Serine supplementation—therapeutic in HSAN—is predicted to exacerbate SPT-ALS by further driving sphingolipid overproduction.\",\n      \"method\": \"Clinical genetic testing; plasma and fibroblast sphingolipid measurement; biochemical investigation of patient-derived cells\",\n      \"journal\": \"Journal of neurology, neurosurgery, and psychiatry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — patient fibroblast and plasma biochemistry with multiple patients from independent families; single coordinated study\",\n      \"pmids\": [\"38041679\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"A novel SPTLC2 variant (p.T66R) in a transmembrane domain reduces inhibitory regulation of SPT by ORMDL proteins, leading to unrestrained SPT activity and excess sphingolipid production, causing childhood-onset ALS. This functionally differs from HSAN-associated SPTLC2 variants.\",\n      \"method\": \"Whole-exome sequencing; UPLC-MS/MS sphingolipid profiling; mutant cell line functional studies; ORMDL3 regulation assay\",\n      \"journal\": \"Journal of neuromuscular diseases\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell-based functional assay with ORMDL regulation tested; sphingolipidomics; single lab\",\n      \"pmids\": [\"40849231\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SPTLC2 directly binds EGFR in ovarian cancer cells (demonstrated by co-immunoprecipitation), and its serine palmitoyltransferase enzymatic activity is required for activation of an EGFR-FAK-HBEGF signaling axis that promotes clonogenic growth, migration, and metastasis.\",\n      \"method\": \"Co-immunoprecipitation (SPTLC2-EGFR); SPTLC2 knockdown and overexpression; in vitro clonogenic and migration assays; in ovo and xenograft metastasis models\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP for binding plus loss/gain-of-function with defined signaling readout; single lab\",\n      \"pmids\": [\"39645550\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SPTLC2 promotes neuronal apoptosis via the TLR4 signaling pathway; co-immunoprecipitation identified physical interaction between SPTLC2 and TLR4 pathway components. miR-124-3p negatively regulates SPTLC2 expression (validated by dual luciferase reporter assay) and suppresses SPTLC2-mediated apoptosis through this pathway.\",\n      \"method\": \"Co-immunoprecipitation; dual luciferase reporter assay; TUNEL staining; western blot; primary neuron injury model\",\n      \"journal\": \"Neurochemical research\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single co-IP without reciprocal validation; pathway placement relies on single lab, single method for protein interaction\",\n      \"pmids\": [\"31372925\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"β-cell-selective deletion of Sptlc2 in mice (Sptlc2ΔIns1) causes marked reductions in ceramide and sphingomyelin levels in islets (despite compensatory upregulation of salvage and sphingomyelinase pathway enzymes), a ~80% loss of β-cell mass, and profound impairment of glucose-regulated insulin secretion and glucose tolerance—establishing that de novo ceramide synthesis via SPTLC2/SPT2 is required for normal β-cell survival and function.\",\n      \"method\": \"β-cell-specific conditional knockout (Cre-lox); metabolic phenotyping; ceramide/sphingomyelin quantification; transcriptomics; histology; glucose tolerance testing\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean cell-type-specific conditional KO with multiple orthogonal readouts; preprint, not yet peer-reviewed\",\n      \"pmids\": [\"bio_10.1101_2025.05.14.653935\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"The mouse SPTLC2 promoter contains initiator and downstream promoter elements within the proximal 335 bp, including two proximal GC boxes that cooperatively stimulate transcription, as determined by deletion analysis and site-directed mutagenesis of luciferase reporter constructs.\",\n      \"method\": \"Luciferase reporter assay; deletion analysis; site-directed mutagenesis of promoter elements\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — promoter mutagenesis with functional reporter readout; single lab\",\n      \"pmids\": [\"17070807\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SPTLC2 (hLCB2a) is the catalytic subunit of the heterodimeric serine palmitoyltransferase (SPT) complex, forming an obligate heterodimer with SPTLC1 (LCB1) at whose interface a single PLP-dependent active site catalyzes the first and rate-limiting step of sphingolipid de novo biosynthesis (condensation of palmitoyl-CoA and L-serine to 3-ketosphinganine); a conserved lysine in SPTLC2 forms the Schiff's base with the PLP cofactor, and disease-causing mutations in SPTLC2 either shift substrate specificity toward alanine (generating neurotoxic 1-deoxysphingolipids in HSAN-I) or abolish ORMDL3-mediated feedback inhibition (causing unrestrained sphingolipid overproduction in juvenile ALS); SPTLC2 activity is transcriptionally induced by NFκB (in response to LPS) and by sXBP1 (in response to ER stress), and the enzyme is required in a cell-autonomous manner for CD8+ T cell metabolic fitness and β-cell survival.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SPTLC2 is the catalytic subunit of serine palmitoyltransferase (SPT), the enzyme that catalyzes the first and committed step of de novo sphingolipid biosynthesis—the PLP-dependent condensation of palmitoyl-CoA and L-serine to 3-ketosphinganine [#0]. It functions as an obligate heterodimer with SPTLC1, the complex co-precipitating both partners together with SPT enzymatic activity, establishing the LCB1·LCB2 heterodimer as the functional enzyme [#2]. A single catalytic site lies at the subunit interface, where a conserved lysine in SPTLC2 forms a Schiff base with the PLP cofactor and a conserved histidine supports cofactor binding [#3]. Disease-causing missense mutations in SPTLC2 partition into two mechanistic classes: HSAN-I mutations clustered near the PLP pocket reduce canonical activity while conferring gain of alternative substrate specificity, mis-incorporating alanine to generate neurotoxic 1-deoxysphingolipids [#4, #6, #7], whereas transmembrane-domain mutations cause juvenile/childhood ALS by escaping ORMDL-mediated feedback inhibition and driving unrestrained ceramide overproduction [#10, #12], with a distinct ALS variant increasing canonical sphingolipid output [#11]. SPTLC2 transcription is inducible: NF\\u03baB p65 binds the Sptlc2 promoter in response to LPS [#5] and spliced XBP1 activates it under ER stress, linking SPTLC2-driven ceramide synthesis to hepatic insulin resistance [#9]. The enzyme is required cell-autonomously for CD8+ T cell metabolic fitness and effector responses [#8] and for \\u03b2-cell survival and glucose-regulated insulin secretion [#15].\",\n  \"teleology\": [\n    {\n      \"year\": 1994,\n      \"claim\": \"Established that SPT, the committed enzyme of sphingolipid synthesis, requires two distinct subunits, identifying LCB2/SPTLC2 as one of them.\",\n      \"evidence\": \"Genetic overexpression and enzymatic assay in S. cerevisiae showing SPT induction needs co-expression of LCB1 and LCB2\",\n      \"pmids\": [\"8058731\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish the physical nature of the LCB1-LCB2 association\", \"Catalytic residues not yet mapped\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Cloned the human ortholog and identified an LCB2-specific catalytic-domain motif shared with the aminolevulinate synthase superfamily, defining the catalytic signature of SPTLC2.\",\n      \"evidence\": \"cDNA cloning, cross-species yeast complementation, and sequence motif analysis\",\n      \"pmids\": [\"8921873\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Motif inferred by homology rather than by direct active-site assignment\", \"Single lab\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Demonstrated that SPTLC2 and SPTLC1 physically associate as the functional SPT heterodimer, moving from genetic to biochemical proof.\",\n      \"evidence\": \"Reciprocal affinity co-precipitation and co-IP with co-precipitating SPT activity in mammalian cells\",\n      \"pmids\": [\"9837968\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and higher-order assembly not resolved\", \"Role of accessory subunits not addressed\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Localized the single SPT active site to the subunit interface and assigned the PLP-anchoring lysine and a critical histidine to SPTLC2, defining the catalytic mechanism.\",\n      \"evidence\": \"Site-directed mutagenesis, yeast genetics, activity assays and structural modeling\",\n      \"pmids\": [\"11781309\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No experimental high-resolution structure of the mammalian complex\", \"Contribution of each subunit to substrate binding not fully partitioned\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Resolved the pathomechanism of HSAN-I SPTLC2 mutations as a shift in substrate specificity producing neurotoxic 1-deoxysphingolipids, with distinct mutations affecting canonical versus alternative activity differently.\",\n      \"evidence\": \"In vitro and cell-based SPT activity assays, bacterial structural mimics with ssSPT subunits, and patient plasma sphingolipidomics across multiple mutations (V359M, G382V, I504F, A182P)\",\n      \"pmids\": [\"20920666\", \"24175284\", \"23658386\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which 1-deoxysphingolipids cause neurodegeneration not defined here\", \"Bacterial mimic used as structural proxy for some assays\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Showed SPTLC2 is transcriptionally inducible by inflammatory signaling, linking SPT output to NF\\u03baB activity.\",\n      \"evidence\": \"p65 overexpression, promoter analysis and ChIP in LPS-treated macrophages with ceramide/sphingomyelin quantification\",\n      \"pmids\": [\"21167294\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Selectivity for SPTLC2 over SPTLC1 mechanistically unexplained beyond promoter binding\", \"Single lab\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Established a cell-autonomous requirement for SPTLC2-driven sphingolipid flux in CD8+ T cell survival and effector function.\",\n      \"evidence\": \"T-cell-specific conditional KO mice with viral challenge, mTORC1/ER-stress readouts, and sphingolipid and ER-stress-inhibitor rescue\",\n      \"pmids\": [\"30952607\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Which downstream sphingolipid species mediate the rescue not pinpointed\", \"Link between mTORC1 dysregulation and ER stress not fully ordered\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Connected ER-stress-driven SPTLC2 induction to a metabolic disease phenotype via the sXBP1-SPTLC2-ceramide axis.\",\n      \"evidence\": \"Promoter analysis, sXBP1 activation assay, and liver-specific transgenic mice with IR\\u03b2 phosphorylation and ceramide measurement\",\n      \"pmids\": [\"35513574\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causality between ceramide species and IR\\u03b2 dephosphorylation correlative\", \"Single lab and overexpression model\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined a second disease class for SPTLC2: transmembrane-domain gain-of-function mutations causing ALS through loss of ORMDL feedback inhibition and ceramide overproduction, mechanistically distinct from HSAN-I substrate shifting.\",\n      \"evidence\": \"Exome/genome sequencing, sphingolipidomics, and mutant expression in HEK cells, plus an additional ALS variant driving excess canonical synthesis\",\n      \"pmids\": [\"38041684\", \"38041679\", \"40849231\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"For some variants ORMDL3 regulatory loss proposed but not directly manipulated\", \"Therapeutic implications (e.g., serine supplementation harm) predicted not demonstrated in vivo\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Implicated SPTLC2 beyond canonical lipid metabolism by linking its enzymatic activity to oncogenic EGFR signaling.\",\n      \"evidence\": \"Co-IP of SPTLC2-EGFR with knockdown/overexpression and EGFR-FAK-HBEGF readouts in ovarian cancer migration and metastasis models\",\n      \"pmids\": [\"39645550\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether the EGFR interaction is direct and stoichiometric versus activity-mediated unclear\", \"Single lab\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Demonstrated that de novo ceramide synthesis via SPTLC2 is required for \\u03b2-cell survival and insulin secretion despite salvage-pathway compensation.\",\n      \"evidence\": \"\\u03b2-cell-specific conditional KO mice with lipidomics, transcriptomics, histology and glucose tolerance testing (preprint)\",\n      \"pmids\": [\"bio_10.1101_2025.05.14.653935\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Preprint, not yet peer-reviewed\", \"Specific ceramide species responsible for \\u03b2-cell loss not isolated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How SPTLC2 transmembrane mutations mechanistically uncouple the enzyme from ORMDL-mediated feedback, and whether HSAN-I versus ALS substrate/regulatory phenotypes can be distinguished structurally, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No experimental structure of the mammalian SPT-ORMDL regulatory complex with disease mutations\", \"Direct ORMDL3 manipulation not performed for all ALS variants\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 2, 3, 4]},\n      {\"term_id\": \"GO:0016874\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"localization\": [],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0, 4, 9]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [5, 9, 16]}\n    ],\n    \"complexes\": [\"serine palmitoyltransferase (SPT) heterodimer\"],\n    \"partners\": [\"SPTLC1\", \"ORMDL3\", \"EGFR\", \"TLR4\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}