Affinage

SPTLC1

Serine palmitoyltransferase 1 · UniProt O15269

Length
473 aa
Mass
52.7 kDa
Annotated
2026-06-10
63 papers in source corpus 25 papers cited in narrative 24 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 24 steps
  1. 1991 High

    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

    PMID:2066332

    Open questions at the time
    • Did not establish whether LCB1 alone is catalytic or requires partner subunits
    • Membrane topology and active-site architecture undefined
  2. 1994 High

    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

    PMID:8058731

    Open questions at the time
    • Physical complex not directly demonstrated
    • Stoichiometry and architecture unknown
  3. 1997 High

    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

    PMID:9405408

    Open questions at the time
    • Did not define the SPTLC1-SPTLC2 physical interaction directly
  4. 1998 High

    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

    PMID:9837968

    Open questions at the time
    • Active-site location within the complex not resolved
    • Higher-order oligomerization unaddressed
  5. 2001 High

    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

    PMID:11242106 PMID:11242114

    Open questions at the time
    • Biochemical mechanism of pathogenicity not yet defined
    • Whether mutations cause loss vs gain of function unresolved
  6. 2002 High

    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

    PMID:12464627

    Open questions at the time
    • Mechanism by which SPTLC1 stabilizes LCB2 unknown
    • Functional role of TMD beyond anchoring not defined
  7. 2002 High

    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

    PMID:11781309

    Open questions at the time
    • Did not yet identify the neurotoxic product of mutant enzyme
    • Dominant-negative versus gain-of-function distinction not fully resolved
  8. 2005 High

    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

    PMID:16210380

    Open questions at the time
    • Molecular species responsible for neurotoxicity not identified
    • Interpreted SPT inhibition as the mechanism before deoxysphingolipid discovery
  9. 2009 High

    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

    PMID:19923297

    Open questions at the time
    • Downstream neurotoxic targets of deoxysphingolipids unknown
    • How active-site changes alter amino-acid selectivity structurally unaddressed here
  10. 2009 High

    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

    PMID:19376777

    Open questions at the time
    • Bacterial enzyme is a structural surrogate, not the human heterodimer
    • Did not directly model the deoxysphingolipid substrate shift
  11. 2009 Medium

    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

    PMID:19592499

    Open questions at the time
    • Single-lab finding without reciprocal in vivo validation
    • Mechanism by which Par3 binding stimulates SPT activity undefined
  12. 2008 High

    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

    PMID:18484747

    Open questions at the time
    • Whether the effect requires SPT catalytic activity not fully separated
    • Structural basis of the SPTLC1-ABCA1 interaction unknown
  13. 2011 Medium

    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

    PMID:21618344

    Open questions at the time
    • Single-lab; genotype-phenotype severity correlation not yet systematized
  14. 2013 Medium

    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

    PMID:23629659

    Open questions at the time
    • Physiological contexts of Tyr164 phosphorylation beyond BCR-ABL cells unknown
    • Single-lab finding
  15. 2014 Medium

    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

    PMID:24175284

    Open questions at the time
    • Bacterial surrogate, not human enzyme
    • Relevance of small-subunit modulation to human SPT regulation not established here
  16. 2015 High

    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

    PMID:26681808

    Open questions at the time
    • Mechanistic basis distinguishing the two mutation classes structurally not fully resolved
  17. 2015 Medium

    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

    PMID:25567748

    Open questions at the time
    • Physiological kinase and trigger for S384 phosphorylation unknown
    • SPTLC2-focused; SPTLC1 contribution to this regulation unaddressed
  18. 2018 High

    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

    PMID:30529276

    Open questions at the time
    • Conducted in yeast; human ORMDL-SPTLC1 TMD interaction inferred
    • Atomic basis of ORM-mediated inhibition not resolved
  19. 2019 Medium

    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

    PMID:31751474

    Open questions at the time
    • Whether ER stress is the sole driver of the differentiation defect unclear
    • Single-lab finding
  20. 2021 Medium

    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

    PMID:34459874

    Open questions at the time
    • ORMDL feedback disruption inferred but not functionally tested in this study
    • Neuronal pathomechanism downstream of excess sphingolipids unknown
  21. 2022 Medium

    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

    PMID:37348646

    Open questions at the time
    • Direct ORMDL-SPTLC1 binding loss inferred from activity, not structurally shown
    • How elevated dihydrosphingolipids cause motor neuron disease unknown
  22. 2022 High

    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

    PMID:36197001

    Open questions at the time
    • Specific sphingolipid species mediating VEGF signaling not pinpointed
    • CNS sphingolipid source remains unidentified
  23. 2025 Medium

    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

    PMID:41378204

    Open questions at the time
    • Sphingolipid species driving neuroplasticity not identified
    • Single-lab, single behavioral paradigm
  24. 2025 Low

    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)

    PMID:40027730

    Open questions at the time
    • Preprint, single lab, negative result in heterozygotes
    • Does not directly test the gain-of-function ALS mutations in vivo

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • Downstream neurotoxic targets of deoxysphingolipids unknown
  • No human holoenzyme-ORMDL structure in the corpus
  • Tissue-specific determinants of disease selectivity undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016740 transferase activity 5 GO:0016829 lyase activity 3 GO:0140096 catalytic activity, acting on a protein 1
Localization
GO:0005783 endoplasmic reticulum 3
Pathway
R-HSA-1643685 Disease 4 R-HSA-1430728 Metabolism 3 R-HSA-8953897 Cellular responses to stimuli 2
Partners
ABCA1ABL1ORMDLPARD3SPTLC2
Complex memberships
serine palmitoyltransferase (SPT) LCB1·LCB2 heterodimer

Evidence

Reading pass · 24 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1991 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. Molecular cloning, genetic complementation of lcb1-defective yeast, sequence analysis, SPT activity assay Journal of Bacteriology High 2066332
1994 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. Yeast overexpression, SPT activity assay, genetic co-expression studies Proceedings of the National Academy of Sciences High 8058731
1997 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. Transfection complementation of SPT-defective CHO cells, Ni2+-affinity purification, SPT activity assay, Northern blot The Journal of Biological Chemistry High 9405408
1998 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. Affinity purification with epitope-tagged LCB1, co-immunoprecipitation with anti-LCB2 antibody, SPT activity assay, genetic complementation of LY-B (LCB1-null) cells The Journal of Biological Chemistry High 9837968
2001 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. Mutation screening in HSN1 families, mapping to chromosome 9q22.1-22.3, de novo ceramide synthesis assay in patient lymphoblasts Nature Genetics High 11242106 11242114
2002 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. Indirect immunostaining with N- and C-terminal epitope tags in stably transfected LY-B cells, Western blot for LCB2 levels, SPT activity assay The Journal of Biological Chemistry High 12464627
2002 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. Yeast co-expression, SPT activity assays, co-immunoprecipitation, structural modeling based on alpha-oxoamine synthase family alignments The Journal of Biological Chemistry High 11781309
2005 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. Transgenic mouse overexpression (wild-type and C133W), SPT activity measurement, nerve histomorphometry, behavioral testing, immunostaining (IB4, ATF3) Human Molecular Genetics High 16210380
2008 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. Affinity purification/mass spectrometry, co-immunoprecipitation in THP-1 macrophages and mouse liver, siRNA knockdown, cholesterol efflux assay, dominant-negative overexpression Biochemistry High 18484747
2009 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. Transgenic and double-transgenic mouse crosses, mass spectrometry-based lipidomics for deoxysphingoid bases, SPT activity assay, behavioral phenotyping, heterozygous knockout analysis The Journal of Neuroscience High 19923297
2009 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. X-ray crystallography (holoenzyme and external aldimine structures), kinetic assays, UV-vis spectroscopy, site-directed mutagenesis of active-site residues The Journal of Biological Chemistry High 19376777
2009 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. PDZ domain protein array screening, overlay and co-immunoprecipitation assays, siRNA knockdown, SPT activity assay, ceramide synthesis assay, chemotaxis assay The Journal of Biological Chemistry Medium 19592499
2011 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. In vitro SPT activity assay, stable HEK293T cell lines, mass spectrometry-based lipidomics of patient plasma and cell lines Human Mutation Medium 21618344
2013 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. 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 The Journal of Biological Chemistry Medium 23629659
2013 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. Site-directed mutagenesis, in vitro SPT activity assay, structural analysis (homology modeling from Sp SPT crystal structure), expression analysis BioMed Research International Medium 24175284
2015 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. Stable isotope-labeling SPT activity assay in patient/transfected cells, mass spectrometry lipidomics, principal component analysis, homology modeling Human Molecular Genetics High 26681808
2015 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. Patient plasma lipidomics, HEK293 cell transfection, isoelectric focusing for phosphorylation, site-directed mutagenesis (S384D/E/A, Y387F), SPT activity assay Neuromolecular Medicine Medium 25567748
2018 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. Co-immunoprecipitation, in vivo fluorescence imaging, yeast genetics (deletion and phosphomimetic mutants), TMD replacement experiments, membrane topology analysis Biochimica et Biophysica Acta. Molecular and Cell Biology of Lipids High 30529276
2019 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. Conditional bone marrow deletion, chimeric mouse transplant assay, flow cytometry, ER stress marker analysis (BiP, thapsigargin treatment), fatty acid supplementation Blood Advances Medium 31751474
2021 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. Trio whole-exome sequencing, genetic screening of juvenile ALS cohort, de novo variant identification JAMA Neurology Medium 34459874
2022 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. HEK293 cell transfection, SPT activity assay, lipidomics (LC-MS), patient plasma lipid analysis Biochimica et Biophysica Acta. Molecular and Cell Biology of Lipids Medium 37348646
2022 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. Endothelial-specific conditional knockout, retinal vascular development assay, oxygen-induced retinopathy model, lipidomics of plasma/organs, lipid raft fractionation, VEGF signaling assays eLife High 36197001
2025 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. 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 Frontiers in Pharmacology Medium 41378204
2025 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. CRISPR/Cas9 exon 2 deletion knockin mouse model, motor function testing, neuropathological analysis bioRxiv (preprint)preprint Low 40027730

Source papers

Stage 0 corpus · 63 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2001 Mutations in SPTLC1, encoding serine palmitoyltransferase, long chain base subunit-1, cause hereditary sensory neuropathy type I. Nature genetics 330 11242114
2001 SPTLC1 is mutated in hereditary sensory neuropathy, type 1. Nature genetics 233 11242106
1994 The LCB2 gene of Saccharomyces and the related LCB1 gene encode subunits of serine palmitoyltransferase, the initial enzyme in sphingolipid synthesis. Proceedings of the National Academy of Sciences of the United States of America 188 8058731
1991 Cloning and characterization of LCB1, a Saccharomyces gene required for biosynthesis of the long-chain base component of sphingolipids. Journal of bacteriology 177 2066332
1998 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. The Journal of biological chemistry 165 9837968
1997 A mammalian homolog of the yeast LCB1 encodes a component of serine palmitoyltransferase, the enzyme catalyzing the first step in sphingolipid synthesis. The Journal of biological chemistry 121 9405408
2002 Mutations in the yeast LCB1 and LCB2 genes, including those corresponding to the hereditary sensory neuropathy type I mutations, dominantly inactivate serine palmitoyltransferase. The Journal of biological chemistry 92 11781309
2009 Overexpression of the wild-type SPT1 subunit lowers desoxysphingolipid levels and rescues the phenotype of HSAN1. The Journal of neuroscience : the official journal of the Society for Neuroscience 90 19923297
2021 Association of Variants in the SPTLC1 Gene With Juvenile Amyotrophic Lateral Sclerosis. JAMA neurology 71 34459874
2002 Localization, topology, and function of the LCB1 subunit of serine palmitoyltransferase in mammalian cells. The Journal of biological chemistry 71 12464627
2015 HSAN1 mutations in serine palmitoyltransferase reveal a close structure-function-phenotype relationship. Human molecular genetics 69 26681808
2009 The external aldimine form of serine palmitoyltransferase: structural, kinetic, and spectroscopic analysis of the wild-type enzyme and HSAN1 mutant mimics. The Journal of biological chemistry 63 19376777
2005 Mutant SPTLC1 dominantly inhibits serine palmitoyltransferase activity in vivo and confers an age-dependent neuropathy. Human molecular genetics 61 16210380
2013 DNMT1 mutation hot spot causes varied phenotypes of HSAN1 with dementia and hearing loss. Neurology 56 23365052
2011 Characterization of two mutations in the SPTLC1 subunit of serine palmitoyltransferase associated with hereditary sensory and autonomic neuropathy type I. Human mutation 36 21618344
2013 Mutations at Ser331 in the HSN type I gene SPTLC1 are associated with a distinct syndromic phenotype. European journal of medical genetics 35 23454272
2004 Activity of partially inhibited serine palmitoyltransferase is sufficient for normal sphingolipid metabolism and viability of HSN1 patient cells. Biochimica et biophysica acta 35 14990347
2008 SPTLC1 binds ABCA1 to negatively regulate trafficking and cholesterol efflux activity of the transporter. Biochemistry 34 18484747
2018 The ORMs interact with transmembrane domain 1 of Lcb1 and regulate serine palmitoyltransferase oligomerization, activity and localization. Biochimica et biophysica acta. Molecular and cell biology of lipids 30 30529276
2004 SPTLC1 mutation in twin sisters with hereditary sensory neuropathy type I. Neurology 30 15037712
2015 Novel HSAN1 mutation in serine palmitoyltransferase resides at a putative phosphorylation site that is involved in regulating substrate specificity. Neuromolecular medicine 25 25567748
2019 Decreased SPTLC1 expression predicts worse outcomes in ccRCC patients. Journal of cellular biochemistry 23 31512789
2014 Mutations in the SPTLC1 protein cause mitochondrial structural abnormalities and endoplasmic reticulum stress in lymphoblasts. DNA and cell biology 22 24673574
2013 Phosphorylation of serine palmitoyltransferase long chain-1 (SPTLC1) on tyrosine 164 inhibits its activity and promotes cell survival. The Journal of biological chemistry 21 23629659
2005 SPTLC1 and RAB7 mutation analysis in dominantly inherited and idiopathic sensory neuropathies. Journal of neurology, neurosurgery, and psychiatry 21 15965219
2013 Early-onset severe hereditary sensory and autonomic neuropathy type 1 with S331F SPTLC1 mutation. Molecular medicine reports 20 24247255
2021 Precision mouse models of Yars/dominant intermediate Charcot-Marie-Tooth disease type C and Sptlc1/hereditary sensory and autonomic neuropathy type 1. Journal of anatomy 19 34875719
2022 Murine endothelial serine palmitoyltransferase 1 (SPTLC1) is required for vascular development and systemic sphingolipid homeostasis. eLife 18 36197001
2009 Cell polarity factor Par3 binds SPTLC1 and modulates monocyte serine palmitoyltransferase activity and chemotaxis. The Journal of biological chemistry 17 19592499
2021 Metabolism of HSAN1- and T2DM-associated 1-deoxy-sphingolipids inhibits the migration of fibroblasts. Journal of lipid research 14 34563520
2005 Late-onset hereditary sensory neuropathy type I due to SPTLC1 mutation: autopsy findings. Clinical neurology and neurosurgery 12 16271825
2023 SPTLC1 p.Leu38Arg, a novel mutation associated with childhood ALS. Biochimica et biophysica acta. Molecular and cell biology of lipids 11 37348646
2022 The SPTLC1 p.S331 mutation bridges sensory neuropathy and motor neuron disease and has implications for treatment. Neuropathology and applied neurobiology 11 35904184
2019 Sptlc1 is essential for myeloid differentiation and hematopoietic homeostasis. Blood advances 11 31751474
2013 The pyridoxal 5'-phosphate (PLP)-dependent enzyme serine palmitoyltransferase (SPT): effects of the small subunits and insights from bacterial mimics of human hLCB2a HSAN1 mutations. BioMed research international 11 24175284
2023 Mutation screening of SPTLC1 and SPTLC2 in amyotrophic lateral sclerosis. Human genomics 10 36966328
2022 Resistance profile and mechanism of severe acute respiratory syndrome coronavirus-2 variants to LCB1 inhibitor targeting the spike receptor-binding motif. Frontiers in microbiology 9 36304946
2008 [The first break-through of the genotype 2.3.2 of high-virulence influenza A virus A/HSN1, which is new for Russia, in the Far East]. Voprosy virusologii 9 19069785
2023 Pathogenic variants in the SPTLC1 gene cause hyperkeratosis lenticularis perstans. The British journal of dermatology 8 36689507
2022 Description of a patient cohort with Hereditary Sensory Neuropathy type 1 without retinal disease Macular Telangiectasia type 2 - implications for retinal screening in HSN1. Journal of the peripheral nervous system : JPNS 7 35837722
2019 SPTLC1 inhibits cell growth via modulating Akt/FOXO1 pathway in renal cell carcinoma cells. Biochemical and biophysical research communications 7 31554600
2018 V144D Mutation of SPTLC1 Can Present with Both Painful and Painless Phenotypes in Hereditary Sensory and Autonomic Neuropathies Type I. Case reports in genetics 7 30420926
2014 Mitochondrial protein alterations in a familial peripheral neuropathy caused by the V144D amino acid mutation in the sphingolipid protein, SPTLC1. Journal of chemical biology 7 25584079
2023 Development of highly effective LCB1-based lipopeptides targeting the spike receptor-binding motif of SARS-CoV-2. Antiviral research 6 36682464
2022 New Insights into the Neuromyogenic Spectrum of a Gain of Function Mutation in SPTLC1. Genes 6 35627278
2022 A de novo c.113 T > C: p.L38R mutation of SPTLC1: case report of a girl with sporadic juvenile amyotrophic lateral sclerosis. Amyotrophic lateral sclerosis & frontotemporal degeneration 6 36204986
2020 Expanding the spectrum of SPTLC1-related disorders beyond hereditary sensory and autonomic neuropathies: A novel case of the distinct "S331 syndrome". Journal of the peripheral nervous system : JPNS 5 32470188
2023 Clinical feature difference between juvenile amyotrophic lateral sclerosis with SPTLC1 and FUS mutations. Chinese medical journal 4 36801857
2013 Enhanced stability of newly isolated trimeric l-methionine-N-carbamoylase from Brevibacillus reuszeri HSN1 by covalent immobilization. Biotechnology and applied biochemistry 4 23682726
2023 Spectrum of SPTLC1-related disorders: a novel case of 'Ser331 syndrome' that expand the phenotype of hereditary sensory and autonomic neuropathy type 1A and motor neuron diseases. Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology 3 36964315
2023 Specific Deoxyceramide Species Correlate with Expression of Macular Telangiectasia Type 2 (MacTel2) in a SPTLC2 Carrier HSAN1 Family. Genes 3 37107689
2023 Susceptibility and Resistance of SARS-CoV-2 Variants to LCB1 and Its Multivalent Derivatives. Viruses 3 38257736
2022 Calcium-Mediated Calpain Activation and Microtubule Dissociation in Cell Model of Hereditary Sensory Neuropathy Type-1 Expressing V144D SPTLC1 Mutation. DNA and cell biology 3 34986032
2013 Trimeric l-N-carbamoylase from newly isolated Brevibacillus reuszeri HSN1: a potential biocatalyst for production of l-α-amino acids. Biotechnology and applied biochemistry 3 23586522
2025 Effect of SPTLC1 on type 2 diabetes mellitus. World journal of diabetes 1 39959268
2025 Fusion of SARS-CoV-2 neutralizing LCB1 peptide with Bacillus amyloliquefaciens RNase improves antiviral efficacy. Scientific reports 1 40744985
2025 Effects of sphingolipid metabolism related genes-SPTLC1, ORMDL3, SPHK1 and S1PR3 polymorphisms on susceptibility to hashimoto's thyroiditis. Journal of endocrinological investigation 1 40782218
2026 Antisense oligonucleotides reverse SPTLC1-related hereditary sensory neuropathy in a mouse model. Brain : a journal of neurology 0 41124364
2026 Health Equality and Socioeconomic Impact of Hereditary Sensory Neuropathy Type 1 (HSN1) in the UK. Journal of the peripheral nervous system : JPNS 0 42231561
2025 Lack of motor defects and ALS-like neuropathology in heterozygous Sptlc1 Exon 2 deletion mice. bioRxiv : the preprint server for biology 0 40027730
2025 The Contradictory Effects of SPTLC1 on Clear Cell Renal Carcinoma Sensitivity to Sunitinib Mediated by Androgen Receptor. Molecular carcinogenesis 0 40793989
2025 ER stress in D1-MSNs mediates cocaine-induced behavioral plasticity via the ATF4-SPTLC1 axis. Frontiers in pharmacology 0 41378204
2019 Comprehensive Computational Analysis of Protein Phenotype Changes Due to Plausible Deleterious Variants of Human SPTLC1 Gene. International journal of molecular and cellular medicine 0 32195206

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