{"gene":"SPTLC1","run_date":"2026-06-10T07:46:41","timeline":{"discoveries":[{"year":1991,"finding":"LCB1 (SPTLC1 yeast ortholog) encodes serine palmitoyltransferase (SPT), the first enzyme in sphingolipid long-chain base synthesis; lcb1 mutants lack SPT activity, and LCB1 restores activity in defective strains. Sequence analysis revealed homology to PLP-dependent alpha-oxoamine synthases (5-aminolevulinic acid synthase, 2-amino-3-ketobutyrate CoA ligase) and predicted a membrane-associated protein with two transmembrane helices.","method":"Molecular cloning, genetic complementation of lcb1-defective yeast, sequence analysis, SPT activity assay","journal":"Journal of Bacteriology","confidence":"High","confidence_rationale":"Tier 1 / Strong — genetic complementation restoring enzymatic activity, replicated across multiple labs in subsequent work","pmids":["2066332"],"is_preprint":false},{"year":1994,"finding":"Both LCB1 and LCB2 subunits are required for serine palmitoyltransferase activity in S. cerevisiae; overproduction of SPT requires co-expression of both genes, providing genetic evidence that both encode subunits of the same enzyme.","method":"Yeast overexpression, SPT activity assay, genetic co-expression studies","journal":"Proceedings of the National Academy of Sciences","confidence":"High","confidence_rationale":"Tier 1 / Strong — enzymatic activity assay with both subunits, foundational result replicated in subsequent mammalian studies","pmids":["8058731"],"is_preprint":false},{"year":1997,"finding":"The mammalian LCB1 protein (SPTLC1) is a component of serine palmitoyltransferase; transfection of SPT-defective CHO mutant cells with LCB1 cDNA restored both SPT activity and de novo sphingolipid synthesis to wild-type levels, and SPT activity co-purified with His6-tagged LCB1 on Ni2+ resin.","method":"Transfection complementation of SPT-defective CHO cells, Ni2+-affinity purification, SPT activity assay, Northern blot","journal":"The Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — enzymatic activity restoration by complementation plus affinity co-purification, replicated in CHO system","pmids":["9405408"],"is_preprint":false},{"year":1998,"finding":"SPTLC1 (LCB1) and SPTLC2 (LCB2) form a physical complex that constitutes the SPT enzyme; affinity-tagged LCB1 co-purified endogenous LCB2, and anti-LCB2 antibody co-immunoprecipitated both SPT activity and wild-type LCB1 from CHO cells.","method":"Affinity purification with epitope-tagged LCB1, co-immunoprecipitation with anti-LCB2 antibody, SPT activity assay, genetic complementation of LY-B (LCB1-null) cells","journal":"The Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — reciprocal co-immunoprecipitation plus co-purification of enzymatic activity, multiple orthogonal methods","pmids":["9837968"],"is_preprint":false},{"year":2001,"finding":"Missense mutations in SPTLC1 (C133Y, C133W in exon 5; V144D in exon 6) cause hereditary sensory neuropathy type I (HSN1) in humans; affected lymphoblasts show increased de novo glucosylceramide synthesis.","method":"Mutation screening in HSN1 families, mapping to chromosome 9q22.1-22.3, de novo ceramide synthesis assay in patient lymphoblasts","journal":"Nature Genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic mapping plus biochemical assay in patient cells, independently replicated in same issue by two groups","pmids":["11242114","11242106"],"is_preprint":false},{"year":2002,"finding":"SPTLC1 is an integral ER membrane protein with a single transmembrane domain near the N-terminus; the N-terminus is oriented luminally and the C-terminus faces the cytosol. LCB1 is required for the stability and maintenance of the LCB2 subunit — in LCB1-null LY-B cells, LCB2 protein is drastically reduced and is restored by LCB1 transfection.","method":"Indirect immunostaining with N- and C-terminal epitope tags in stably transfected LY-B cells, Western blot for LCB2 levels, SPT activity assay","journal":"The Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — direct localization experiment with dual epitope tagging plus functional consequence (LCB2 stability), single lab but multiple orthogonal methods","pmids":["12464627"],"is_preprint":false},{"year":2002,"finding":"SPT is an LCB1·LCB2 heterodimer; HSAN1-equivalent mutations in yeast Lcb1p (C133Y/W equivalents) dominantly reduce SPT activity by ~50% when co-expressed with wild-type LCB1, and the mutant Lcb1p proteins retain their ability to interact with Lcb2p. Modeling indicates SPT has a single active site at the Lcb1p·Lcb2p interface, and the mutations reside near the PLP-binding lysine of Lcb2p.","method":"Yeast co-expression, SPT activity assays, co-immunoprecipitation, structural modeling based on alpha-oxoamine synthase family alignments","journal":"The Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — enzymatic assay plus co-IP plus structural modeling in a single focused study; dominant-negative mechanism confirmed","pmids":["11781309"],"is_preprint":false},{"year":2005,"finding":"Transgenic mice expressing mutant SPTLC1 (C133W) show dominant inhibition of SPT activity in vivo, develop age-dependent sensory and motor impairments, and lose large myelinated axons with myelin thinning, confirming the link between mutant SPT and neuronal dysfunction in a mammalian in vivo model.","method":"Transgenic mouse overexpression (wild-type and C133W), SPT activity measurement, nerve histomorphometry, behavioral testing, immunostaining (IB4, ATF3)","journal":"Human Molecular Genetics","confidence":"High","confidence_rationale":"Tier 2 / Moderate — in vivo loss/gain of function with defined neuropathological readouts and SPT activity measurement, single lab","pmids":["16210380"],"is_preprint":false},{"year":2008,"finding":"SPTLC1 (but not SPTLC2) physically interacts with the cholesterol transporter ABCA1 and negatively regulates its trafficking and cholesterol efflux activity; SPTLC1 inhibition (myriocin or siRNA) disrupts the complex and increases ABCA1-dependent cholesterol efflux by ~60%, while dominant-negative SPTLC1 inhibits ABCA1 efflux. The interaction blocks ABCA1 exit from the ER.","method":"Affinity purification/mass spectrometry, co-immunoprecipitation in THP-1 macrophages and mouse liver, siRNA knockdown, cholesterol efflux assay, dominant-negative overexpression","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP in physiological settings plus multiple functional readouts (efflux assay, ER exit block), single lab with orthogonal methods","pmids":["18484747"],"is_preprint":false},{"year":2009,"finding":"HSAN1 mutations in SPTLC1 alter the amino acid substrate selectivity of SPT, causing palmitate to be condensed with alanine and glycine in addition to serine, generating deoxysphingoid bases (1-deoxy-sphinganine, 1-deoxymethyl-sphinganine) that accumulate in tgSPTLC1(C133W) mice. Overexpression of wild-type SPTLC1 in double-transgenic mice reverses the phenotype and reduces deoxysphingoid base levels. Heterozygous SPTLC1 knockout mice have reduced SPT activity but are otherwise normal.","method":"Transgenic and double-transgenic mouse crosses, mass spectrometry-based lipidomics for deoxysphingoid bases, SPT activity assay, behavioral phenotyping, heterozygous knockout analysis","journal":"The Journal of Neuroscience","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal in vivo models (transgenic, double-transgenic, knockout), biochemical substrate-selectivity shift confirmed by lipidomics, replicated in subsequent studies","pmids":["19923297"],"is_preprint":false},{"year":2009,"finding":"Bacterial SPT HSAN1 mimic mutations (N100Y and N100W, equivalent to human C133Y/W) reduce enzyme activity, alter the active-site PLP chemistry, impair stabilization of the quinonoid intermediate, and transmit structural changes across the dimer interface. Crystal structures of the external aldimine form reveal that N100Y hinders movement of a catalytically critical Arg378 into the active site.","method":"X-ray crystallography (holoenzyme and external aldimine structures), kinetic assays, UV-vis spectroscopy, site-directed mutagenesis of active-site residues","journal":"The Journal of Biological Chemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structures combined with kinetics and mutagenesis in a single rigorous study; bacterial mimic of human mutations","pmids":["19376777"],"is_preprint":false},{"year":2009,"finding":"SPTLC1 interacts with the PDZ protein Par3 via a conserved C-terminal type II PDZ-binding motif; Par3 binds the third PDZ domain of Par3 and associates with the SPTLC1/2 holoenzyme. siRNA knockdown of Par3 in THP-1 monocytes reduces SPT activity and de novo ceramide synthesis by ~40% and impairs MCP-1-directed chemotaxis in an SPT-activity-dependent manner.","method":"PDZ domain protein array screening, overlay and co-immunoprecipitation assays, siRNA knockdown, SPT activity assay, ceramide synthesis assay, chemotaxis assay","journal":"The Journal of Biological Chemistry","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — PDZ array plus co-IP plus functional siRNA knockdown, single lab with multiple orthogonal methods","pmids":["19592499"],"is_preprint":false},{"year":2011,"finding":"SPTLC1 mutations p.S331F and p.A352V reduce SPT activity in vitro and are associated with increased plasma levels of 1-deoxy-sphinganine and 1-deoxymethyl-sphinganine; HEK293T cells stably expressing p.S331F-SPTLC1 accumulate deoxysphingoid bases, consistent with a substrate-shift gain-of-function mechanism.","method":"In vitro SPT activity assay, stable HEK293T cell lines, mass spectrometry-based lipidomics of patient plasma and cell lines","journal":"Human Mutation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro enzymatic assay plus patient plasma and cell-line lipidomics, single lab","pmids":["21618344"],"is_preprint":false},{"year":2013,"finding":"SPTLC1 is phosphorylated at Tyr164 by the tyrosine kinase ABL in ER microsomes; this phosphorylation inhibits SPT activity, and the Y164F mutation increases SPT activity, remodels sphingolipid content, and sensitizes BCR-ABL-expressing cells to apoptosis. BCR-ABL inhibition with imatinib activates SPTLC1 by reducing Y164 phosphorylation.","method":"Phosphoproteomic analysis of ER microsomes, in vitro kinase validation, shRNA silencing of BCR-ABL, site-directed mutagenesis (Y164F), SPT activity assay, sphingolipid profiling, apoptosis assay","journal":"The Journal of Biological Chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — phosphoproteomics plus in vitro validation plus mutagenesis plus functional assays, single lab","pmids":["23629659"],"is_preprint":false},{"year":2013,"finding":"Bacterial SPT hLCB2a HSAN1 mutation mimics (V246M, G268V, G385F in Sphingomonas paucimobilis SPT) perturb PLP cofactor binding, reduce affinity for both substrates, decrease enzyme activity, and in the most severe case cause insoluble expression; ssSPTa and ssSPTb small subunits modulate the activity of hLCB2a mutants.","method":"Site-directed mutagenesis, in vitro SPT activity assay, structural analysis (homology modeling from Sp SPT crystal structure), expression analysis","journal":"BioMed Research International","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — enzymatic assays with mutagenesis and structural modeling using bacterial mimic; indirect inference for human enzyme","pmids":["24175284"],"is_preprint":false},{"year":2015,"finding":"Systematic comparison of 11 SPTLC1 and 6 SPTLC2 HSAN1 mutants by isotope-labeling shows that eight mutants increase 1-deoxySL synthesis without reducing canonical serine-based SPT activity. Three mutations (SPTLC1 p.S331F/Y, SPTLC2 p.I505Y) additionally increase canonical activity and C20 sphingoid base levels, correlating with a more severe clinical phenotype. Homology modeling clusters mutations by active-site proximity and clinical severity.","method":"Stable isotope-labeling SPT activity assay in patient/transfected cells, mass spectrometry lipidomics, principal component analysis, homology modeling","journal":"Human Molecular Genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — uniform isotope-labeling across 17 mutants in a single study, corroborated by patient plasma measurements and structural modeling","pmids":["26681808"],"is_preprint":false},{"year":2015,"finding":"A novel SPTLC2-S384F HSAN1 variant is associated with increased 1-deoxySL formation; wild-type SPTLC2 is phosphorylated at S384, and a phosphomimetic S384D (but not S384E) mutation also increases 1-deoxySL, suggesting that phosphorylation at this residue dynamically regulates SPT substrate specificity.","method":"Patient plasma lipidomics, HEK293 cell transfection, isoelectric focusing for phosphorylation, site-directed mutagenesis (S384D/E/A, Y387F), SPT activity assay","journal":"Neuromolecular Medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — phosphorylation confirmed by isoelectric focusing plus mutagenesis panel plus functional assay, single lab","pmids":["25567748"],"is_preprint":false},{"year":2018,"finding":"The first transmembrane domain (TMD1) of Lcb1 (SPTLC1 yeast ortholog) is required for ORM protein binding to SPT; loss of TMD1 abolishes ORM-dependent SPT oligomerization (assessed by co-IP and live imaging) and partially redistributes SPT to peripheral ER. ORMs with non-phosphorylatable sites cause constitutive SPT oligomerization and inhibition, while phosphomimetic ORMs do not. Sac1 binding to SPT requires the Tsc3 small subunit but not the ORMs.","method":"Co-immunoprecipitation, in vivo fluorescence imaging, yeast genetics (deletion and phosphomimetic mutants), TMD replacement experiments, membrane topology analysis","journal":"Biochimica et Biophysica Acta. Molecular and Cell Biology of Lipids","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP plus live imaging plus multiple genetic mutants in a single focused study","pmids":["30529276"],"is_preprint":false},{"year":2019,"finding":"Sptlc1 deletion in adult mouse bone marrow results in defective myeloid differentiation with expansion of multipotent progenitors; the mechanism involves ER stress triggered by accumulation of fatty acid substrates due to deficient sphingolipid biosynthesis in the ER.","method":"Conditional bone marrow deletion, chimeric mouse transplant assay, flow cytometry, ER stress marker analysis (BiP, thapsigargin treatment), fatty acid supplementation","journal":"Blood Advances","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — conditional KO with defined cellular phenotype and mechanistic ER stress pathway placement, single lab","pmids":["31751474"],"is_preprint":false},{"year":2021,"finding":"De novo gain-of-function mutations in SPTLC1 (p.Ala20Ser, p.Ser331Tyr, p.Leu39del) cause juvenile ALS; these variants are located in the transmembrane/regulatory domain and are associated with disruption of the homeostatic ORMDL-mediated feedback regulation of the SPT complex.","method":"Trio whole-exome sequencing, genetic screening of juvenile ALS cohort, de novo variant identification","journal":"JAMA Neurology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — genetic identification with pathway mechanistic inference; functional mechanism proposed based on prior biochemical data but not directly tested in this paper","pmids":["34459874"],"is_preprint":false},{"year":2022,"finding":"SPTLC1 mutations causing juvenile ALS (including p.L38R) cluster in the transmembrane domain (exon 2) and impede interaction with the regulatory ORMDL subunit of SPT, leading to loss of homeostatic feedback control; p.L38R-expressing HEK293 cells show increased SPT activity, increased total sphingolipids, and particularly elevated dihydrosphingolipids.","method":"HEK293 cell transfection, SPT activity assay, lipidomics (LC-MS), patient plasma lipid analysis","journal":"Biochimica et Biophysica Acta. Molecular and Cell Biology of Lipids","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — cell-based SPT activity assay and lipidomics with mechanistic placement (ORMDL interaction loss), single lab","pmids":["37348646"],"is_preprint":false},{"year":2022,"finding":"Endothelial-specific knockout of SPTLC1 (Sptlc1 ECKO) in mice reduces EC sphingolipid synthesis, impairs lipid raft formation and VEGF signaling, reduces EC proliferation and tip/stalk cell differentiation, delays retinal vascular development, and reduces retinal neovascularization. Post-natal deletion rapidly reduces sphingolipid metabolites in plasma and peripheral organs but not in CNS (retina), identifying EC as a major source of circulating sphingolipids.","method":"Endothelial-specific conditional knockout, retinal vascular development assay, oxygen-induced retinopathy model, lipidomics of plasma/organs, lipid raft fractionation, VEGF signaling assays","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Moderate — conditional KO with multiple orthogonal mechanistic readouts (lipid rafts, VEGF signaling, vascular development), single lab with rigorous controls","pmids":["36197001"],"is_preprint":false},{"year":2025,"finding":"In the nucleus accumbens, cocaine selectively activates ER stress in D1-MSNs, inducing ATF4 which directly targets the Sptlc1 promoter and upregulates SPTLC1 expression; D1-MSN-specific knockdown of either Atf4 or Sptlc1 markedly reduces cocaine-induced behavioral and neuroplastic changes.","method":"Cocaine administration, immunohistochemistry/molecular profiling of ER stress, promoter analysis with functional validation (ATF4→Sptlc1), cell-type-specific AAV knockdown, behavioral assays, sphingolipid synthesis assay","journal":"Frontiers in Pharmacology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — promoter functional validation plus cell-type-specific knockdown with behavioral readouts, single lab","pmids":["41378204"],"is_preprint":false},{"year":2025,"finding":"Heterozygous deletion of Sptlc1 exon 2 in mice does not produce motor defects or ALS-like neuropathology, while homozygous deletion is lethal, indicating that complete loss of SPTLC1 function is incompatible with viability but heterozygous loss-of-function is insufficient to model ALS.","method":"CRISPR/Cas9 exon 2 deletion knockin mouse model, motor function testing, neuropathological analysis","journal":"bioRxiv (preprint)","confidence":"Low","confidence_rationale":"Tier 2 / Weak — preprint, single lab, negative result (no phenotype in heterozygotes) with homozygous lethality as positive control","pmids":["40027730"],"is_preprint":true}],"current_model":"SPTLC1 encodes the LCB1 subunit of serine palmitoyltransferase (SPT), a PLP-dependent alpha-oxoamine synthase that forms a heterodimer with SPTLC2/LCB2 at the ER membrane (N-terminus luminal, C-terminus cytosolic) to catalyze the first and rate-limiting step of sphingolipid biosynthesis (condensation of L-serine and palmitoyl-CoA); HSAN1-causing mutations in SPTLC1 shift substrate selectivity toward L-alanine/glycine, generating neurotoxic 1-deoxysphingolipids rather than reducing canonical activity, while juvenile ALS-causing mutations cluster in the TMD1 transmembrane domain and disrupt ORMDL-mediated homeostatic feedback inhibition, causing unrestrained sphingolipid synthesis; SPTLC1 stability is required for LCB2 subunit maintenance, its activity is negatively regulated by ABL-mediated phosphorylation at Tyr164, it physically interacts with ABCA1 to suppress cholesterol efflux and with Par3 to promote SPT activity and monocyte chemotaxis, and endothelial SPTLC1-derived sphingolipids are essential for VEGF signaling, vascular development, and systemic sphingolipid homeostasis."},"narrative":{"mechanistic_narrative":"SPTLC1 encodes the LCB1 subunit of serine palmitoyltransferase (SPT), the enzyme that catalyzes the first and rate-limiting step of de novo sphingolipid biosynthesis [PMID:2066332, PMID:9405408]. SPT functions as an LCB1·LCB2 (SPTLC1·SPTLC2) heterodimer in which both subunits are required for activity, with a single catalytic site formed at the subunit interface and homology to PLP-dependent alpha-oxoamine synthases [PMID:8058731, PMID:9837968, PMID:11781309]; SPTLC1 is an integral ER membrane protein with a single N-terminal transmembrane domain (luminal N-terminus, cytosolic C-terminus) and is required to stabilize the LCB2 subunit [PMID:12464627]. The TMD1 of SPTLC1 mediates binding of the ORM/ORMDL regulatory proteins that impose homeostatic feedback inhibition on the complex [PMID:30529276]. SPTLC1 activity is further controlled by ABL-mediated phosphorylation at Tyr164, which inhibits the enzyme and remodels sphingolipid content [PMID:23629659], and the protein physically engages partners beyond the core complex, interacting with ABCA1 to block its ER exit and suppress cholesterol efflux [PMID:18484747] and with the PDZ protein Par3 to promote SPT activity and monocyte chemotaxis [PMID:19592499]. Two distinct disease mechanisms arise from SPTLC1 mutations: HSAN1-causing missense changes (e.g. C133W) shift substrate selectivity so that palmitate condenses with alanine and glycine, generating neurotoxic 1-deoxysphingolipids rather than abolishing canonical activity [PMID:11242114, PMID:11242106, PMID:19923297, PMID:26681808], whereas de novo juvenile-ALS mutations cluster in the transmembrane/regulatory domain and disrupt ORMDL-mediated feedback, causing unrestrained sphingolipid synthesis [PMID:34459874, PMID:37348646]. Physiologically, endothelial SPTLC1-derived sphingolipids support lipid-raft–dependent VEGF signaling and vascular development and are a major source of circulating sphingolipids [PMID:36197001], and SPTLC1 is required for myeloid differentiation by preventing ER stress from fatty acid accumulation [PMID:31751474].","teleology":[{"year":1991,"claim":"Established that the SPTLC1 ortholog encodes the catalytic machinery for the first committed step of sphingolipid synthesis, defining the gene's core enzymatic identity.","evidence":"Molecular cloning and genetic complementation of lcb1-defective yeast with SPT activity assay","pmids":["2066332"],"confidence":"High","gaps":["Did not establish whether LCB1 alone is catalytic or requires partner subunits","Membrane topology and active-site architecture undefined"]},{"year":1994,"claim":"Showed SPT is a two-subunit enzyme requiring both LCB1 and LCB2, resolving whether the activity resides in one or multiple gene products.","evidence":"Yeast co-expression and overexpression with SPT activity assay","pmids":["8058731"],"confidence":"High","gaps":["Physical complex not directly demonstrated","Stoichiometry and architecture unknown"]},{"year":1997,"claim":"Demonstrated that the mammalian SPTLC1 protein is a bona fide SPT component, extending the yeast finding to human/mammalian sphingolipid synthesis.","evidence":"Transfection complementation of SPT-defective CHO cells plus Ni2+-affinity co-purification of activity","pmids":["9405408"],"confidence":"High","gaps":["Did not define the SPTLC1-SPTLC2 physical interaction directly"]},{"year":1998,"claim":"Confirmed SPTLC1 and SPTLC2 form a stable physical complex constituting the enzyme, establishing the heterodimer as the functional unit.","evidence":"Reciprocal co-immunoprecipitation and co-purification of activity from CHO cells","pmids":["9837968"],"confidence":"High","gaps":["Active-site location within the complex not resolved","Higher-order oligomerization unaddressed"]},{"year":2001,"claim":"Linked SPTLC1 to human hereditary sensory neuropathy type I, connecting the enzyme to a Mendelian disease.","evidence":"Mutation screening in HSN1 families with de novo sphingolipid synthesis assay in patient lymphoblasts","pmids":["11242114","11242106"],"confidence":"High","gaps":["Biochemical mechanism of pathogenicity not yet defined","Whether mutations cause loss vs gain of function unresolved"]},{"year":2002,"claim":"Defined SPTLC1 membrane topology and its role in stabilizing the LCB2 subunit, establishing SPTLC1 as a structural anchor of the complex.","evidence":"Dual epitope-tag immunostaining and Western blot of LCB2 levels in LCB1-null LY-B cells","pmids":["12464627"],"confidence":"High","gaps":["Mechanism by which SPTLC1 stabilizes LCB2 unknown","Functional role of TMD beyond anchoring not defined"]},{"year":2002,"claim":"Showed HSAN1 mutations act dominantly while preserving subunit interaction, and modeling placed them near the active-site interface — reframing the mutation mechanism away from simple subunit loss.","evidence":"Yeast co-expression, SPT assays, co-IP and alpha-oxoamine synthase structural modeling","pmids":["11781309"],"confidence":"High","gaps":["Did not yet identify the neurotoxic product of mutant enzyme","Dominant-negative versus gain-of-function distinction not fully resolved"]},{"year":2005,"claim":"Provided an in vivo mammalian model proving mutant SPTLC1 causes the sensory/motor neuropathy phenotype.","evidence":"Transgenic mice expressing C133W with SPT activity, nerve histomorphometry and behavior","pmids":["16210380"],"confidence":"High","gaps":["Molecular species responsible for neurotoxicity not identified","Interpreted SPT inhibition as the mechanism before deoxysphingolipid discovery"]},{"year":2009,"claim":"Resolved the HSAN1 mechanism as a substrate-selectivity shift generating neurotoxic 1-deoxysphingolipids rather than loss of canonical activity — a gain-of-function model.","evidence":"Transgenic/double-transgenic mouse lipidomics, heterozygous knockout, SPT assays","pmids":["19923297"],"confidence":"High","gaps":["Downstream neurotoxic targets of deoxysphingolipids unknown","How active-site changes alter amino-acid selectivity structurally unaddressed here"]},{"year":2009,"claim":"Provided structural basis for HSAN1 active-site perturbation using a bacterial SPT mimic, explaining altered PLP chemistry and cross-dimer transmission of mutational effects.","evidence":"X-ray crystallography, kinetics, UV-vis spectroscopy and mutagenesis of bacterial SPT","pmids":["19376777"],"confidence":"High","gaps":["Bacterial enzyme is a structural surrogate, not the human heterodimer","Did not directly model the deoxysphingolipid substrate shift"]},{"year":2009,"claim":"Identified Par3 as a PDZ-domain partner that promotes SPT activity and links the enzyme to monocyte chemotaxis, extending SPTLC1 function into cell migration.","evidence":"PDZ array, overlay/co-IP, siRNA knockdown, SPT and chemotaxis assays in THP-1 cells","pmids":["19592499"],"confidence":"Medium","gaps":["Single-lab finding without reciprocal in vivo validation","Mechanism by which Par3 binding stimulates SPT activity undefined"]},{"year":2008,"claim":"Revealed a non-enzymatic moonlighting role: SPTLC1 binds ABCA1 and restrains cholesterol efflux by blocking ABCA1 ER exit, connecting sphingolipid machinery to cholesterol transport.","evidence":"AP-MS, reciprocal co-IP in macrophages/liver, siRNA, cholesterol efflux and dominant-negative assays","pmids":["18484747"],"confidence":"High","gaps":["Whether the effect requires SPT catalytic activity not fully separated","Structural basis of the SPTLC1-ABCA1 interaction unknown"]},{"year":2011,"claim":"Extended the substrate-shift model to additional HSAN1 variants (S331F, A352V) correlating reduced canonical activity with elevated plasma deoxysphingolipids.","evidence":"In vitro SPT assays, stable HEK293T lines and patient plasma lipidomics","pmids":["21618344"],"confidence":"Medium","gaps":["Single-lab; genotype-phenotype severity correlation not yet systematized"]},{"year":2013,"claim":"Established post-translational control of SPT by ABL-mediated Tyr164 phosphorylation, linking SPTLC1 activity to BCR-ABL signaling and apoptotic sensitivity.","evidence":"Phosphoproteomics of ER microsomes, in vitro kinase validation, Y164F mutagenesis, sphingolipid and apoptosis assays","pmids":["23629659"],"confidence":"Medium","gaps":["Physiological contexts of Tyr164 phosphorylation beyond BCR-ABL cells unknown","Single-lab finding"]},{"year":2014,"claim":"Showed via bacterial mimics that LCB2-side HSAN1 mutations perturb PLP binding and substrate affinity and are modulated by small subunits, broadening the mutational mechanism across the complex.","evidence":"Site-directed mutagenesis, in vitro SPT assays and homology modeling of bacterial SPT","pmids":["24175284"],"confidence":"Medium","gaps":["Bacterial surrogate, not human enzyme","Relevance of small-subunit modulation to human SPT regulation not established here"]},{"year":2015,"claim":"Systematically separated two classes of HSAN1 mutations — those raising 1-deoxySL only versus those also increasing canonical activity and C20 bases — correlating biochemistry with clinical severity.","evidence":"Isotope-labeling SPT assays across 17 mutants, lipidomics, PCA and homology modeling","pmids":["26681808"],"confidence":"High","gaps":["Mechanistic basis distinguishing the two mutation classes structurally not fully resolved"]},{"year":2015,"claim":"Implicated phosphorylation of SPTLC2 (S384) in dynamically tuning SPT substrate specificity, suggesting regulated control of deoxysphingolipid output.","evidence":"Patient lipidomics, isoelectric focusing, phosphomimetic mutagenesis and SPT assays in HEK293","pmids":["25567748"],"confidence":"Medium","gaps":["Physiological kinase and trigger for S384 phosphorylation unknown","SPTLC2-focused; SPTLC1 contribution to this regulation unaddressed"]},{"year":2018,"claim":"Localized ORM/ORMDL regulatory binding to the SPTLC1 TMD1, defining the structural element underlying homeostatic feedback inhibition.","evidence":"Co-IP, live fluorescence imaging, TMD-replacement and phosphomimetic ORM mutants in yeast","pmids":["30529276"],"confidence":"High","gaps":["Conducted in yeast; human ORMDL-SPTLC1 TMD interaction inferred","Atomic basis of ORM-mediated inhibition not resolved"]},{"year":2019,"claim":"Demonstrated a hematopoietic requirement for SPTLC1, with its loss causing ER stress from fatty acid accumulation and defective myeloid differentiation.","evidence":"Conditional bone marrow deletion, transplant chimeras, flow cytometry and ER stress markers","pmids":["31751474"],"confidence":"Medium","gaps":["Whether ER stress is the sole driver of the differentiation defect unclear","Single-lab finding"]},{"year":2021,"claim":"Identified SPTLC1 transmembrane-domain de novo mutations as a cause of juvenile ALS, distinct from HSAN1 variants.","evidence":"Trio whole-exome sequencing of juvenile ALS cohort","pmids":["34459874"],"confidence":"Medium","gaps":["ORMDL feedback disruption inferred but not functionally tested in this study","Neuronal pathomechanism downstream of excess sphingolipids unknown"]},{"year":2022,"claim":"Provided functional confirmation that ALS-associated TMD mutations (e.g. L38R) impair ORMDL interaction and cause unrestrained sphingolipid synthesis, mechanistically separating ALS from HSAN1.","evidence":"HEK293 transfection, SPT activity assay, LC-MS lipidomics and patient plasma analysis","pmids":["37348646"],"confidence":"Medium","gaps":["Direct ORMDL-SPTLC1 binding loss inferred from activity, not structurally shown","How elevated dihydrosphingolipids cause motor neuron disease unknown"]},{"year":2022,"claim":"Established endothelial SPTLC1 as essential for lipid-raft-dependent VEGF signaling and vascular development and as a major source of circulating sphingolipids.","evidence":"Endothelial-specific knockout mice, retinal vascular and oxygen-induced retinopathy models, lipid raft fractionation and plasma/organ lipidomics","pmids":["36197001"],"confidence":"High","gaps":["Specific sphingolipid species mediating VEGF signaling not pinpointed","CNS sphingolipid source remains unidentified"]},{"year":2025,"claim":"Placed SPTLC1 downstream of stress-induced ATF4 transcription in neurons, showing cocaine-driven ER stress upregulates SPTLC1 to drive behavioral and neuroplastic responses.","evidence":"Cocaine administration, promoter validation of ATF4→Sptlc1, cell-type-specific AAV knockdown and behavioral assays","pmids":["41378204"],"confidence":"Medium","gaps":["Sphingolipid species driving neuroplasticity not identified","Single-lab, single behavioral paradigm"]},{"year":2025,"claim":"Tested whether heterozygous SPTLC1 loss models ALS, finding it does not while homozygous loss is lethal — supporting a gain-of-function, not haploinsufficiency, disease mechanism.","evidence":"CRISPR exon 2 deletion knockin mice with motor and neuropathological analysis (preprint)","pmids":["40027730"],"confidence":"Low","gaps":["Preprint, single lab, negative result in heterozygotes","Does not directly test the gain-of-function ALS mutations in vivo"]},{"year":null,"claim":"How specific sphingolipid and deoxysphingolipid species mechanistically cause neuronal death in HSAN1 and juvenile ALS, and the atomic structure of the human SPTLC1-SPTLC2-ORMDL regulatory complex, remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["Downstream neurotoxic targets of deoxysphingolipids unknown","No human holoenzyme-ORMDL structure in the corpus","Tissue-specific determinants of disease selectivity undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016740","term_label":"transferase activity","supporting_discovery_ids":[0,1,2,3,9]},{"term_id":"GO:0016829","term_label":"lyase 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Sequence analysis revealed homology to PLP-dependent alpha-oxoamine synthases (5-aminolevulinic acid synthase, 2-amino-3-ketobutyrate CoA ligase) and predicted a membrane-associated protein with two transmembrane helices.\",\n      \"method\": \"Molecular cloning, genetic complementation of lcb1-defective yeast, sequence analysis, SPT activity assay\",\n      \"journal\": \"Journal of Bacteriology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — genetic complementation restoring enzymatic activity, replicated across multiple labs in subsequent work\",\n      \"pmids\": [\"2066332\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"Both LCB1 and LCB2 subunits are required for serine palmitoyltransferase activity in S. cerevisiae; overproduction of SPT requires co-expression of both genes, providing genetic evidence that both encode subunits of the same enzyme.\",\n      \"method\": \"Yeast overexpression, SPT activity assay, genetic co-expression studies\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — enzymatic activity assay with both subunits, foundational result replicated in subsequent mammalian studies\",\n      \"pmids\": [\"8058731\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"The mammalian LCB1 protein (SPTLC1) is a component of serine palmitoyltransferase; transfection of SPT-defective CHO mutant cells with LCB1 cDNA restored both SPT activity and de novo sphingolipid synthesis to wild-type levels, and SPT activity co-purified with His6-tagged LCB1 on Ni2+ resin.\",\n      \"method\": \"Transfection complementation of SPT-defective CHO cells, Ni2+-affinity purification, SPT activity assay, Northern blot\",\n      \"journal\": \"The Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — enzymatic activity restoration by complementation plus affinity co-purification, replicated in CHO system\",\n      \"pmids\": [\"9405408\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"SPTLC1 (LCB1) and SPTLC2 (LCB2) form a physical complex that constitutes the SPT enzyme; affinity-tagged LCB1 co-purified endogenous LCB2, and anti-LCB2 antibody co-immunoprecipitated both SPT activity and wild-type LCB1 from CHO cells.\",\n      \"method\": \"Affinity purification with epitope-tagged LCB1, co-immunoprecipitation with anti-LCB2 antibody, SPT activity assay, genetic complementation of LY-B (LCB1-null) cells\",\n      \"journal\": \"The Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — reciprocal co-immunoprecipitation plus co-purification of enzymatic activity, multiple orthogonal methods\",\n      \"pmids\": [\"9837968\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Missense mutations in SPTLC1 (C133Y, C133W in exon 5; V144D in exon 6) cause hereditary sensory neuropathy type I (HSN1) in humans; affected lymphoblasts show increased de novo glucosylceramide synthesis.\",\n      \"method\": \"Mutation screening in HSN1 families, mapping to chromosome 9q22.1-22.3, de novo ceramide synthesis assay in patient lymphoblasts\",\n      \"journal\": \"Nature Genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic mapping plus biochemical assay in patient cells, independently replicated in same issue by two groups\",\n      \"pmids\": [\"11242114\", \"11242106\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"SPTLC1 is an integral ER membrane protein with a single transmembrane domain near the N-terminus; the N-terminus is oriented luminally and the C-terminus faces the cytosol. LCB1 is required for the stability and maintenance of the LCB2 subunit — in LCB1-null LY-B cells, LCB2 protein is drastically reduced and is restored by LCB1 transfection.\",\n      \"method\": \"Indirect immunostaining with N- and C-terminal epitope tags in stably transfected LY-B cells, Western blot for LCB2 levels, SPT activity assay\",\n      \"journal\": \"The Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization experiment with dual epitope tagging plus functional consequence (LCB2 stability), single lab but multiple orthogonal methods\",\n      \"pmids\": [\"12464627\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"SPT is an LCB1·LCB2 heterodimer; HSAN1-equivalent mutations in yeast Lcb1p (C133Y/W equivalents) dominantly reduce SPT activity by ~50% when co-expressed with wild-type LCB1, and the mutant Lcb1p proteins retain their ability to interact with Lcb2p. Modeling indicates SPT has a single active site at the Lcb1p·Lcb2p interface, and the mutations reside near the PLP-binding lysine of Lcb2p.\",\n      \"method\": \"Yeast co-expression, SPT activity assays, co-immunoprecipitation, structural modeling based on alpha-oxoamine synthase family alignments\",\n      \"journal\": \"The Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — enzymatic assay plus co-IP plus structural modeling in a single focused study; dominant-negative mechanism confirmed\",\n      \"pmids\": [\"11781309\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Transgenic mice expressing mutant SPTLC1 (C133W) show dominant inhibition of SPT activity in vivo, develop age-dependent sensory and motor impairments, and lose large myelinated axons with myelin thinning, confirming the link between mutant SPT and neuronal dysfunction in a mammalian in vivo model.\",\n      \"method\": \"Transgenic mouse overexpression (wild-type and C133W), SPT activity measurement, nerve histomorphometry, behavioral testing, immunostaining (IB4, ATF3)\",\n      \"journal\": \"Human Molecular Genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo loss/gain of function with defined neuropathological readouts and SPT activity measurement, single lab\",\n      \"pmids\": [\"16210380\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"SPTLC1 (but not SPTLC2) physically interacts with the cholesterol transporter ABCA1 and negatively regulates its trafficking and cholesterol efflux activity; SPTLC1 inhibition (myriocin or siRNA) disrupts the complex and increases ABCA1-dependent cholesterol efflux by ~60%, while dominant-negative SPTLC1 inhibits ABCA1 efflux. The interaction blocks ABCA1 exit from the ER.\",\n      \"method\": \"Affinity purification/mass spectrometry, co-immunoprecipitation in THP-1 macrophages and mouse liver, siRNA knockdown, cholesterol efflux assay, dominant-negative overexpression\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP in physiological settings plus multiple functional readouts (efflux assay, ER exit block), single lab with orthogonal methods\",\n      \"pmids\": [\"18484747\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"HSAN1 mutations in SPTLC1 alter the amino acid substrate selectivity of SPT, causing palmitate to be condensed with alanine and glycine in addition to serine, generating deoxysphingoid bases (1-deoxy-sphinganine, 1-deoxymethyl-sphinganine) that accumulate in tgSPTLC1(C133W) mice. Overexpression of wild-type SPTLC1 in double-transgenic mice reverses the phenotype and reduces deoxysphingoid base levels. Heterozygous SPTLC1 knockout mice have reduced SPT activity but are otherwise normal.\",\n      \"method\": \"Transgenic and double-transgenic mouse crosses, mass spectrometry-based lipidomics for deoxysphingoid bases, SPT activity assay, behavioral phenotyping, heterozygous knockout analysis\",\n      \"journal\": \"The Journal of Neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal in vivo models (transgenic, double-transgenic, knockout), biochemical substrate-selectivity shift confirmed by lipidomics, replicated in subsequent studies\",\n      \"pmids\": [\"19923297\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Bacterial SPT HSAN1 mimic mutations (N100Y and N100W, equivalent to human C133Y/W) reduce enzyme activity, alter the active-site PLP chemistry, impair stabilization of the quinonoid intermediate, and transmit structural changes across the dimer interface. Crystal structures of the external aldimine form reveal that N100Y hinders movement of a catalytically critical Arg378 into the active site.\",\n      \"method\": \"X-ray crystallography (holoenzyme and external aldimine structures), kinetic assays, UV-vis spectroscopy, site-directed mutagenesis of active-site residues\",\n      \"journal\": \"The Journal of Biological Chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structures combined with kinetics and mutagenesis in a single rigorous study; bacterial mimic of human mutations\",\n      \"pmids\": [\"19376777\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"SPTLC1 interacts with the PDZ protein Par3 via a conserved C-terminal type II PDZ-binding motif; Par3 binds the third PDZ domain of Par3 and associates with the SPTLC1/2 holoenzyme. siRNA knockdown of Par3 in THP-1 monocytes reduces SPT activity and de novo ceramide synthesis by ~40% and impairs MCP-1-directed chemotaxis in an SPT-activity-dependent manner.\",\n      \"method\": \"PDZ domain protein array screening, overlay and co-immunoprecipitation assays, siRNA knockdown, SPT activity assay, ceramide synthesis assay, chemotaxis assay\",\n      \"journal\": \"The Journal of Biological Chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — PDZ array plus co-IP plus functional siRNA knockdown, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"19592499\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"SPTLC1 mutations p.S331F and p.A352V reduce SPT activity in vitro and are associated with increased plasma levels of 1-deoxy-sphinganine and 1-deoxymethyl-sphinganine; HEK293T cells stably expressing p.S331F-SPTLC1 accumulate deoxysphingoid bases, consistent with a substrate-shift gain-of-function mechanism.\",\n      \"method\": \"In vitro SPT activity assay, stable HEK293T cell lines, mass spectrometry-based lipidomics of patient plasma and cell lines\",\n      \"journal\": \"Human Mutation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro enzymatic assay plus patient plasma and cell-line lipidomics, single lab\",\n      \"pmids\": [\"21618344\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"SPTLC1 is phosphorylated at Tyr164 by the tyrosine kinase ABL in ER microsomes; this phosphorylation inhibits SPT activity, and the Y164F mutation increases SPT activity, remodels sphingolipid content, and sensitizes BCR-ABL-expressing cells to apoptosis. BCR-ABL inhibition with imatinib activates SPTLC1 by reducing Y164 phosphorylation.\",\n      \"method\": \"Phosphoproteomic analysis of ER microsomes, in vitro kinase validation, shRNA silencing of BCR-ABL, site-directed mutagenesis (Y164F), SPT activity assay, sphingolipid profiling, apoptosis assay\",\n      \"journal\": \"The Journal of Biological Chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — phosphoproteomics plus in vitro validation plus mutagenesis plus functional assays, single lab\",\n      \"pmids\": [\"23629659\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Bacterial SPT hLCB2a HSAN1 mutation mimics (V246M, G268V, G385F in Sphingomonas paucimobilis SPT) perturb PLP cofactor binding, reduce affinity for both substrates, decrease enzyme activity, and in the most severe case cause insoluble expression; ssSPTa and ssSPTb small subunits modulate the activity of hLCB2a mutants.\",\n      \"method\": \"Site-directed mutagenesis, in vitro SPT activity assay, structural analysis (homology modeling from Sp SPT crystal structure), expression analysis\",\n      \"journal\": \"BioMed Research International\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — enzymatic assays with mutagenesis and structural modeling using bacterial mimic; indirect inference for human enzyme\",\n      \"pmids\": [\"24175284\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Systematic comparison of 11 SPTLC1 and 6 SPTLC2 HSAN1 mutants by isotope-labeling shows that eight mutants increase 1-deoxySL synthesis without reducing canonical serine-based SPT activity. Three mutations (SPTLC1 p.S331F/Y, SPTLC2 p.I505Y) additionally increase canonical activity and C20 sphingoid base levels, correlating with a more severe clinical phenotype. Homology modeling clusters mutations by active-site proximity and clinical severity.\",\n      \"method\": \"Stable isotope-labeling SPT activity assay in patient/transfected cells, mass spectrometry lipidomics, principal component analysis, homology modeling\",\n      \"journal\": \"Human Molecular Genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — uniform isotope-labeling across 17 mutants in a single study, corroborated by patient plasma measurements and structural modeling\",\n      \"pmids\": [\"26681808\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"A novel SPTLC2-S384F HSAN1 variant is associated with increased 1-deoxySL formation; wild-type SPTLC2 is phosphorylated at S384, and a phosphomimetic S384D (but not S384E) mutation also increases 1-deoxySL, suggesting that phosphorylation at this residue dynamically regulates SPT substrate specificity.\",\n      \"method\": \"Patient plasma lipidomics, HEK293 cell transfection, isoelectric focusing for phosphorylation, site-directed mutagenesis (S384D/E/A, Y387F), SPT activity assay\",\n      \"journal\": \"Neuromolecular Medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — phosphorylation confirmed by isoelectric focusing plus mutagenesis panel plus functional assay, single lab\",\n      \"pmids\": [\"25567748\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"The first transmembrane domain (TMD1) of Lcb1 (SPTLC1 yeast ortholog) is required for ORM protein binding to SPT; loss of TMD1 abolishes ORM-dependent SPT oligomerization (assessed by co-IP and live imaging) and partially redistributes SPT to peripheral ER. ORMs with non-phosphorylatable sites cause constitutive SPT oligomerization and inhibition, while phosphomimetic ORMs do not. Sac1 binding to SPT requires the Tsc3 small subunit but not the ORMs.\",\n      \"method\": \"Co-immunoprecipitation, in vivo fluorescence imaging, yeast genetics (deletion and phosphomimetic mutants), TMD replacement experiments, membrane topology analysis\",\n      \"journal\": \"Biochimica et Biophysica Acta. Molecular and Cell Biology of Lipids\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP plus live imaging plus multiple genetic mutants in a single focused study\",\n      \"pmids\": [\"30529276\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Sptlc1 deletion in adult mouse bone marrow results in defective myeloid differentiation with expansion of multipotent progenitors; the mechanism involves ER stress triggered by accumulation of fatty acid substrates due to deficient sphingolipid biosynthesis in the ER.\",\n      \"method\": \"Conditional bone marrow deletion, chimeric mouse transplant assay, flow cytometry, ER stress marker analysis (BiP, thapsigargin treatment), fatty acid supplementation\",\n      \"journal\": \"Blood Advances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with defined cellular phenotype and mechanistic ER stress pathway placement, single lab\",\n      \"pmids\": [\"31751474\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"De novo gain-of-function mutations in SPTLC1 (p.Ala20Ser, p.Ser331Tyr, p.Leu39del) cause juvenile ALS; these variants are located in the transmembrane/regulatory domain and are associated with disruption of the homeostatic ORMDL-mediated feedback regulation of the SPT complex.\",\n      \"method\": \"Trio whole-exome sequencing, genetic screening of juvenile ALS cohort, de novo variant identification\",\n      \"journal\": \"JAMA Neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — genetic identification with pathway mechanistic inference; functional mechanism proposed based on prior biochemical data but not directly tested in this paper\",\n      \"pmids\": [\"34459874\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SPTLC1 mutations causing juvenile ALS (including p.L38R) cluster in the transmembrane domain (exon 2) and impede interaction with the regulatory ORMDL subunit of SPT, leading to loss of homeostatic feedback control; p.L38R-expressing HEK293 cells show increased SPT activity, increased total sphingolipids, and particularly elevated dihydrosphingolipids.\",\n      \"method\": \"HEK293 cell transfection, SPT activity assay, lipidomics (LC-MS), patient plasma lipid analysis\",\n      \"journal\": \"Biochimica et Biophysica Acta. Molecular and Cell Biology of Lipids\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — cell-based SPT activity assay and lipidomics with mechanistic placement (ORMDL interaction loss), single lab\",\n      \"pmids\": [\"37348646\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Endothelial-specific knockout of SPTLC1 (Sptlc1 ECKO) in mice reduces EC sphingolipid synthesis, impairs lipid raft formation and VEGF signaling, reduces EC proliferation and tip/stalk cell differentiation, delays retinal vascular development, and reduces retinal neovascularization. Post-natal deletion rapidly reduces sphingolipid metabolites in plasma and peripheral organs but not in CNS (retina), identifying EC as a major source of circulating sphingolipids.\",\n      \"method\": \"Endothelial-specific conditional knockout, retinal vascular development assay, oxygen-induced retinopathy model, lipidomics of plasma/organs, lipid raft fractionation, VEGF signaling assays\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO with multiple orthogonal mechanistic readouts (lipid rafts, VEGF signaling, vascular development), single lab with rigorous controls\",\n      \"pmids\": [\"36197001\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In the nucleus accumbens, cocaine selectively activates ER stress in D1-MSNs, inducing ATF4 which directly targets the Sptlc1 promoter and upregulates SPTLC1 expression; D1-MSN-specific knockdown of either Atf4 or Sptlc1 markedly reduces cocaine-induced behavioral and neuroplastic changes.\",\n      \"method\": \"Cocaine administration, immunohistochemistry/molecular profiling of ER stress, promoter analysis with functional validation (ATF4→Sptlc1), cell-type-specific AAV knockdown, behavioral assays, sphingolipid synthesis assay\",\n      \"journal\": \"Frontiers in Pharmacology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — promoter functional validation plus cell-type-specific knockdown with behavioral readouts, single lab\",\n      \"pmids\": [\"41378204\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Heterozygous deletion of Sptlc1 exon 2 in mice does not produce motor defects or ALS-like neuropathology, while homozygous deletion is lethal, indicating that complete loss of SPTLC1 function is incompatible with viability but heterozygous loss-of-function is insufficient to model ALS.\",\n      \"method\": \"CRISPR/Cas9 exon 2 deletion knockin mouse model, motor function testing, neuropathological analysis\",\n      \"journal\": \"bioRxiv (preprint)\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 2 / Weak — preprint, single lab, negative result (no phenotype in heterozygotes) with homozygous lethality as positive control\",\n      \"pmids\": [\"40027730\"],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"SPTLC1 encodes the LCB1 subunit of serine palmitoyltransferase (SPT), a PLP-dependent alpha-oxoamine synthase that forms a heterodimer with SPTLC2/LCB2 at the ER membrane (N-terminus luminal, C-terminus cytosolic) to catalyze the first and rate-limiting step of sphingolipid biosynthesis (condensation of L-serine and palmitoyl-CoA); HSAN1-causing mutations in SPTLC1 shift substrate selectivity toward L-alanine/glycine, generating neurotoxic 1-deoxysphingolipids rather than reducing canonical activity, while juvenile ALS-causing mutations cluster in the TMD1 transmembrane domain and disrupt ORMDL-mediated homeostatic feedback inhibition, causing unrestrained sphingolipid synthesis; SPTLC1 stability is required for LCB2 subunit maintenance, its activity is negatively regulated by ABL-mediated phosphorylation at Tyr164, it physically interacts with ABCA1 to suppress cholesterol efflux and with Par3 to promote SPT activity and monocyte chemotaxis, and endothelial SPTLC1-derived sphingolipids are essential for VEGF signaling, vascular development, and systemic sphingolipid homeostasis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SPTLC1 encodes the LCB1 subunit of serine palmitoyltransferase (SPT), the enzyme that catalyzes the first and rate-limiting step of de novo sphingolipid biosynthesis [#0, #2]. SPT functions as an LCB1·LCB2 (SPTLC1·SPTLC2) heterodimer in which both subunits are required for activity, with a single catalytic site formed at the subunit interface and homology to PLP-dependent alpha-oxoamine synthases [#1, #3, #6]; SPTLC1 is an integral ER membrane protein with a single N-terminal transmembrane domain (luminal N-terminus, cytosolic C-terminus) and is required to stabilize the LCB2 subunit [#5]. The TMD1 of SPTLC1 mediates binding of the ORM/ORMDL regulatory proteins that impose homeostatic feedback inhibition on the complex [#17]. SPTLC1 activity is further controlled by ABL-mediated phosphorylation at Tyr164, which inhibits the enzyme and remodels sphingolipid content [#13], and the protein physically engages partners beyond the core complex, interacting with ABCA1 to block its ER exit and suppress cholesterol efflux [#8] and with the PDZ protein Par3 to promote SPT activity and monocyte chemotaxis [#11]. Two distinct disease mechanisms arise from SPTLC1 mutations: HSAN1-causing missense changes (e.g. C133W) shift substrate selectivity so that palmitate condenses with alanine and glycine, generating neurotoxic 1-deoxysphingolipids rather than abolishing canonical activity [#4, #9, #15], whereas de novo juvenile-ALS mutations cluster in the transmembrane/regulatory domain and disrupt ORMDL-mediated feedback, causing unrestrained sphingolipid synthesis [#19, #20]. Physiologically, endothelial SPTLC1-derived sphingolipids support lipid-raft–dependent VEGF signaling and vascular development and are a major source of circulating sphingolipids [#21], and SPTLC1 is required for myeloid differentiation by preventing ER stress from fatty acid accumulation [#18].\",\n  \"teleology\": [\n    {\n      \"year\": 1991,\n      \"claim\": \"Established that the SPTLC1 ortholog encodes the catalytic machinery for the first committed step of sphingolipid synthesis, defining the gene's core enzymatic identity.\",\n      \"evidence\": \"Molecular cloning and genetic complementation of lcb1-defective yeast with SPT activity assay\",\n      \"pmids\": [\"2066332\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish whether LCB1 alone is catalytic or requires partner subunits\", \"Membrane topology and active-site architecture undefined\"]\n    },\n    {\n      \"year\": 1994,\n      \"claim\": \"Showed SPT is a two-subunit enzyme requiring both LCB1 and LCB2, resolving whether the activity resides in one or multiple gene products.\",\n      \"evidence\": \"Yeast co-expression and overexpression with SPT activity assay\",\n      \"pmids\": [\"8058731\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physical complex not directly demonstrated\", \"Stoichiometry and architecture unknown\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Demonstrated that the mammalian SPTLC1 protein is a bona fide SPT component, extending the yeast finding to human/mammalian sphingolipid synthesis.\",\n      \"evidence\": \"Transfection complementation of SPT-defective CHO cells plus Ni2+-affinity co-purification of activity\",\n      \"pmids\": [\"9405408\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the SPTLC1-SPTLC2 physical interaction directly\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Confirmed SPTLC1 and SPTLC2 form a stable physical complex constituting the enzyme, establishing the heterodimer as the functional unit.\",\n      \"evidence\": \"Reciprocal co-immunoprecipitation and co-purification of activity from CHO cells\",\n      \"pmids\": [\"9837968\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Active-site location within the complex not resolved\", \"Higher-order oligomerization unaddressed\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Linked SPTLC1 to human hereditary sensory neuropathy type I, connecting the enzyme to a Mendelian disease.\",\n      \"evidence\": \"Mutation screening in HSN1 families with de novo sphingolipid synthesis assay in patient lymphoblasts\",\n      \"pmids\": [\"11242114\", \"11242106\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Biochemical mechanism of pathogenicity not yet defined\", \"Whether mutations cause loss vs gain of function unresolved\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Defined SPTLC1 membrane topology and its role in stabilizing the LCB2 subunit, establishing SPTLC1 as a structural anchor of the complex.\",\n      \"evidence\": \"Dual epitope-tag immunostaining and Western blot of LCB2 levels in LCB1-null LY-B cells\",\n      \"pmids\": [\"12464627\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which SPTLC1 stabilizes LCB2 unknown\", \"Functional role of TMD beyond anchoring not defined\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Showed HSAN1 mutations act dominantly while preserving subunit interaction, and modeling placed them near the active-site interface — reframing the mutation mechanism away from simple subunit loss.\",\n      \"evidence\": \"Yeast co-expression, SPT assays, co-IP and alpha-oxoamine synthase structural modeling\",\n      \"pmids\": [\"11781309\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not yet identify the neurotoxic product of mutant enzyme\", \"Dominant-negative versus gain-of-function distinction not fully resolved\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Provided an in vivo mammalian model proving mutant SPTLC1 causes the sensory/motor neuropathy phenotype.\",\n      \"evidence\": \"Transgenic mice expressing C133W with SPT activity, nerve histomorphometry and behavior\",\n      \"pmids\": [\"16210380\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular species responsible for neurotoxicity not identified\", \"Interpreted SPT inhibition as the mechanism before deoxysphingolipid discovery\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Resolved the HSAN1 mechanism as a substrate-selectivity shift generating neurotoxic 1-deoxysphingolipids rather than loss of canonical activity — a gain-of-function model.\",\n      \"evidence\": \"Transgenic/double-transgenic mouse lipidomics, heterozygous knockout, SPT assays\",\n      \"pmids\": [\"19923297\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Downstream neurotoxic targets of deoxysphingolipids unknown\", \"How active-site changes alter amino-acid selectivity structurally unaddressed here\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Provided structural basis for HSAN1 active-site perturbation using a bacterial SPT mimic, explaining altered PLP chemistry and cross-dimer transmission of mutational effects.\",\n      \"evidence\": \"X-ray crystallography, kinetics, UV-vis spectroscopy and mutagenesis of bacterial SPT\",\n      \"pmids\": [\"19376777\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Bacterial enzyme is a structural surrogate, not the human heterodimer\", \"Did not directly model the deoxysphingolipid substrate shift\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Identified Par3 as a PDZ-domain partner that promotes SPT activity and links the enzyme to monocyte chemotaxis, extending SPTLC1 function into cell migration.\",\n      \"evidence\": \"PDZ array, overlay/co-IP, siRNA knockdown, SPT and chemotaxis assays in THP-1 cells\",\n      \"pmids\": [\"19592499\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab finding without reciprocal in vivo validation\", \"Mechanism by which Par3 binding stimulates SPT activity undefined\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Revealed a non-enzymatic moonlighting role: SPTLC1 binds ABCA1 and restrains cholesterol efflux by blocking ABCA1 ER exit, connecting sphingolipid machinery to cholesterol transport.\",\n      \"evidence\": \"AP-MS, reciprocal co-IP in macrophages/liver, siRNA, cholesterol efflux and dominant-negative assays\",\n      \"pmids\": [\"18484747\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether the effect requires SPT catalytic activity not fully separated\", \"Structural basis of the SPTLC1-ABCA1 interaction unknown\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Extended the substrate-shift model to additional HSAN1 variants (S331F, A352V) correlating reduced canonical activity with elevated plasma deoxysphingolipids.\",\n      \"evidence\": \"In vitro SPT assays, stable HEK293T lines and patient plasma lipidomics\",\n      \"pmids\": [\"21618344\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab; genotype-phenotype severity correlation not yet systematized\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Established post-translational control of SPT by ABL-mediated Tyr164 phosphorylation, linking SPTLC1 activity to BCR-ABL signaling and apoptotic sensitivity.\",\n      \"evidence\": \"Phosphoproteomics of ER microsomes, in vitro kinase validation, Y164F mutagenesis, sphingolipid and apoptosis assays\",\n      \"pmids\": [\"23629659\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological contexts of Tyr164 phosphorylation beyond BCR-ABL cells unknown\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Showed via bacterial mimics that LCB2-side HSAN1 mutations perturb PLP binding and substrate affinity and are modulated by small subunits, broadening the mutational mechanism across the complex.\",\n      \"evidence\": \"Site-directed mutagenesis, in vitro SPT assays and homology modeling of bacterial SPT\",\n      \"pmids\": [\"24175284\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Bacterial surrogate, not human enzyme\", \"Relevance of small-subunit modulation to human SPT regulation not established here\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Systematically separated two classes of HSAN1 mutations — those raising 1-deoxySL only versus those also increasing canonical activity and C20 bases — correlating biochemistry with clinical severity.\",\n      \"evidence\": \"Isotope-labeling SPT assays across 17 mutants, lipidomics, PCA and homology modeling\",\n      \"pmids\": [\"26681808\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanistic basis distinguishing the two mutation classes structurally not fully resolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Implicated phosphorylation of SPTLC2 (S384) in dynamically tuning SPT substrate specificity, suggesting regulated control of deoxysphingolipid output.\",\n      \"evidence\": \"Patient lipidomics, isoelectric focusing, phosphomimetic mutagenesis and SPT assays in HEK293\",\n      \"pmids\": [\"25567748\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological kinase and trigger for S384 phosphorylation unknown\", \"SPTLC2-focused; SPTLC1 contribution to this regulation unaddressed\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Localized ORM/ORMDL regulatory binding to the SPTLC1 TMD1, defining the structural element underlying homeostatic feedback inhibition.\",\n      \"evidence\": \"Co-IP, live fluorescence imaging, TMD-replacement and phosphomimetic ORM mutants in yeast\",\n      \"pmids\": [\"30529276\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Conducted in yeast; human ORMDL-SPTLC1 TMD interaction inferred\", \"Atomic basis of ORM-mediated inhibition not resolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstrated a hematopoietic requirement for SPTLC1, with its loss causing ER stress from fatty acid accumulation and defective myeloid differentiation.\",\n      \"evidence\": \"Conditional bone marrow deletion, transplant chimeras, flow cytometry and ER stress markers\",\n      \"pmids\": [\"31751474\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether ER stress is the sole driver of the differentiation defect unclear\", \"Single-lab finding\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified SPTLC1 transmembrane-domain de novo mutations as a cause of juvenile ALS, distinct from HSAN1 variants.\",\n      \"evidence\": \"Trio whole-exome sequencing of juvenile ALS cohort\",\n      \"pmids\": [\"34459874\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"ORMDL feedback disruption inferred but not functionally tested in this study\", \"Neuronal pathomechanism downstream of excess sphingolipids unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Provided functional confirmation that ALS-associated TMD mutations (e.g. L38R) impair ORMDL interaction and cause unrestrained sphingolipid synthesis, mechanistically separating ALS from HSAN1.\",\n      \"evidence\": \"HEK293 transfection, SPT activity assay, LC-MS lipidomics and patient plasma analysis\",\n      \"pmids\": [\"37348646\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct ORMDL-SPTLC1 binding loss inferred from activity, not structurally shown\", \"How elevated dihydrosphingolipids cause motor neuron disease unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Established endothelial SPTLC1 as essential for lipid-raft-dependent VEGF signaling and vascular development and as a major source of circulating sphingolipids.\",\n      \"evidence\": \"Endothelial-specific knockout mice, retinal vascular and oxygen-induced retinopathy models, lipid raft fractionation and plasma/organ lipidomics\",\n      \"pmids\": [\"36197001\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific sphingolipid species mediating VEGF signaling not pinpointed\", \"CNS sphingolipid source remains unidentified\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Placed SPTLC1 downstream of stress-induced ATF4 transcription in neurons, showing cocaine-driven ER stress upregulates SPTLC1 to drive behavioral and neuroplastic responses.\",\n      \"evidence\": \"Cocaine administration, promoter validation of ATF4→Sptlc1, cell-type-specific AAV knockdown and behavioral assays\",\n      \"pmids\": [\"41378204\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Sphingolipid species driving neuroplasticity not identified\", \"Single-lab, single behavioral paradigm\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Tested whether heterozygous SPTLC1 loss models ALS, finding it does not while homozygous loss is lethal — supporting a gain-of-function, not haploinsufficiency, disease mechanism.\",\n      \"evidence\": \"CRISPR exon 2 deletion knockin mice with motor and neuropathological analysis (preprint)\",\n      \"pmids\": [\"40027730\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Preprint, single lab, negative result in heterozygotes\", \"Does not directly test the gain-of-function ALS mutations in vivo\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How specific sphingolipid and deoxysphingolipid species mechanistically cause neuronal death in HSAN1 and juvenile ALS, and the atomic structure of the human SPTLC1-SPTLC2-ORMDL regulatory complex, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Downstream neurotoxic targets of deoxysphingolipids unknown\", \"No human holoenzyme-ORMDL structure in the corpus\", \"Tissue-specific determinants of disease selectivity undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016740\", \"supporting_discovery_ids\": [0, 1, 2, 3, 9]},\n      {\"term_id\": \"GO:0016829\", \"supporting_discovery_ids\": [0, 6, 10]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [5, 8, 13]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [0, 2, 9]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [4, 9, 19, 20]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [18, 22]}\n    ],\n    \"complexes\": [\"serine palmitoyltransferase (SPT) LCB1·LCB2 heterodimer\"],\n    \"partners\": [\"SPTLC2\", \"ORMDL\", \"ABCA1\", \"PARD3\", \"ABL1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}