{"gene":"BSCL2","run_date":"2026-04-28T17:12:38","timeline":{"discoveries":[{"year":2007,"finding":"Seipin localizes to the endoplasmic reticulum and concentrates at ER-lipid droplet junctions; its absence in yeast results in irregular and clustered lipid droplets with proliferated ER, and human seipin can functionally replace yeast seipin (but lipodystrophy-causing missense mutations cannot), establishing seipin's role in lipid droplet morphology and maintenance.","method":"Yeast genetic screen, fluorescence microscopy of seipin-GFP, complementation assay with human seipin, fibroblast analysis from BSCL2 patient","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (genetic screen, live imaging, cross-species complementation) in highly-cited foundational paper","pmids":["18093937"],"is_preprint":false},{"year":2006,"finding":"Seipin is an integral ER membrane protein with an N-cytoplasm/C-cytoplasm topology and a long luminal loop between two transmembrane helices; this topology was established by in vitro topology mapping assay.","method":"In vitro topology mapping assay","journal":"FEBS letters","confidence":"High","confidence_rationale":"Tier 1 — direct biochemical topology mapping in vitro","pmids":["16574104"],"is_preprint":false},{"year":2004,"finding":"Heterozygous N88S and S90L missense mutations in BSCL2 disrupt N-glycosylation of seipin and cause aggregate formation in the ER, linking aberrant glycosylation and protein aggregation to dominantly inherited motor neuropathy (dHMN/Silver syndrome).","method":"Direct sequencing, expression of mutant constructs in cells, glycosylation assay, immunofluorescence detection of aggregates","journal":"Nature genetics","confidence":"High","confidence_rationale":"Tier 2 — mutation identification linked to biochemical mechanism (glycosylation disruption + aggregation), replicated in multiple families","pmids":["14981520"],"is_preprint":false},{"year":2008,"finding":"Seipin is essential for adipocyte differentiation in a cell-autonomous manner; its knockdown in mesenchymal stem cells impairs sustained expression of PPARγ and C/EBPα and persistently reduces expression of triglyceride synthesis genes (AGPAT2, lipin 1, DGAT2), blocking lipid accumulation. A pathogenic missense mutant (A212P) shows aberrant subcellular targeting.","method":"shRNA knockdown in C3H10T1/2 cells, qRT-PCR, immunofluorescence of mutant localization","journal":"Diabetes","confidence":"High","confidence_rationale":"Tier 2 — clean KD with defined adipogenic phenotype and molecular pathway placement, multiple readouts","pmids":["18458148"],"is_preprint":false},{"year":2008,"finding":"Yeast seipin (Fld1p/YLR404W) regulates lipid droplet size; its deletion causes supersized LDs with enhanced fusion activity both in vivo and in vitro, and lipid profiling reveals altered acyl chain compositions of major phospholipids in fld1Δ cells. Human seipin rescues these defects.","method":"Yeast genetic screen (~4700 mutants), fluorescence microscopy, in vitro and in vivo LD fusion assay, lipidomics, cross-species complementation","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods in highly-cited paper; complementation establishes functional conservation","pmids":["18250201"],"is_preprint":false},{"year":2010,"finding":"Seipin forms a discrete homo-oligomeric complex of ~9 copies (~500 kDa) in the ER and appears as a toroid by negative-stain EM; the A212P lipodystrophy allele forms only smaller, unstable complexes, suggesting oligomer integrity is required for function.","method":"Affinity purification, detergent sucrose gradients (H2O and D2O), gel filtration, negative-stain electron microscopy","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 — purification and physical characterization with multiple hydrodynamic methods plus EM","pmids":["21062080"],"is_preprint":false},{"year":2007,"finding":"N88S and S90L mutant seipin is polyubiquitinated, degraded via ER-associated degradation (ERAD), stably binds the ER chaperone calnexin (indicating unfolded protein accumulation), and triggers ER stress-mediated apoptosis in neuronal cells, establishing that seipinopathies are conformational diseases linked to ER stress.","method":"Co-immunoprecipitation (seipin–calnexin), ubiquitination assay, proteasome inhibitor treatment, ER stress marker measurements, apoptosis assay","journal":"Annals of neurology","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP plus multiple orthogonal biochemical readouts in neuronal cells","pmids":["17387721"],"is_preprint":false},{"year":2011,"finding":"Absence of Bscl2 in mouse embryonic fibroblasts and stromal vascular cells causes normal early adipocyte differentiation but failure of terminal differentiation due to unrestrained cAMP/PKA-activated lipolysis, leading to loss of lipid droplets and silencing of adipose-specific transcription factors; this defect is rescued by lipolysis inhibitors but not by PPARγ agonist alone.","method":"Bscl2−/− mouse model, in vitro MEF/SVC differentiation, lipolysis inhibitor rescue experiments, gene expression analysis","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 — genetic KO with defined cellular phenotype, pathway placement via pharmacological rescue","pmids":["22269949"],"is_preprint":false},{"year":2012,"finding":"Seipin acts as an ER membrane adaptor that inducibly binds the phosphatidic acid (PA) phosphatase lipin 1 during adipogenesis; seipin knockdown decreases lipin 1 membrane association and increases PA accumulation, while wild-type but not a lipin-1-binding-deficient mutant of seipin reduces PA levels in differentiating cells.","method":"Co-immunoprecipitation, PA measurement, lipin 1 membrane fractionation, seipin overexpression/mutant expression in differentiating adipocytes","journal":"Molecular metabolism","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP plus functional rescue with point mutant, multiple methods","pmids":["24024128"],"is_preprint":false},{"year":2015,"finding":"Seipin dodecamers can directly and simultaneously bind both AGPAT2 and lipin 1, physically scaffolding these two consecutive enzymes of the PA biosynthetic/catabolic pathway; atomic force microscopy demonstrates direct protein–protein association and defines the molecular architecture of the complex.","method":"Co-immunoprecipitation, atomic force microscopy (direct binding), immunofluorescence","journal":"Molecular metabolism","confidence":"High","confidence_rationale":"Tier 1/2 — direct binding demonstrated by AFM plus Co-IP; complex architecture resolved","pmids":["25737955"],"is_preprint":false},{"year":2013,"finding":"Seipin interacts with 14-3-3β through its N- and C-termini; 14-3-3β recruits cofilin-1 to remodel actin cytoskeleton from stress fibers to cortical structures during adipogenesis, and knockdown of cofilin-1, 14-3-3β, or seipin impairs adipocyte development with retention of stress fibers.","method":"Co-immunoprecipitation, fluorescence microscopy of actin structures, shRNA knockdown in 3T3-L1 cells, severing-resistant actin mutant expression","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP plus functional KD phenotype, single lab","pmids":["24026679"],"is_preprint":false},{"year":2016,"finding":"Seipin physically interacts with microsomal glycerol-3-phosphate acyltransferase (GPAT) isoforms; SEIPIN-deficient cells and tissues show elevated GPAT activity and altered GPAT kinetics, and GPAT overexpression phenocopies seipin loss (supersized LDs, blocked adipogenesis) while GPAT3 knockdown partially rescues adipogenesis in seipin-deficient preadipocytes.","method":"Co-immunoprecipitation, GPAT activity assay (kinetics), genetic overexpression/knockdown across yeast/fly/mammalian systems, pharmacological GPAT inhibition in Seipin−/− preadipocytes","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1/2 — enzymatic activity measurement + interaction + multi-organism epistasis, strong converging evidence","pmids":["27806294"],"is_preprint":false},{"year":2016,"finding":"Seipin is stably associated with nascent ER-LD contacts (typically one focal point per LD) in human cells; seipin knockout or patient (BSCL2) cells completely lack or have aberrant ER-LD contacts, leading to increased LD mobility, impaired protein delivery from ER to LDs, and defective fatty acid incorporation into neutral lipids in cells with pre-existing LDs.","method":"Live-cell fluorescence microscopy, electron tomography, seipin KO and patient cell lines, LD mobility tracking, lipid/protein cargo delivery assays","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal imaging and biochemical methods, patient cells confirm findings","pmids":["27879284"],"is_preprint":false},{"year":2018,"finding":"Cryo-EM structure of human SEIPIN at 3.8 Å reveals an undecameric ring; the lumenal domain forms an eight-stranded β-sandwich fold. Both full-length SEIPIN and its lumenal domain bind anionic phospholipids including phosphatidic acid, suggesting seipin maintains phospholipid homeostasis and ER surface tension.","method":"Cryo-electron microscopy (3.8 Å structure), lipid-binding assay (phospholipid binding to full-length and lumenal domain)","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 1 — near-atomic cryo-EM structure with biochemical validation of lipid binding","pmids":["30293840"],"is_preprint":false},{"year":2018,"finding":"Cryo-EM structure of Drosophila seipin reveals a ring-shaped dodecamer; each monomer has a hydrophobic helix (HH) positioned toward the ER bilayer and a β-sandwich domain with structural similarity to lipid-binding proteins. Functional testing in cells supports a model in which seipin HHs detect forming LDs and then act as membrane anchors enabling lipid transfer and LD growth.","method":"Cryo-electron microscopy (~4.0 Å), cell-based functional assays of HH mutants","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1 — near-atomic cryo-EM structure plus functional mutagenesis in cells","pmids":["30327422"],"is_preprint":false},{"year":2019,"finding":"LDAF1 (TMEM159) is a direct interaction partner of seipin; together they form an ~600 kDa oligomeric complex that co-purifies with triacylglycerol. LDs form at LDAF1-seipin complexes, and relocalization of LDAF1 to the plasma membrane co-recruits seipin and redirects LD formation. After LD formation, LDAF1 dissociates from seipin and moves to the LD surface. Without LDAF1, LDs only form at significantly higher TG concentrations.","method":"Co-immunoprecipitation, mass spectrometry, TG co-purification, live-cell imaging of LDAF1/seipin relocalization, TG concentration assays","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 1/2 — Co-purification with TG, reciprocal Co-IP, live-cell functional relocalization, multiple orthogonal methods","pmids":["31708432"],"is_preprint":false},{"year":2019,"finding":"Seipin mediates uniform ER-LD neck contacts that facilitate triglyceride flow from the ER to LDs; without seipin, LDs become heterogeneous in size via a biophysical ripening (Ostwald ripening) process where TG partitions from smaller to larger LDs through droplet-bilayer contacts. Relocalizing seipin to the nuclear envelope redirects LD formation to seipin-defined sites.","method":"Seipin relocalization to nuclear envelope, acute seipin removal (auxin-inducible degron), live-cell imaging, electron tomography, model membrane experiments, coarse-grained simulations","journal":"Developmental cell","confidence":"High","confidence_rationale":"Tier 1/2 — multiple orthogonal approaches including reconstitution in model membranes and acute protein removal","pmids":["31178403"],"is_preprint":false},{"year":2021,"finding":"Molecular dynamics simulations show that seipin clusters triacylglycerol and diacylglycerol inside its ring-like oligomeric structure via interactions involving both luminal and transmembrane regions; polar residues responsible for TG interactions are identified, and mutations of these to hydrophobic residues abolish TG clustering.","method":"Molecular dynamics simulations (coarse-grained and all-atom), mutagenesis of polar residues","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 1 (simulation + mutagenesis) but single study; computational approach","pmids":["33674387"],"is_preprint":false},{"year":2022,"finding":"Cryo-EM structure of S. cerevisiae seipin reveals a decameric cage; lumenal domains form a stable ring and transmembrane segments form cage sides/top with two alternating conformations regulated by switch regions. Switch region mutations abolish seipin function. A model is proposed in which the closed cage enables TG phase separation and an open conformation allows LD budding.","method":"Cryo-electron microscopy plus structural modeling, functional mutagenesis of switch regions in cells","journal":"Nature structural & molecular biology","confidence":"High","confidence_rationale":"Tier 1 — high-resolution cryo-EM structure with functional mutagenesis validation","pmids":["35210614"],"is_preprint":false},{"year":2022,"finding":"All-atom MD simulations show that seipin TM segment residues and hydrophobic helix residues (in the phospholipid tail region) attract TG, and coarse-grained models show TM segments form a constricted neck to facilitate conversion of a flat oil lens into a budding LD. Conserved positively charged residues at TM segment ends affect LD maturation in cell experiments.","method":"Molecular dynamics simulations (all-atom and coarse-grained), cell-based experiments with TM charge mutants","journal":"eLife","confidence":"Medium","confidence_rationale":"Tier 1/2 — simulation plus cell-based mutagenesis, single study","pmids":["35583926"],"is_preprint":false},{"year":2021,"finding":"Structural and biochemical analysis of yeast Sei1/Ldb16 complex shows that Sei1 luminal domain assembles a homooligomeric ring but cannot itself concentrate TG; instead, Sei1 positions Ldb16, which concentrates TG within the Sei1 ring via critical hydroxyl residues. Sei1 TM segments also promote TG recruitment and control Ldb16 stability.","method":"Cryo-EM structure, biochemical assays, molecular dynamics simulations, mutagenesis of Ldb16 hydroxyl residues","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 1 — cryo-EM structure plus reconstituted biochemical assays plus mutagenesis, multiple orthogonal methods","pmids":["34625558"],"is_preprint":false},{"year":2022,"finding":"Yeast Seipin (Sei1/Ldb16) promotes storage of diverse neutral lipids (TAG, steryl esters, retinyl esters) in LDs; human seipin restores normal SE-containing LDs in yeast seipin mutants. The mechanism involves interactions between hydroxyl residues in human seipin or yeast Ldb16 with neutral lipid carboxyl esters.","method":"Yeast genetics, complementation with human seipin, mutagenesis of hydroxyl residues, neutral lipid profiling","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1/2 — mutagenesis plus cross-species complementation plus lipidomics","pmids":["35938957"],"is_preprint":false},{"year":2018,"finding":"In Drosophila, Seipin promotes ER calcium homeostasis through SERCA; loss of dSeipin impairs mitochondrial TCA cycle activity and reduces citrate levels (required for lipogenesis) by reducing mitochondrial calcium import. Lipid storage defects in dSeipin mutant fat cells can be rescued by restoring mitochondrial calcium or citrate.","method":"Drosophila genetics, metabolomics, calcium measurement, genetic rescue with citrate supplementation","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis in Drosophila with metabolic rescue, multiple orthogonal methods","pmids":["30049710"],"is_preprint":false},{"year":2022,"finding":"A subset of seipin localizes to ER-mitochondria contact sites (MAMs) in human and mouse adipocytes, in the vicinity of calcium regulators SERCA2, IP3R, and VDAC; acute seipin removal leads to defective mitochondrial calcium import, widespread reduction in Krebs cycle metabolites, and decreased ATP levels without altering ER calcium stores.","method":"Proximity ligation assay, subcellular fractionation, live-cell calcium imaging, metabolomics, acute seipin deletion (inducible), proximity to MAM calcium regulators","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods; localization linked to functional consequence of acute protein removal","pmids":["35021082"],"is_preprint":false},{"year":2015,"finding":"In yeast, absence of seipin leads to localized accumulation of phosphatidic acid (PA puncta) at ER-LD junctions detected by three independent probes; this PA accumulation requires the first 14 amino acids (N-terminus) of Sei1p, and suppression of PA puncta requires functional cooperation between Sei1p N-terminus and Ldb16p.","method":"Yeast genetics, multiple PA probes (Opi1p, Spo20p, Pah1p), deletion/complementation analysis","journal":"BMC cell biology","confidence":"Medium","confidence_rationale":"Tier 2 — three independent probes confirm PA accumulation; domain mapping via deletion mutants; single lab","pmids":["26637296"],"is_preprint":false},{"year":2019,"finding":"Yeast seipin negatively regulates sphingolipid production by associating with serine palmitoyltransferase (SPT) and fatty acid elongase at ER-LD contacts; cells lacking seipin show elevated SPT and FA elongase activities and accumulate sphingoid precursors/intermediates. Human seipin rescues altered sphingolipid levels in yeast seipin mutants.","method":"Co-immunoprecipitation of seipin with SPT and FA elongase, sphingolipid enzyme activity assays, lipidomics, yeast genetics, cross-species complementation","journal":"The Journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP plus enzyme activity assays plus complementation; single lab","pmids":["31594806"],"is_preprint":false},{"year":2018,"finding":"In yeast, seipin cooperates with the membrane-shaping protein Pex30 to facilitate organelle budding (both lipid droplets and peroxisomes) from the ER; absence of both leads to ER accumulation of TG and peroxisomal membrane proteins without affecting COPII vesicle formation, and this can be reversed by remodeling ER phospholipid composition.","method":"Yeast genetics (double deletion), electron microscopy, lipid composition analysis, organelle fractionation","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis with multiple organelle readouts plus phospholipid rescue","pmids":["30054465"],"is_preprint":false},{"year":2011,"finding":"Drosophila dSeipin loss causes ectopic lipid droplet accumulation in a tissue-autonomous manner in the salivary gland; dSeipin mutants show synergistic genetic interactions with lipogenic genes, and the phenotype is consistent with seipin participating in phosphatidic acid metabolism to down-regulate lipogenesis.","method":"Drosophila genetics, tissue-specific rescue, genetic epistasis with lipogenic genes, lipid droplet imaging","journal":"PLoS genetics","confidence":"Medium","confidence_rationale":"Tier 2 — tissue-autonomous rescue plus genetic epistasis; mechanistic link to PA metabolism is genetic inference","pmids":["21533227"],"is_preprint":false},{"year":2011,"finding":"Seipin functions as a scaffolding protein in the ER; deletion of FLD1 (yeast seipin) leads to impaired lipid droplet dynamics and defective lipolysis associated with aberrant ER structures, consistent with seipin organizing a specific ER subdomain.","method":"4D live-cell imaging, transmission electron microscopy, electron tomography, quantitative microscopy in S. cerevisiae","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 — multiple imaging modalities; functional consequence of seipin loss established, but scaffolding role is inferential","pmids":["22100922"],"is_preprint":false},{"year":2013,"finding":"Wild-type human seipin forms dodecamers (12 subunits in a circular configuration) as shown by atomic force microscopy; the L91P and A212P lipodystrophy mutants fail to form this 12-mer structure, and several mutants (R275X, frameshift) fail to bind lipin 1 appropriately.","method":"Atomic force microscopy, co-immunoprecipitation (seipin–lipin 1 interaction), expression analysis of mutant constructs","journal":"Diabetologia","confidence":"High","confidence_rationale":"Tier 1/2 — AFM resolution of oligomeric stoichiometry plus functional interaction studies, comprehensive mutant panel","pmids":["23989774"],"is_preprint":false},{"year":2008,"finding":"The transmembrane domains of seipin are critical for its ER retention, ubiquitination, formation of inclusion bodies, and activation of the unfolded protein response (UPR); seipin is expressed in neurons of the spinal cord and frontal cortex.","method":"Deletion/domain mutagenesis of seipin constructs, ubiquitination assay, UPR marker measurements, immunohistochemistry","journal":"Neurobiology of disease","confidence":"Medium","confidence_rationale":"Tier 2 — domain mutagenesis with multiple functional readouts; single lab","pmids":["18585921"],"is_preprint":false},{"year":2011,"finding":"Seipin knockdown in mammalian cells increases oleate incorporation into TAG and steady-state TAG levels, and induces proliferation and clustering of small LDs; overexpression reduces TAG synthesis and LD formation. The N88S/S90L neuropathy mutants dominantly cause small LD clustering by trapping wild-type seipin in inclusions; seipin can interact with itself and its mutant forms.","method":"shRNA knockdown, seipin overexpression, lipid incorporation assay (oleate-TAG), co-immunoprecipitation (seipin self-interaction), fluorescence microscopy","journal":"Journal of lipid research","confidence":"Medium","confidence_rationale":"Tier 2 — multiple biochemical and imaging methods; self-interaction by Co-IP; single lab","pmids":["21957196"],"is_preprint":false},{"year":2009,"finding":"Seipin deficiency in lymphoblastoid cells from BSCL patients (null BSCL2 mutations) alters lipid droplet morphology (decreased size, increased number) and causes a defect in fatty acid Δ9-desaturation, with increased saturated fatty acids in TG and phosphatidylethanolamine, suggesting seipin acts at a proximal step linking Δ9-desaturase activity to lipid droplet formation.","method":"Lipid profiling of patient lymphoblastoid cells, fatty acid composition analysis by GC, fluorescence microscopy of LDs","journal":"Biochimie","confidence":"Medium","confidence_rationale":"Tier 3 — patient cell phenotype with lipidomics; no direct enzyme interaction demonstrated","pmids":["19278620"],"is_preprint":false},{"year":2012,"finding":"Seipin regulates excitatory synaptic transmission in cortical neurons via a post-synaptic mechanism; seipin knockdown reduces AMPA receptor surface levels and AMPA-induced currents without altering inhibitory post-synaptic currents or pre-synaptic ultrastructure. These defects are rescued by expression of shRNA-resistant human seipin.","method":"shRNA knockdown in cultured neurons, whole-cell patch-clamp electrophysiology, AMPA/IPSC recording, surface AMPA receptor immunostaining and biochemistry","journal":"Journal of neurochemistry","confidence":"Medium","confidence_rationale":"Tier 2 — electrophysiology plus surface receptor biochemistry plus rescue; single lab","pmids":["23173741"],"is_preprint":false},{"year":2016,"finding":"Neuronal seipin deficiency causes selective reduction of AMPA receptor expression in hippocampal CA1 pyramidal neurons via decreased ERK-CREB phosphorylation and reduced PPARγ, leading to impaired LTP and spatial memory deficits; PPARγ agonist rosiglitazone rescues AMPAR expression and LTP through ERK-CREB pathway.","method":"Neuronal seipin-knockout mice, Morris water maze, LTP recording (hippocampal slices), whole-cell patch-clamp, AMPAR immunostaining, MEK inhibitor experiments","journal":"The Journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 — genetic KO with electrophysiology plus pharmacological pathway dissection; single lab","pmids":["26818512"],"is_preprint":false},{"year":2016,"finding":"BSCL2 deletion specifically in brown adipocyte progenitors in mice causes unrestrained cAMP/PKA-mediated lipolysis and premature metabolic activation of differentiating brown adipocytes, ultimately resulting in BAT atrophy via apoptosis; BSCL2 is not required for the core brown adipogenic transcriptional program.","method":"Brown adipocyte-specific Bscl2 knockout mice, BAT morphology/function analysis, cAMP/PKA pathway measurement, apoptosis assays, gene expression profiling","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 — tissue-specific genetic KO with defined mechanistic pathway (cAMP/PKA); multiple readouts","pmids":["27185876"],"is_preprint":false},{"year":2019,"finding":"Bscl2−/− hearts exhibit increased ATGL protein stability and expression, causing drastic reduction of glycerolipids and excessive fatty acid oxidation; pharmacological or genetic inhibition of ATGL rescues adipocyte differentiation and lipodystrophy in Bscl2−/− cells and mice, placing BSCL2 upstream of ATGL in regulating adipocyte lipid storage.","method":"Bscl2−/− mouse model, ATGL inhibitor/genetic deletion rescue, lipidomics, cardiac function measurement, hyperinsulinemic-euglycemic clamp","journal":"JCI insight","confidence":"High","confidence_rationale":"Tier 2 — genetic epistasis (ATGL deletion rescues seipin KO phenotype) plus mechanistic pathway","pmids":["31185001"],"is_preprint":false},{"year":2016,"finding":"BSCL2/Seipin knockdown in hepatocytes increases LD number and size and induces SCD1 expression and activity; SCD1 knockdown reverses the LD phenotype associated with Seipin deficiency, placing SCD1 downstream of Seipin in regulating hepatic LD homeostasis.","method":"siRNA knockdown in primary and cultured hepatocytes, LD imaging, SCD1 activity assay, double knockdown epistasis","journal":"Lipids","confidence":"Medium","confidence_rationale":"Tier 2 — epistasis via double KD plus enzyme activity assay; single lab","pmids":["27838812"],"is_preprint":false},{"year":2016,"finding":"SEIPIN interacts with ADRP (adipose differentiation-related protein/perilipin 2) as shown by co-immunoprecipitation; seipin defines ADRP's punctate cytoplasmic localization, and restoration of BSCL2 in patient-derived iPSCs rescues both lipid droplet formation and cytoplasmic punctate ADRP localization.","method":"Co-immunoprecipitation, iPSC differentiation model from BSCL2-null patients, rescue with wild-type BSCL2, fluorescence microscopy","journal":"Metabolism: clinical and experimental","confidence":"Medium","confidence_rationale":"Tier 3 — single Co-IP plus iPSC rescue; functional consequence tied to localization","pmids":["26975546"],"is_preprint":false},{"year":2020,"finding":"Seipin and GPAT3 associate via direct protein-protein interaction; seipin can simultaneously bind GPAT3 and AGPAT2 in the same complex; loss of GPAT3 in seipin-deficient preadipocytes exacerbates adipogenic failure, indicating GPAT3 has a modest positive role in adipogenesis within the seipin-regulated pathway.","method":"Co-immunoprecipitation, siRNA knockdown, adipocyte differentiation assays","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2/3 — Co-IP plus functional epistasis; single lab","pmids":["32094408"],"is_preprint":false},{"year":2019,"finding":"Promethin (TMEM159/LDAF1) is a seipin partner protein that forms a complex with seipin; promethin localizes to LD surfaces, and its LD targeting is modulated by seipin expression levels.","method":"Co-immunoprecipitation, fluorescence microscopy, modulation of seipin expression levels","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 3 — Co-IP plus localization; functional consequences partially characterized","pmids":["30901948"],"is_preprint":false}],"current_model":"Seipin (BSCL2) is an oligomeric ER integral membrane protein (forming rings/cages of 9–12 subunits) that concentrates at ER-LD junctions, where it clusters neutral lipids (triacylglycerol and diacylglycerol) via its lumenal β-sandwich domain and transmembrane segments to nucleate LD biogenesis, stabilizes ER-LD neck contacts to facilitate lipid and protein cargo delivery from the ER to growing LDs, scaffolds key lipid metabolism enzymes (AGPAT2, lipin 1, GPAT3) during adipogenesis, and restrains cAMP/PKA-mediated lipolysis to permit terminal adipocyte differentiation; additionally, a subset of seipin localizes to ER-mitochondria contact sites where it supports mitochondrial calcium import and TCA cycle metabolism, and dominant N-glycosylation-site mutations (N88S, S90L) cause ER stress and motor neuropathy via protein misfolding and calnexin sequestration."},"narrative":{"teleology":[{"year":2004,"claim":"The discovery that heterozygous N88S/S90L mutations disrupt seipin N-glycosylation and cause ER aggregation established that BSCL2 mutations can act dominantly through a protein misfolding mechanism, linking seipin to hereditary motor neuropathy.","evidence":"Mutation identification in multiple families, glycosylation assays, and aggregate detection in transfected cells","pmids":["14981520"],"confidence":"High","gaps":["Mechanism by which aggregates specifically damage motor neurons unknown","Whether aggregation triggers neurodegeneration via gain-of-function toxicity versus loss of seipin function unresolved"]},{"year":2006,"claim":"Topology mapping established seipin as a two-pass ER transmembrane protein with a large lumenal loop and cytoplasmic N- and C-termini, defining the structural framework for subsequent functional studies.","evidence":"In vitro topology mapping assay","pmids":["16574104"],"confidence":"High","gaps":["Structural basis of the lumenal domain not yet resolved","Post-translational modifications beyond N-glycosylation uncharacterized"]},{"year":2007,"claim":"Two studies established that seipin concentrates at ER–LD junctions and that its absence causes aberrant LD morphology, while neuropathy-mutant seipin undergoes ERAD and triggers ER stress via stable calnexin binding, separating lipodystrophy from neuropathy mechanisms.","evidence":"Yeast seipin-GFP imaging and cross-species complementation (LD phenotype); co-immunoprecipitation with calnexin, ubiquitination, and apoptosis assays in neuronal cells (ER stress)","pmids":["18093937","17387721"],"confidence":"High","gaps":["Whether seipin directly contacts lipid or acts indirectly unknown","Molecular basis of ER–LD junction stabilization unresolved"]},{"year":2008,"claim":"Cell-autonomous requirement of seipin for adipocyte differentiation was demonstrated, with seipin knockdown impairing PPARγ/C/EBPα expression and triglyceride synthesis gene induction, while yeast studies showed seipin controls LD size by preventing LD–LD fusion and altering phospholipid composition.","evidence":"shRNA knockdown in mesenchymal stem cells with adipogenic readouts; yeast genome-wide screen with LD fusion assays and lipidomics","pmids":["18458148","18250201"],"confidence":"High","gaps":["Direct mechanism linking seipin to PPARγ maintenance unknown","Whether phospholipid changes are cause or consequence of LD defects unclear"]},{"year":2011,"claim":"Seipin was shown to form homo-oligomeric toroidal complexes (~9–12-mers), and Bscl2-knockout mouse studies revealed that unrestrained cAMP/PKA-mediated lipolysis—not failure of early adipogenic transcription—causes terminal differentiation failure, rescuable by lipolysis inhibition.","evidence":"Purification with sucrose gradients, gel filtration, and negative-stain EM (oligomer); Bscl2−/− MEF differentiation with pharmacological lipolysis rescue (adipogenesis)","pmids":["21062080","22269949"],"confidence":"High","gaps":["How seipin restrains cAMP/PKA signaling molecularly unresolved","Whether oligomer stoichiometry is fixed or dynamic unclear"]},{"year":2012,"claim":"Seipin was identified as a regulated adaptor for lipin 1 at the ER membrane during adipogenesis; seipin loss decreased lipin 1 membrane association and elevated phosphatidic acid, placing seipin in the glycerolipid biosynthetic pathway.","evidence":"Co-immunoprecipitation, PA measurement, and lipin 1 membrane fractionation in differentiating adipocytes; mutant seipin unable to bind lipin 1 fails to reduce PA","pmids":["24024128"],"confidence":"High","gaps":["Whether PA accumulation is the proximal cause of differentiation failure or a secondary effect unknown","Structural basis of seipin–lipin 1 interaction unresolved"]},{"year":2015,"claim":"Atomic force microscopy demonstrated that seipin dodecamers simultaneously bind AGPAT2 and lipin 1, establishing seipin as a physical scaffold organizing consecutive glycerolipid biosynthetic enzymes.","evidence":"AFM imaging of direct protein–protein association and co-immunoprecipitation of ternary complex","pmids":["25737955"],"confidence":"High","gaps":["Stoichiometry of AGPAT2 and lipin 1 within the dodecameric complex not determined","Whether scaffolding alters enzyme kinetics not tested"]},{"year":2016,"claim":"Seipin was shown to physically interact with and regulate GPAT3 activity; GPAT overexpression phenocopied seipin loss, while GPAT3 knockdown partially rescued seipin-deficient adipogenesis, extending the enzyme scaffold to three consecutive glycerolipid pathway steps. Separately, seipin was shown to maintain stable ER–LD contacts, with its absence causing loss of contacts, increased LD mobility, and defective protein/lipid cargo delivery to LDs.","evidence":"Co-IP, GPAT kinetics, multi-organism epistasis (yeast/fly/mammalian); live-cell imaging, electron tomography, and patient-cell LD tracking","pmids":["27806294","27879284"],"confidence":"High","gaps":["How seipin modulates GPAT catalytic rate mechanistically unclear","Whether ER–LD contact stabilization and enzyme scaffolding are separable functions not tested"]},{"year":2018,"claim":"Cryo-EM structures of human (undecamer) and Drosophila (dodecamer) seipin revealed lumenal β-sandwich folds with structural similarity to lipid-binding proteins and hydrophobic helices positioned within the bilayer; the lumenal domain binds anionic phospholipids including PA. In parallel, Drosophila studies linked seipin to ER calcium homeostasis via SERCA, with downstream effects on mitochondrial calcium import and TCA-cycle-dependent lipogenesis.","evidence":"Cryo-EM at ~3.8–4.0 Å with lipid-binding assays and functional mutagenesis; Drosophila metabolomics with calcium measurements and citrate rescue","pmids":["30293840","30049710","30327422"],"confidence":"High","gaps":["Atomic-resolution lipid-binding pose within the lumenal domain not resolved","Whether the calcium-homeostasis function is structurally separable from the LD-biogenesis function unknown"]},{"year":2019,"claim":"LDAF1/TMEM159 was identified as a stoichiometric seipin partner that co-purifies with TAG; LDs form at LDAF1–seipin complexes, and LDAF1 dissociates to the LD surface after budding. Seipin was also shown to mediate uniform ER–LD necks that prevent Ostwald ripening, and its relocalization redirects LD formation sites. Additionally, ATGL was placed downstream of seipin: genetic or pharmacological ATGL inhibition rescued lipodystrophy in Bscl2−/− mice.","evidence":"Co-purification with TAG, LDAF1 relocalization assay, auxin-inducible seipin degron, model membranes, ATGL KO rescue of Bscl2−/− mice","pmids":["31708432","31178403","31185001"],"confidence":"High","gaps":["Structural basis of LDAF1 engagement within the seipin ring unresolved","Mechanism by which seipin regulates ATGL protein stability unknown"]},{"year":2021,"claim":"Molecular dynamics and the yeast Sei1/Ldb16 cryo-EM structure revealed that seipin concentrates TAG and DAG inside its ring via polar/hydroxyl residues in transmembrane and partner subunits, providing a molecular explanation for neutral lipid nucleation.","evidence":"Coarse-grained and all-atom MD simulations with mutagenesis; cryo-EM of Sei1/Ldb16 complex plus biochemical reconstitution","pmids":["33674387","34625558"],"confidence":"High","gaps":["Direct experimental visualization of lipid within the ring at atomic resolution lacking","How opening of the cage permits LD budding in real time not observed"]},{"year":2022,"claim":"Yeast seipin cryo-EM revealed a decameric cage with two alternating TM conformations regulated by switch regions; functional mutagenesis showed switch regions are essential, supporting a model in which conformational switching enables TAG phase separation then LD budding. Mammalian studies confirmed seipin at MAMs facilitates mitochondrial calcium import, sustaining Krebs cycle metabolites and ATP.","evidence":"Cryo-EM structure with switch-region mutagenesis; proximity ligation, live calcium imaging, and metabolomics upon acute seipin removal in adipocytes","pmids":["35210614","35021082","35938957"],"confidence":"High","gaps":["Conformational transition between open and closed states not captured in time-resolved experiments","Whether the MAM-localized pool of seipin is structurally distinct from ER–LD pool unknown"]},{"year":null,"claim":"Key unresolved questions include how seipin's LD-biogenesis and ER–mitochondria contact functions are structurally partitioned, the atomic mechanism by which seipin cage opening permits LD budding, and how seipin restrains cAMP/PKA lipolytic signaling at the molecular level.","evidence":"","pmids":[],"confidence":"Low","gaps":["No time-resolved structural data capturing cage conformational dynamics","Molecular link between seipin and cAMP/PKA pathway components unidentified","Whether LDAF1 occupies a defined site within the seipin ring structurally unresolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[13,17,20,21]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[8,9,11,39]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[5,13,14,18]}],"localization":[{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[0,1,12]},{"term_id":"GO:0005811","term_label":"lipid droplet","supporting_discovery_ids":[0,12,16]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[22,23]}],"pathway":[{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[4,8,9,11,24,32]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[3,7,35]},{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[0,12,16,26]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[2,6]}],"complexes":["Seipin oligomeric ring (9-12mer)","Seipin-LDAF1 complex"],"partners":["TMEM159","LPIN1","AGPAT2","GPAT3","CANX","PLIN2","YWHAB"],"other_free_text":[]},"mechanistic_narrative":"Seipin (BSCL2) is an ER-resident integral membrane protein that oligomerizes into ring-shaped assemblies of 9–12 subunits at ER–lipid droplet junctions, where it nucleates lipid droplet (LD) biogenesis by concentrating triacylglycerol and other neutral lipids within its lumenal β-sandwich domain and transmembrane cage, thereby defining LD formation sites, stabilizing ER–LD neck contacts, and preventing aberrant LD ripening [PMID:18093937, PMID:30293840, PMID:35938957, PMID:31178403]. Seipin scaffolds consecutive glycerolipid biosynthetic enzymes—AGPAT2, lipin 1, and GPAT3—at the ER membrane during adipogenesis, and restrains cAMP/PKA-mediated lipolysis and ATGL-dependent lipid mobilization, thereby enabling terminal adipocyte differentiation; loss-of-function mutations cause Berardinelli–Seip congenital generalized lipodystrophy type 2 [PMID:24026679, PMID:25737955, PMID:27806294, PMID:22269949, PMID:31185001]. A subset of seipin localizes to ER–mitochondria contact sites where it facilitates mitochondrial calcium import required for TCA cycle flux and lipogenesis [PMID:30049710, PMID:35021082]. Dominant N-glycosylation-disrupting mutations (N88S, S90L) cause seipin misfolding, ER stress via calnexin sequestration, and motor neuropathy (dHMN-V/Silver syndrome) [PMID:14981520, PMID:17387721]."},"prefetch_data":{"uniprot":{"accession":"Q96G97","full_name":"Seipin","aliases":["Bernardinelli-Seip congenital lipodystrophy type 2 protein"],"length_aa":398,"mass_kda":44.4,"function":"Plays a crucial role in the formation of lipid droplets (LDs) which are storage organelles at the center of lipid and energy homeostasis (PubMed:19278620, PubMed:21533227, PubMed:30293840, PubMed:31708432). In association with LDAF1, defines the sites of LD formation in the ER (PubMed:31708432). Also required for growth and maturation of small nascent LDs into larger mature LDs (PubMed:27564575). Mediates the formation and/or stabilization of endoplasmic reticulum-lipid droplets (ER-LD) contacts, facilitating protein and lipid delivery from the ER into growing LDs (PubMed:27879284, PubMed:31178403). Regulates the maturation of ZFYVE1-positive nascent LDs and the function of the RAB18-ZFYVE1 complex in mediating the formation of ER-LD contacts (PubMed:30970241). Binds anionic phospholipids including phosphatidic acid (PubMed:30293840). Plays an important role in the differentiation and development of adipocytes (By similarity)","subcellular_location":"Endoplasmic reticulum membrane; Lipid droplet","url":"https://www.uniprot.org/uniprotkb/Q96G97/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/BSCL2","classification":"Not Classified","n_dependent_lines":32,"n_total_lines":1208,"dependency_fraction":0.026490066225165563},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/BSCL2","total_profiled":1310},"omim":[{"mim_id":"620271","title":"TRANSMEMBRANE PROTEIN 41B; TMEM41B","url":"https://www.omim.org/entry/620271"},{"mim_id":"619112","title":"NEURONOPATHY, DISTAL HEREDITARY MOTOR, AUTOSOMAL DOMINANT 13; HMND13","url":"https://www.omim.org/entry/619112"},{"mim_id":"615924","title":"ENCEPHALOPATHY, PROGRESSIVE, WITH OR WITHOUT LIPODYSTROPHY; PELD","url":"https://www.omim.org/entry/615924"},{"mim_id":"614751","title":"NEURONOPATHY, DISTAL HEREDITARY MOTOR, AUTOSOMAL DOMINANT 12; HMND12","url":"https://www.omim.org/entry/614751"},{"mim_id":"611753","title":"VACUOLE MEMBRANE PROTEIN 1; VMP1","url":"https://www.omim.org/entry/611753"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"brain","ntpm":274.6},{"tissue":"pituitary gland","ntpm":219.0}],"url":"https://www.proteinatlas.org/search/BSCL2"},"hgnc":{"alias_symbol":["seipin"],"prev_symbol":["GNG3LG","SPG17"]},"alphafold":{"accession":"Q96G97","domains":[{"cath_id":"2.60.120","chopping":"60-150_177-219","consensus_level":"high","plddt":91.149,"start":60,"end":219},{"cath_id":"1.10.287","chopping":"19-56_228-257","consensus_level":"high","plddt":92.9018,"start":19,"end":257}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96G97","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q96G97-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q96G97-F1-predicted_aligned_error_v6.png","plddt_mean":74.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=BSCL2","jax_strain_url":"https://www.jax.org/strain/search?query=BSCL2"},"sequence":{"accession":"Q96G97","fasta_url":"https://rest.uniprot.org/uniprotkb/Q96G97.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q96G97/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q96G97"}},"corpus_meta":[{"pmid":"18093937","id":"PMC_18093937","title":"The lipodystrophy protein seipin is found at endoplasmic reticulum lipid droplet junctions and is important for droplet morphology.","date":"2007","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/18093937","citation_count":503,"is_preprint":false},{"pmid":"18250201","id":"PMC_18250201","title":"Fld1p, a functional homologue of human seipin, regulates the size of lipid droplets in yeast.","date":"2008","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/18250201","citation_count":402,"is_preprint":false},{"pmid":"14981520","id":"PMC_14981520","title":"Heterozygous missense mutations in BSCL2 are associated with distal hereditary motor neuropathy and Silver syndrome.","date":"2004","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/14981520","citation_count":305,"is_preprint":false},{"pmid":"27879284","id":"PMC_27879284","title":"Seipin regulates ER-lipid droplet contacts and cargo delivery.","date":"2016","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/27879284","citation_count":251,"is_preprint":false},{"pmid":"31708432","id":"PMC_31708432","title":"LDAF1 and Seipin Form a Lipid Droplet Assembly Complex.","date":"2019","source":"Developmental cell","url":"https://pubmed.ncbi.nlm.nih.gov/31708432","citation_count":177,"is_preprint":false},{"pmid":"18458148","id":"PMC_18458148","title":"The human lipodystrophy gene BSCL2/seipin may be essential for normal adipocyte differentiation.","date":"2008","source":"Diabetes","url":"https://pubmed.ncbi.nlm.nih.gov/18458148","citation_count":167,"is_preprint":false},{"pmid":"30293840","id":"PMC_30293840","title":"Human SEIPIN Binds Anionic Phospholipids.","date":"2018","source":"Developmental cell","url":"https://pubmed.ncbi.nlm.nih.gov/30293840","citation_count":167,"is_preprint":false},{"pmid":"31178403","id":"PMC_31178403","title":"Seipin Facilitates Triglyceride Flow to Lipid Droplet and Counteracts Droplet Ripening via Endoplasmic Reticulum Contact.","date":"2019","source":"Developmental cell","url":"https://pubmed.ncbi.nlm.nih.gov/31178403","citation_count":165,"is_preprint":false},{"pmid":"21551454","id":"PMC_21551454","title":"Seipin ablation in mice results in severe generalized lipodystrophy.","date":"2011","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/21551454","citation_count":150,"is_preprint":false},{"pmid":"30327422","id":"PMC_30327422","title":"Cryo-electron microscopy structure of the lipid droplet-formation protein seipin.","date":"2018","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/30327422","citation_count":142,"is_preprint":false},{"pmid":"22269949","id":"PMC_22269949","title":"Berardinelli-seip congenital lipodystrophy 2/seipin is a cell-autonomous regulator of lipolysis essential for adipocyte differentiation.","date":"2012","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/22269949","citation_count":140,"is_preprint":false},{"pmid":"26362606","id":"PMC_26362606","title":"Arabidopsis SEIPIN Proteins Modulate Triacylglycerol Accumulation and Influence Lipid Droplet Proliferation.","date":"2015","source":"The Plant cell","url":"https://pubmed.ncbi.nlm.nih.gov/26362606","citation_count":137,"is_preprint":false},{"pmid":"27806294","id":"PMC_27806294","title":"SEIPIN Regulates Lipid Droplet Expansion and Adipocyte Development by Modulating the Activity of Glycerol-3-phosphate Acyltransferase.","date":"2016","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/27806294","citation_count":136,"is_preprint":false},{"pmid":"21533227","id":"PMC_21533227","title":"Tissue-autonomous function of Drosophila seipin in preventing ectopic lipid droplet formation.","date":"2011","source":"PLoS genetics","url":"https://pubmed.ncbi.nlm.nih.gov/21533227","citation_count":124,"is_preprint":false},{"pmid":"30054465","id":"PMC_30054465","title":"Seipin and the membrane-shaping protein Pex30 cooperate in organelle budding from the endoplasmic reticulum.","date":"2018","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/30054465","citation_count":119,"is_preprint":false},{"pmid":"14602785","id":"PMC_14602785","title":"Phenotypic heterogeneity in body fat distribution in patients with congenital generalized lipodystrophy caused by mutations in the AGPAT2 or seipin genes.","date":"2003","source":"The Journal of clinical endocrinology and metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/14602785","citation_count":114,"is_preprint":false},{"pmid":"19574402","id":"PMC_19574402","title":"The human lipodystrophy gene product Berardinelli-Seip congenital lipodystrophy 2/seipin plays a key role in adipocyte differentiation.","date":"2009","source":"Endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/19574402","citation_count":113,"is_preprint":false},{"pmid":"22100922","id":"PMC_22100922","title":"A role for seipin in lipid droplet dynamics and inheritance in yeast.","date":"2011","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/22100922","citation_count":110,"is_preprint":false},{"pmid":"19278620","id":"PMC_19278620","title":"Seipin deficiency alters fatty acid Delta9 desaturation and lipid droplet formation in Berardinelli-Seip congenital lipodystrophy.","date":"2009","source":"Biochimie","url":"https://pubmed.ncbi.nlm.nih.gov/19278620","citation_count":108,"is_preprint":false},{"pmid":"22474068","id":"PMC_22474068","title":"Seipin: from human disease to molecular mechanism.","date":"2012","source":"Journal of lipid research","url":"https://pubmed.ncbi.nlm.nih.gov/22474068","citation_count":105,"is_preprint":false},{"pmid":"21062080","id":"PMC_21062080","title":"Seipin is a discrete homooligomer.","date":"2010","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21062080","citation_count":105,"is_preprint":false},{"pmid":"29187527","id":"PMC_29187527","title":"Identification of seipin-linked factors that act as determinants of a lipid droplet subpopulation.","date":"2017","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/29187527","citation_count":104,"is_preprint":false},{"pmid":"16574104","id":"PMC_16574104","title":"Membrane topology of the human seipin protein.","date":"2006","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/16574104","citation_count":104,"is_preprint":false},{"pmid":"24622797","id":"PMC_24622797","title":"Adipose-specific knockout of SEIPIN/BSCL2 results in progressive lipodystrophy.","date":"2014","source":"Diabetes","url":"https://pubmed.ncbi.nlm.nih.gov/24622797","citation_count":92,"is_preprint":false},{"pmid":"21497513","id":"PMC_21497513","title":"Seipin, adipogenesis and lipid droplets.","date":"2011","source":"Trends in endocrinology and metabolism: TEM","url":"https://pubmed.ncbi.nlm.nih.gov/21497513","citation_count":89,"is_preprint":false},{"pmid":"33674387","id":"PMC_33674387","title":"Seipin accumulates and traps diacylglycerols and triglycerides in its ring-like structure.","date":"2021","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/33674387","citation_count":82,"is_preprint":false},{"pmid":"15242882","id":"PMC_15242882","title":"The phenotype of motor neuropathies associated with BSCL2 mutations is broader than Silver syndrome and distal HMN type V.","date":"2004","source":"Brain : a journal of neurology","url":"https://pubmed.ncbi.nlm.nih.gov/15242882","citation_count":81,"is_preprint":false},{"pmid":"35210614","id":"PMC_35210614","title":"Seipin forms a flexible cage at lipid droplet formation sites.","date":"2022","source":"Nature structural & molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/35210614","citation_count":81,"is_preprint":false},{"pmid":"17387721","id":"PMC_17387721","title":"Molecular pathogenesis of seipin/BSCL2-related motor neuron diseases.","date":"2007","source":"Annals of neurology","url":"https://pubmed.ncbi.nlm.nih.gov/17387721","citation_count":80,"is_preprint":false},{"pmid":"21957196","id":"PMC_21957196","title":"Molecular characterization of seipin and its mutants: implications for seipin in triacylglycerol synthesis.","date":"2011","source":"Journal of lipid research","url":"https://pubmed.ncbi.nlm.nih.gov/21957196","citation_count":75,"is_preprint":false},{"pmid":"25737955","id":"PMC_25737955","title":"Seipin oligomers can interact directly with AGPAT2 and lipin 1, physically scaffolding critical regulators of adipogenesis.","date":"2015","source":"Molecular metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/25737955","citation_count":73,"is_preprint":false},{"pmid":"30049710","id":"PMC_30049710","title":"Seipin regulates lipid homeostasis by ensuring calcium-dependent mitochondrial metabolism.","date":"2018","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/30049710","citation_count":72,"is_preprint":false},{"pmid":"33315072","id":"PMC_33315072","title":"Nuclear lipid droplets form in the inner nuclear membrane in a seipin-independent manner.","date":"2021","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/33315072","citation_count":69,"is_preprint":false},{"pmid":"18585921","id":"PMC_18585921","title":"Characterization of seipin/BSCL2, a protein associated with spastic paraplegia 17.","date":"2008","source":"Neurobiology of disease","url":"https://pubmed.ncbi.nlm.nih.gov/18585921","citation_count":67,"is_preprint":false},{"pmid":"24024128","id":"PMC_24024128","title":"The human lipodystrophy protein seipin is an ER membrane adaptor for the adipogenic PA phosphatase lipin 1.","date":"2012","source":"Molecular metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/24024128","citation_count":66,"is_preprint":false},{"pmid":"24026679","id":"PMC_24026679","title":"BSCL2/seipin regulates adipogenesis through actin cytoskeleton remodelling.","date":"2013","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/24026679","citation_count":61,"is_preprint":false},{"pmid":"34625558","id":"PMC_34625558","title":"Mechanism of lipid droplet formation by the yeast Sei1/Ldb16 Seipin complex.","date":"2021","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/34625558","citation_count":61,"is_preprint":false},{"pmid":"29203558","id":"PMC_29203558","title":"SEIPIN Proteins Mediate Lipid Droplet Biogenesis to Promote Pollen Transmission and Reduce Seed Dormancy.","date":"2017","source":"Plant physiology","url":"https://pubmed.ncbi.nlm.nih.gov/29203558","citation_count":60,"is_preprint":false},{"pmid":"30901948","id":"PMC_30901948","title":"Promethin Is a Conserved Seipin Partner Protein.","date":"2019","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/30901948","citation_count":59,"is_preprint":false},{"pmid":"35021082","id":"PMC_35021082","title":"Seipin localizes at endoplasmic-reticulum-mitochondria contact sites to control mitochondrial calcium import and metabolism in adipocytes.","date":"2022","source":"Cell reports","url":"https://pubmed.ncbi.nlm.nih.gov/35021082","citation_count":57,"is_preprint":false},{"pmid":"23564749","id":"PMC_23564749","title":"A new seipin-associated neurodegenerative syndrome.","date":"2013","source":"Journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/23564749","citation_count":57,"is_preprint":false},{"pmid":"26637296","id":"PMC_26637296","title":"Dissecting seipin function: the localized accumulation of phosphatidic acid at ER/LD junctions in the absence of seipin is suppressed by Sei1p(ΔNterm) only in combination with Ldb16p.","date":"2015","source":"BMC cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/26637296","citation_count":55,"is_preprint":false},{"pmid":"31263173","id":"PMC_31263173","title":"Dietary fatty acids promote lipid droplet diversity through seipin enrichment in an ER subdomain.","date":"2019","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/31263173","citation_count":53,"is_preprint":false},{"pmid":"15181077","id":"PMC_15181077","title":"Mutations in Gng3lg and AGPAT2 in Berardinelli-Seip congenital lipodystrophy and Brunzell syndrome: phenotype variability suggests important modifier effects.","date":"2004","source":"The Journal of clinical endocrinology and metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/15181077","citation_count":50,"is_preprint":false},{"pmid":"35583926","id":"PMC_35583926","title":"Seipin transmembrane segments critically function in triglyceride nucleation and lipid droplet budding from the membrane.","date":"2022","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/35583926","citation_count":50,"is_preprint":false},{"pmid":"21750110","id":"PMC_21750110","title":"N88S seipin mutant transgenic mice develop features of seipinopathy/BSCL2-related motor neuron disease via endoplasmic reticulum stress.","date":"2011","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/21750110","citation_count":50,"is_preprint":false},{"pmid":"34244767","id":"PMC_34244767","title":"LDIP cooperates with SEIPIN and LDAP to facilitate lipid droplet biogenesis in Arabidopsis.","date":"2021","source":"The Plant cell","url":"https://pubmed.ncbi.nlm.nih.gov/34244767","citation_count":49,"is_preprint":false},{"pmid":"24651066","id":"PMC_24651066","title":"Lack of seipin in neurons results in anxiety- and depression-like behaviors via down regulation of PPARγ.","date":"2014","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/24651066","citation_count":46,"is_preprint":false},{"pmid":"32690719","id":"PMC_32690719","title":"SEIPIN Isoforms Interact with the Membrane-Tethering Protein VAP27-1 for Lipid Droplet Formation.","date":"2020","source":"The Plant cell","url":"https://pubmed.ncbi.nlm.nih.gov/32690719","citation_count":45,"is_preprint":false},{"pmid":"27287266","id":"PMC_27287266","title":"Neuronal seipin knockout facilitates Aβ-induced neuroinflammation and neurotoxicity via reduction of PPARγ in hippocampus of mouse.","date":"2016","source":"Journal of neuroinflammation","url":"https://pubmed.ncbi.nlm.nih.gov/27287266","citation_count":42,"is_preprint":false},{"pmid":"34215489","id":"PMC_34215489","title":"Seipin: harvesting fat and keeping adipocytes healthy.","date":"2021","source":"Trends in cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/34215489","citation_count":41,"is_preprint":false},{"pmid":"15126564","id":"PMC_15126564","title":"Gene and phenotype analysis of congenital generalized lipodystrophy in Japanese: a novel homozygous nonsense mutation in seipin gene.","date":"2004","source":"The Journal of clinical endocrinology and metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/15126564","citation_count":41,"is_preprint":false},{"pmid":"20097706","id":"PMC_20097706","title":"Higher adiponectin levels in patients with Berardinelli-Seip congenital lipodystrophy due to seipin as compared with 1-acylglycerol-3-phosphate-o-acyltransferase-2 deficiency.","date":"2010","source":"The Journal of clinical endocrinology and metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/20097706","citation_count":40,"is_preprint":false},{"pmid":"25934999","id":"PMC_25934999","title":"Seipin is necessary for normal brain development and spermatogenesis in addition to adipogenesis.","date":"2015","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/25934999","citation_count":39,"is_preprint":false},{"pmid":"26818512","id":"PMC_26818512","title":"Activation of PPARγ Ameliorates Spatial Cognitive Deficits through Restoring Expression of AMPA Receptors in Seipin Knock-Out Mice.","date":"2016","source":"The Journal of neuroscience : the official journal of the Society for Neuroscience","url":"https://pubmed.ncbi.nlm.nih.gov/26818512","citation_count":38,"is_preprint":false},{"pmid":"23458123","id":"PMC_23458123","title":"Seipin differentially regulates lipogenesis and adipogenesis through a conserved core sequence and an evolutionarily acquired C-terminus.","date":"2013","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/23458123","citation_count":37,"is_preprint":false},{"pmid":"19226263","id":"PMC_19226263","title":"Novel mutations of the BSCL2 and AGPAT2 genes in 10 families with Berardinelli-Seip congenital generalized lipodystrophy syndrome.","date":"2009","source":"Clinical endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/19226263","citation_count":36,"is_preprint":false},{"pmid":"23989774","id":"PMC_23989774","title":"Analysis of naturally occurring mutations in the human lipodystrophy protein seipin reveals multiple potential pathogenic mechanisms.","date":"2013","source":"Diabetologia","url":"https://pubmed.ncbi.nlm.nih.gov/23989774","citation_count":36,"is_preprint":false},{"pmid":"29459250","id":"PMC_29459250","title":"Adipose specific disruption of seipin causes early-onset generalised lipodystrophy and altered fuel utilisation without severe metabolic disease.","date":"2018","source":"Molecular metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/29459250","citation_count":35,"is_preprint":false},{"pmid":"25093462","id":"PMC_25093462","title":"Molecular mechanisms underlying fasting modulated liver insulin sensitivity and metabolism in male lipodystrophic Bscl2/Seipin-deficient mice.","date":"2014","source":"Endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/25093462","citation_count":33,"is_preprint":false},{"pmid":"22234369","id":"PMC_22234369","title":"Overexpression of a short human seipin/BSCL2 isoform in mouse adipose tissue results in mild lipodystrophy.","date":"2012","source":"American journal of physiology. Endocrinology and metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/22234369","citation_count":33,"is_preprint":false},{"pmid":"31185001","id":"PMC_31185001","title":"Targeting ATGL to rescue BSCL2 lipodystrophy and its associated cardiomyopathy.","date":"2019","source":"JCI insight","url":"https://pubmed.ncbi.nlm.nih.gov/31185001","citation_count":32,"is_preprint":false},{"pmid":"28767194","id":"PMC_28767194","title":"Echinacoside's nigrostriatal dopaminergic protection against 6-OHDA-Induced endoplasmic reticulum stress through reducing the accumulation of Seipin.","date":"2017","source":"Journal of cellular and molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/28767194","citation_count":32,"is_preprint":false},{"pmid":"14715872","id":"PMC_14715872","title":"Mutations in the seipin and AGPAT2 genes clustering in consanguineous families with Berardinelli-Seip congenital lipodystrophy from two separate geographical regions of Brazil.","date":"2004","source":"The Journal of clinical endocrinology and metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/14715872","citation_count":31,"is_preprint":false},{"pmid":"29670081","id":"PMC_29670081","title":"Seipin deficiency in mice causes loss of dopaminergic neurons via aggregation and phosphorylation of α-synuclein and neuroinflammation.","date":"2018","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/29670081","citation_count":29,"is_preprint":false},{"pmid":"35938957","id":"PMC_35938957","title":"Seipin concentrates distinct neutral lipids via interactions with their acyl chain carboxyl esters.","date":"2022","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/35938957","citation_count":29,"is_preprint":false},{"pmid":"34323918","id":"PMC_34323918","title":"Retinyl esters form lipid droplets independently of triacylglycerol and seipin.","date":"2021","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/34323918","citation_count":28,"is_preprint":false},{"pmid":"19041432","id":"PMC_19041432","title":"Severe cardiac phenotype of Berardinelli-Seip congenital lipodystrophy in an infant with homozygous E189X BSCL2 mutation.","date":"2008","source":"European journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/19041432","citation_count":28,"is_preprint":false},{"pmid":"17486577","id":"PMC_17486577","title":"Identification of de novo BSCL2 Ser90Leu mutation in a Korean family with Silver syndrome and distal hereditary motor neuropathy.","date":"2007","source":"Muscle & nerve","url":"https://pubmed.ncbi.nlm.nih.gov/17486577","citation_count":26,"is_preprint":false},{"pmid":"31594806","id":"PMC_31594806","title":"Seipin negatively regulates sphingolipid production at the ER-LD contact site.","date":"2019","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/31594806","citation_count":26,"is_preprint":false},{"pmid":"32820022","id":"PMC_32820022","title":"Loss of the seipin gene perturbs eggshell formation in Caenorhabditiselegans.","date":"2020","source":"Development (Cambridge, England)","url":"https://pubmed.ncbi.nlm.nih.gov/32820022","citation_count":25,"is_preprint":false},{"pmid":"9790771","id":"PMC_9790771","title":"Structure and mapping of the G protein gamma3 subunit gene and a divergently transcribed novel gene, gng3lg.","date":"1998","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/9790771","citation_count":25,"is_preprint":false},{"pmid":"26690553","id":"PMC_26690553","title":"Diet rich in Docosahexaenoic Acid/Eicosapentaenoic Acid robustly ameliorates hepatic steatosis and insulin resistance in seipin deficient lipodystrophy mice.","date":"2015","source":"Nutrition & metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/26690553","citation_count":25,"is_preprint":false},{"pmid":"23831461","id":"PMC_23831461","title":"Function of seipin: new insights from Bscl2/seipin knockout mouse models.","date":"2013","source":"Biochimie","url":"https://pubmed.ncbi.nlm.nih.gov/23831461","citation_count":24,"is_preprint":false},{"pmid":"26181198","id":"PMC_26181198","title":"Seipin deficiency increases chromocenter fragmentation and disrupts acrosome formation leading to male infertility.","date":"2015","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/26181198","citation_count":24,"is_preprint":false},{"pmid":"26975546","id":"PMC_26975546","title":"Impaired adipogenic capacity in induced pluripotent stem cells from lipodystrophic patients with BSCL2 mutations.","date":"2016","source":"Metabolism: clinical and experimental","url":"https://pubmed.ncbi.nlm.nih.gov/26975546","citation_count":23,"is_preprint":false},{"pmid":"32094408","id":"PMC_32094408","title":"Oligomers of the lipodystrophy protein seipin may co-ordinate GPAT3 and AGPAT2 enzymes to facilitate adipocyte differentiation.","date":"2020","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/32094408","citation_count":23,"is_preprint":false},{"pmid":"22045697","id":"PMC_22045697","title":"Characterization of inclusion bodies with cytoprotective properties formed by seipinopathy-linked mutant seipin.","date":"2011","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/22045697","citation_count":23,"is_preprint":false},{"pmid":"27838812","id":"PMC_27838812","title":"Hepatic BSCL2 (Seipin) Deficiency Disrupts Lipid Droplet Homeostasis and Increases Lipid Metabolism via SCD1 Activity.","date":"2016","source":"Lipids","url":"https://pubmed.ncbi.nlm.nih.gov/27838812","citation_count":22,"is_preprint":false},{"pmid":"25195639","id":"PMC_25195639","title":"Towards a mechanistic understanding of lipodystrophy and seipin functions.","date":"2014","source":"Bioscience reports","url":"https://pubmed.ncbi.nlm.nih.gov/25195639","citation_count":22,"is_preprint":false},{"pmid":"32402516","id":"PMC_32402516","title":"New friends for seipin - Implications of seipin partner proteins in the life cycle of lipid droplets.","date":"2020","source":"Seminars in cell & developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/32402516","citation_count":22,"is_preprint":false},{"pmid":"23142943","id":"PMC_23142943","title":"Clinical and histopathological study of Charcot-Marie-Tooth neuropathy with a novel S90W mutation in BSCL2.","date":"2012","source":"Neurogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/23142943","citation_count":22,"is_preprint":false},{"pmid":"30457912","id":"PMC_30457912","title":"Adipose tissue transplantation ameliorates lipodystrophy-associated metabolic disorders in seipin-deficient mice.","date":"2018","source":"American journal of physiology. Endocrinology and metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/30457912","citation_count":22,"is_preprint":false},{"pmid":"16435205","id":"PMC_16435205","title":"Phenotypic heterogeneity in biochemical parameters correlates with mutations in AGPAT2 or Seipin genes among Berardinelli-Seip congenital lipodystrophy patients.","date":"2005","source":"Journal of inherited metabolic disease","url":"https://pubmed.ncbi.nlm.nih.gov/16435205","citation_count":22,"is_preprint":false},{"pmid":"23173741","id":"PMC_23173741","title":"Seipin regulates excitatory synaptic transmission in cortical neurons.","date":"2012","source":"Journal of neurochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/23173741","citation_count":22,"is_preprint":false},{"pmid":"29738274","id":"PMC_29738274","title":"Renal injury in Seipin-deficient lipodystrophic mice and its reversal by adipose tissue transplantation or leptin administration alone: adipose tissue-kidney crosstalk.","date":"2018","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/29738274","citation_count":21,"is_preprint":false},{"pmid":"25757906","id":"PMC_25757906","title":"Expression of seipin in adipose tissue rescues lipodystrophy, hepatic steatosis and insulin resistance in seipin null mice.","date":"2015","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/25757906","citation_count":21,"is_preprint":false},{"pmid":"23049863","id":"PMC_23049863","title":"Neuroanatomical characterisation of the expression of the lipodystrophy and motor-neuropathy gene Bscl2 in adult mouse brain.","date":"2012","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23049863","citation_count":21,"is_preprint":false},{"pmid":"29428127","id":"PMC_29428127","title":"Dyslipidemia, steatohepatitis and atherogenesis in lipodystrophic apoE deficient mice with Seipin deletion.","date":"2018","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/29428127","citation_count":20,"is_preprint":false},{"pmid":"27554469","id":"PMC_27554469","title":"FGF21 Improves the Adipocyte Dysfunction Related to Seipin Deficiency.","date":"2016","source":"Diabetes","url":"https://pubmed.ncbi.nlm.nih.gov/27554469","citation_count":20,"is_preprint":false},{"pmid":"30910747","id":"PMC_30910747","title":"Seipin deletion in mice enhances phosphorylation and aggregation of tau protein through reduced neuronal PPARγ and insulin resistance.","date":"2019","source":"Neurobiology of disease","url":"https://pubmed.ncbi.nlm.nih.gov/30910747","citation_count":20,"is_preprint":false},{"pmid":"26398946","id":"PMC_26398946","title":"Seipin knockout in mice impairs stem cell proliferation and progenitor cell differentiation in the adult hippocampal dentate gyrus via reduced levels of PPARγ.","date":"2015","source":"Disease models & mechanisms","url":"https://pubmed.ncbi.nlm.nih.gov/26398946","citation_count":20,"is_preprint":false},{"pmid":"35306312","id":"PMC_35306312","title":"Seipin collaborates with the ER membrane to control the sites of lipid droplet formation.","date":"2022","source":"Current opinion in cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/35306312","citation_count":20,"is_preprint":false},{"pmid":"35740965","id":"PMC_35740965","title":"Role of Seipin in Human Diseases and Experimental Animal Models.","date":"2022","source":"Biomolecules","url":"https://pubmed.ncbi.nlm.nih.gov/35740965","citation_count":19,"is_preprint":false},{"pmid":"33147895","id":"PMC_33147895","title":"SEIPIN: A Key Factor for Nuclear Lipid Droplet Generation and Lipid Homeostasis.","date":"2020","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/33147895","citation_count":19,"is_preprint":false},{"pmid":"23659685","id":"PMC_23659685","title":"Deletion mutation in BSCL2 gene underlies congenital generalized lipodystrophy in a Pakistani family.","date":"2013","source":"Diagnostic pathology","url":"https://pubmed.ncbi.nlm.nih.gov/23659685","citation_count":19,"is_preprint":false},{"pmid":"26815532","id":"PMC_26815532","title":"Clinical and Molecular Characterization of BSCL2 Mutations in a Taiwanese Cohort with Hereditary Neuropathy.","date":"2016","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/26815532","citation_count":19,"is_preprint":false},{"pmid":"32705147","id":"PMC_32705147","title":"miR‑187‑3p inhibitor attenuates cerebral ischemia/reperfusion injury by regulating Seipin‑mediated autophagic flux.","date":"2020","source":"International journal of molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/32705147","citation_count":19,"is_preprint":false},{"pmid":"27185876","id":"PMC_27185876","title":"Berardinelli-Seip Congenital Lipodystrophy 2/Seipin Is Not Required for Brown Adipogenesis but Regulates Brown Adipose Tissue Development and Function.","date":"2016","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/27185876","citation_count":19,"is_preprint":false},{"pmid":"24358199","id":"PMC_24358199","title":"Altered lipid metabolism in residual white adipose tissues of Bscl2 deficient mice.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/24358199","citation_count":18,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":48714,"output_tokens":9335,"usd":0.143084},"stage2":{"model":"claude-opus-4-6","input_tokens":13306,"output_tokens":3688,"usd":0.238095},"total_usd":0.381179,"stage1_batch_id":"msgbatch_01TqNM6p6FsoMBT2jzQTwKBr","stage2_batch_id":"msgbatch_01Ya473eco8sTHbvRymQaU8o","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2007,\n      \"finding\": \"Seipin localizes to the endoplasmic reticulum and concentrates at ER-lipid droplet junctions; its absence in yeast results in irregular and clustered lipid droplets with proliferated ER, and human seipin can functionally replace yeast seipin (but lipodystrophy-causing missense mutations cannot), establishing seipin's role in lipid droplet morphology and maintenance.\",\n      \"method\": \"Yeast genetic screen, fluorescence microscopy of seipin-GFP, complementation assay with human seipin, fibroblast analysis from BSCL2 patient\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (genetic screen, live imaging, cross-species complementation) in highly-cited foundational paper\",\n      \"pmids\": [\"18093937\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Seipin is an integral ER membrane protein with an N-cytoplasm/C-cytoplasm topology and a long luminal loop between two transmembrane helices; this topology was established by in vitro topology mapping assay.\",\n      \"method\": \"In vitro topology mapping assay\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct biochemical topology mapping in vitro\",\n      \"pmids\": [\"16574104\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Heterozygous N88S and S90L missense mutations in BSCL2 disrupt N-glycosylation of seipin and cause aggregate formation in the ER, linking aberrant glycosylation and protein aggregation to dominantly inherited motor neuropathy (dHMN/Silver syndrome).\",\n      \"method\": \"Direct sequencing, expression of mutant constructs in cells, glycosylation assay, immunofluorescence detection of aggregates\",\n      \"journal\": \"Nature genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — mutation identification linked to biochemical mechanism (glycosylation disruption + aggregation), replicated in multiple families\",\n      \"pmids\": [\"14981520\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Seipin is essential for adipocyte differentiation in a cell-autonomous manner; its knockdown in mesenchymal stem cells impairs sustained expression of PPARγ and C/EBPα and persistently reduces expression of triglyceride synthesis genes (AGPAT2, lipin 1, DGAT2), blocking lipid accumulation. A pathogenic missense mutant (A212P) shows aberrant subcellular targeting.\",\n      \"method\": \"shRNA knockdown in C3H10T1/2 cells, qRT-PCR, immunofluorescence of mutant localization\",\n      \"journal\": \"Diabetes\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KD with defined adipogenic phenotype and molecular pathway placement, multiple readouts\",\n      \"pmids\": [\"18458148\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Yeast seipin (Fld1p/YLR404W) regulates lipid droplet size; its deletion causes supersized LDs with enhanced fusion activity both in vivo and in vitro, and lipid profiling reveals altered acyl chain compositions of major phospholipids in fld1Δ cells. Human seipin rescues these defects.\",\n      \"method\": \"Yeast genetic screen (~4700 mutants), fluorescence microscopy, in vitro and in vivo LD fusion assay, lipidomics, cross-species complementation\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods in highly-cited paper; complementation establishes functional conservation\",\n      \"pmids\": [\"18250201\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Seipin forms a discrete homo-oligomeric complex of ~9 copies (~500 kDa) in the ER and appears as a toroid by negative-stain EM; the A212P lipodystrophy allele forms only smaller, unstable complexes, suggesting oligomer integrity is required for function.\",\n      \"method\": \"Affinity purification, detergent sucrose gradients (H2O and D2O), gel filtration, negative-stain electron microscopy\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — purification and physical characterization with multiple hydrodynamic methods plus EM\",\n      \"pmids\": [\"21062080\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"N88S and S90L mutant seipin is polyubiquitinated, degraded via ER-associated degradation (ERAD), stably binds the ER chaperone calnexin (indicating unfolded protein accumulation), and triggers ER stress-mediated apoptosis in neuronal cells, establishing that seipinopathies are conformational diseases linked to ER stress.\",\n      \"method\": \"Co-immunoprecipitation (seipin–calnexin), ubiquitination assay, proteasome inhibitor treatment, ER stress marker measurements, apoptosis assay\",\n      \"journal\": \"Annals of neurology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP plus multiple orthogonal biochemical readouts in neuronal cells\",\n      \"pmids\": [\"17387721\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Absence of Bscl2 in mouse embryonic fibroblasts and stromal vascular cells causes normal early adipocyte differentiation but failure of terminal differentiation due to unrestrained cAMP/PKA-activated lipolysis, leading to loss of lipid droplets and silencing of adipose-specific transcription factors; this defect is rescued by lipolysis inhibitors but not by PPARγ agonist alone.\",\n      \"method\": \"Bscl2−/− mouse model, in vitro MEF/SVC differentiation, lipolysis inhibitor rescue experiments, gene expression analysis\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with defined cellular phenotype, pathway placement via pharmacological rescue\",\n      \"pmids\": [\"22269949\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Seipin acts as an ER membrane adaptor that inducibly binds the phosphatidic acid (PA) phosphatase lipin 1 during adipogenesis; seipin knockdown decreases lipin 1 membrane association and increases PA accumulation, while wild-type but not a lipin-1-binding-deficient mutant of seipin reduces PA levels in differentiating cells.\",\n      \"method\": \"Co-immunoprecipitation, PA measurement, lipin 1 membrane fractionation, seipin overexpression/mutant expression in differentiating adipocytes\",\n      \"journal\": \"Molecular metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP plus functional rescue with point mutant, multiple methods\",\n      \"pmids\": [\"24024128\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Seipin dodecamers can directly and simultaneously bind both AGPAT2 and lipin 1, physically scaffolding these two consecutive enzymes of the PA biosynthetic/catabolic pathway; atomic force microscopy demonstrates direct protein–protein association and defines the molecular architecture of the complex.\",\n      \"method\": \"Co-immunoprecipitation, atomic force microscopy (direct binding), immunofluorescence\",\n      \"journal\": \"Molecular metabolism\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1/2 — direct binding demonstrated by AFM plus Co-IP; complex architecture resolved\",\n      \"pmids\": [\"25737955\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Seipin interacts with 14-3-3β through its N- and C-termini; 14-3-3β recruits cofilin-1 to remodel actin cytoskeleton from stress fibers to cortical structures during adipogenesis, and knockdown of cofilin-1, 14-3-3β, or seipin impairs adipocyte development with retention of stress fibers.\",\n      \"method\": \"Co-immunoprecipitation, fluorescence microscopy of actin structures, shRNA knockdown in 3T3-L1 cells, severing-resistant actin mutant expression\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP plus functional KD phenotype, single lab\",\n      \"pmids\": [\"24026679\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Seipin physically interacts with microsomal glycerol-3-phosphate acyltransferase (GPAT) isoforms; SEIPIN-deficient cells and tissues show elevated GPAT activity and altered GPAT kinetics, and GPAT overexpression phenocopies seipin loss (supersized LDs, blocked adipogenesis) while GPAT3 knockdown partially rescues adipogenesis in seipin-deficient preadipocytes.\",\n      \"method\": \"Co-immunoprecipitation, GPAT activity assay (kinetics), genetic overexpression/knockdown across yeast/fly/mammalian systems, pharmacological GPAT inhibition in Seipin−/− preadipocytes\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1/2 — enzymatic activity measurement + interaction + multi-organism epistasis, strong converging evidence\",\n      \"pmids\": [\"27806294\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Seipin is stably associated with nascent ER-LD contacts (typically one focal point per LD) in human cells; seipin knockout or patient (BSCL2) cells completely lack or have aberrant ER-LD contacts, leading to increased LD mobility, impaired protein delivery from ER to LDs, and defective fatty acid incorporation into neutral lipids in cells with pre-existing LDs.\",\n      \"method\": \"Live-cell fluorescence microscopy, electron tomography, seipin KO and patient cell lines, LD mobility tracking, lipid/protein cargo delivery assays\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal imaging and biochemical methods, patient cells confirm findings\",\n      \"pmids\": [\"27879284\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Cryo-EM structure of human SEIPIN at 3.8 Å reveals an undecameric ring; the lumenal domain forms an eight-stranded β-sandwich fold. Both full-length SEIPIN and its lumenal domain bind anionic phospholipids including phosphatidic acid, suggesting seipin maintains phospholipid homeostasis and ER surface tension.\",\n      \"method\": \"Cryo-electron microscopy (3.8 Å structure), lipid-binding assay (phospholipid binding to full-length and lumenal domain)\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — near-atomic cryo-EM structure with biochemical validation of lipid binding\",\n      \"pmids\": [\"30293840\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Cryo-EM structure of Drosophila seipin reveals a ring-shaped dodecamer; each monomer has a hydrophobic helix (HH) positioned toward the ER bilayer and a β-sandwich domain with structural similarity to lipid-binding proteins. Functional testing in cells supports a model in which seipin HHs detect forming LDs and then act as membrane anchors enabling lipid transfer and LD growth.\",\n      \"method\": \"Cryo-electron microscopy (~4.0 Å), cell-based functional assays of HH mutants\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — near-atomic cryo-EM structure plus functional mutagenesis in cells\",\n      \"pmids\": [\"30327422\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"LDAF1 (TMEM159) is a direct interaction partner of seipin; together they form an ~600 kDa oligomeric complex that co-purifies with triacylglycerol. LDs form at LDAF1-seipin complexes, and relocalization of LDAF1 to the plasma membrane co-recruits seipin and redirects LD formation. After LD formation, LDAF1 dissociates from seipin and moves to the LD surface. Without LDAF1, LDs only form at significantly higher TG concentrations.\",\n      \"method\": \"Co-immunoprecipitation, mass spectrometry, TG co-purification, live-cell imaging of LDAF1/seipin relocalization, TG concentration assays\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1/2 — Co-purification with TG, reciprocal Co-IP, live-cell functional relocalization, multiple orthogonal methods\",\n      \"pmids\": [\"31708432\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Seipin mediates uniform ER-LD neck contacts that facilitate triglyceride flow from the ER to LDs; without seipin, LDs become heterogeneous in size via a biophysical ripening (Ostwald ripening) process where TG partitions from smaller to larger LDs through droplet-bilayer contacts. Relocalizing seipin to the nuclear envelope redirects LD formation to seipin-defined sites.\",\n      \"method\": \"Seipin relocalization to nuclear envelope, acute seipin removal (auxin-inducible degron), live-cell imaging, electron tomography, model membrane experiments, coarse-grained simulations\",\n      \"journal\": \"Developmental cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1/2 — multiple orthogonal approaches including reconstitution in model membranes and acute protein removal\",\n      \"pmids\": [\"31178403\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Molecular dynamics simulations show that seipin clusters triacylglycerol and diacylglycerol inside its ring-like oligomeric structure via interactions involving both luminal and transmembrane regions; polar residues responsible for TG interactions are identified, and mutations of these to hydrophobic residues abolish TG clustering.\",\n      \"method\": \"Molecular dynamics simulations (coarse-grained and all-atom), mutagenesis of polar residues\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 (simulation + mutagenesis) but single study; computational approach\",\n      \"pmids\": [\"33674387\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Cryo-EM structure of S. cerevisiae seipin reveals a decameric cage; lumenal domains form a stable ring and transmembrane segments form cage sides/top with two alternating conformations regulated by switch regions. Switch region mutations abolish seipin function. A model is proposed in which the closed cage enables TG phase separation and an open conformation allows LD budding.\",\n      \"method\": \"Cryo-electron microscopy plus structural modeling, functional mutagenesis of switch regions in cells\",\n      \"journal\": \"Nature structural & molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — high-resolution cryo-EM structure with functional mutagenesis validation\",\n      \"pmids\": [\"35210614\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"All-atom MD simulations show that seipin TM segment residues and hydrophobic helix residues (in the phospholipid tail region) attract TG, and coarse-grained models show TM segments form a constricted neck to facilitate conversion of a flat oil lens into a budding LD. Conserved positively charged residues at TM segment ends affect LD maturation in cell experiments.\",\n      \"method\": \"Molecular dynamics simulations (all-atom and coarse-grained), cell-based experiments with TM charge mutants\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1/2 — simulation plus cell-based mutagenesis, single study\",\n      \"pmids\": [\"35583926\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Structural and biochemical analysis of yeast Sei1/Ldb16 complex shows that Sei1 luminal domain assembles a homooligomeric ring but cannot itself concentrate TG; instead, Sei1 positions Ldb16, which concentrates TG within the Sei1 ring via critical hydroxyl residues. Sei1 TM segments also promote TG recruitment and control Ldb16 stability.\",\n      \"method\": \"Cryo-EM structure, biochemical assays, molecular dynamics simulations, mutagenesis of Ldb16 hydroxyl residues\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — cryo-EM structure plus reconstituted biochemical assays plus mutagenesis, multiple orthogonal methods\",\n      \"pmids\": [\"34625558\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Yeast Seipin (Sei1/Ldb16) promotes storage of diverse neutral lipids (TAG, steryl esters, retinyl esters) in LDs; human seipin restores normal SE-containing LDs in yeast seipin mutants. The mechanism involves interactions between hydroxyl residues in human seipin or yeast Ldb16 with neutral lipid carboxyl esters.\",\n      \"method\": \"Yeast genetics, complementation with human seipin, mutagenesis of hydroxyl residues, neutral lipid profiling\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1/2 — mutagenesis plus cross-species complementation plus lipidomics\",\n      \"pmids\": [\"35938957\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"In Drosophila, Seipin promotes ER calcium homeostasis through SERCA; loss of dSeipin impairs mitochondrial TCA cycle activity and reduces citrate levels (required for lipogenesis) by reducing mitochondrial calcium import. Lipid storage defects in dSeipin mutant fat cells can be rescued by restoring mitochondrial calcium or citrate.\",\n      \"method\": \"Drosophila genetics, metabolomics, calcium measurement, genetic rescue with citrate supplementation\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis in Drosophila with metabolic rescue, multiple orthogonal methods\",\n      \"pmids\": [\"30049710\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"A subset of seipin localizes to ER-mitochondria contact sites (MAMs) in human and mouse adipocytes, in the vicinity of calcium regulators SERCA2, IP3R, and VDAC; acute seipin removal leads to defective mitochondrial calcium import, widespread reduction in Krebs cycle metabolites, and decreased ATP levels without altering ER calcium stores.\",\n      \"method\": \"Proximity ligation assay, subcellular fractionation, live-cell calcium imaging, metabolomics, acute seipin deletion (inducible), proximity to MAM calcium regulators\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods; localization linked to functional consequence of acute protein removal\",\n      \"pmids\": [\"35021082\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"In yeast, absence of seipin leads to localized accumulation of phosphatidic acid (PA puncta) at ER-LD junctions detected by three independent probes; this PA accumulation requires the first 14 amino acids (N-terminus) of Sei1p, and suppression of PA puncta requires functional cooperation between Sei1p N-terminus and Ldb16p.\",\n      \"method\": \"Yeast genetics, multiple PA probes (Opi1p, Spo20p, Pah1p), deletion/complementation analysis\",\n      \"journal\": \"BMC cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — three independent probes confirm PA accumulation; domain mapping via deletion mutants; single lab\",\n      \"pmids\": [\"26637296\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Yeast seipin negatively regulates sphingolipid production by associating with serine palmitoyltransferase (SPT) and fatty acid elongase at ER-LD contacts; cells lacking seipin show elevated SPT and FA elongase activities and accumulate sphingoid precursors/intermediates. Human seipin rescues altered sphingolipid levels in yeast seipin mutants.\",\n      \"method\": \"Co-immunoprecipitation of seipin with SPT and FA elongase, sphingolipid enzyme activity assays, lipidomics, yeast genetics, cross-species complementation\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP plus enzyme activity assays plus complementation; single lab\",\n      \"pmids\": [\"31594806\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"In yeast, seipin cooperates with the membrane-shaping protein Pex30 to facilitate organelle budding (both lipid droplets and peroxisomes) from the ER; absence of both leads to ER accumulation of TG and peroxisomal membrane proteins without affecting COPII vesicle formation, and this can be reversed by remodeling ER phospholipid composition.\",\n      \"method\": \"Yeast genetics (double deletion), electron microscopy, lipid composition analysis, organelle fractionation\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis with multiple organelle readouts plus phospholipid rescue\",\n      \"pmids\": [\"30054465\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Drosophila dSeipin loss causes ectopic lipid droplet accumulation in a tissue-autonomous manner in the salivary gland; dSeipin mutants show synergistic genetic interactions with lipogenic genes, and the phenotype is consistent with seipin participating in phosphatidic acid metabolism to down-regulate lipogenesis.\",\n      \"method\": \"Drosophila genetics, tissue-specific rescue, genetic epistasis with lipogenic genes, lipid droplet imaging\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — tissue-autonomous rescue plus genetic epistasis; mechanistic link to PA metabolism is genetic inference\",\n      \"pmids\": [\"21533227\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Seipin functions as a scaffolding protein in the ER; deletion of FLD1 (yeast seipin) leads to impaired lipid droplet dynamics and defective lipolysis associated with aberrant ER structures, consistent with seipin organizing a specific ER subdomain.\",\n      \"method\": \"4D live-cell imaging, transmission electron microscopy, electron tomography, quantitative microscopy in S. cerevisiae\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple imaging modalities; functional consequence of seipin loss established, but scaffolding role is inferential\",\n      \"pmids\": [\"22100922\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Wild-type human seipin forms dodecamers (12 subunits in a circular configuration) as shown by atomic force microscopy; the L91P and A212P lipodystrophy mutants fail to form this 12-mer structure, and several mutants (R275X, frameshift) fail to bind lipin 1 appropriately.\",\n      \"method\": \"Atomic force microscopy, co-immunoprecipitation (seipin–lipin 1 interaction), expression analysis of mutant constructs\",\n      \"journal\": \"Diabetologia\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1/2 — AFM resolution of oligomeric stoichiometry plus functional interaction studies, comprehensive mutant panel\",\n      \"pmids\": [\"23989774\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"The transmembrane domains of seipin are critical for its ER retention, ubiquitination, formation of inclusion bodies, and activation of the unfolded protein response (UPR); seipin is expressed in neurons of the spinal cord and frontal cortex.\",\n      \"method\": \"Deletion/domain mutagenesis of seipin constructs, ubiquitination assay, UPR marker measurements, immunohistochemistry\",\n      \"journal\": \"Neurobiology of disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — domain mutagenesis with multiple functional readouts; single lab\",\n      \"pmids\": [\"18585921\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Seipin knockdown in mammalian cells increases oleate incorporation into TAG and steady-state TAG levels, and induces proliferation and clustering of small LDs; overexpression reduces TAG synthesis and LD formation. The N88S/S90L neuropathy mutants dominantly cause small LD clustering by trapping wild-type seipin in inclusions; seipin can interact with itself and its mutant forms.\",\n      \"method\": \"shRNA knockdown, seipin overexpression, lipid incorporation assay (oleate-TAG), co-immunoprecipitation (seipin self-interaction), fluorescence microscopy\",\n      \"journal\": \"Journal of lipid research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple biochemical and imaging methods; self-interaction by Co-IP; single lab\",\n      \"pmids\": [\"21957196\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Seipin deficiency in lymphoblastoid cells from BSCL patients (null BSCL2 mutations) alters lipid droplet morphology (decreased size, increased number) and causes a defect in fatty acid Δ9-desaturation, with increased saturated fatty acids in TG and phosphatidylethanolamine, suggesting seipin acts at a proximal step linking Δ9-desaturase activity to lipid droplet formation.\",\n      \"method\": \"Lipid profiling of patient lymphoblastoid cells, fatty acid composition analysis by GC, fluorescence microscopy of LDs\",\n      \"journal\": \"Biochimie\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — patient cell phenotype with lipidomics; no direct enzyme interaction demonstrated\",\n      \"pmids\": [\"19278620\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Seipin regulates excitatory synaptic transmission in cortical neurons via a post-synaptic mechanism; seipin knockdown reduces AMPA receptor surface levels and AMPA-induced currents without altering inhibitory post-synaptic currents or pre-synaptic ultrastructure. These defects are rescued by expression of shRNA-resistant human seipin.\",\n      \"method\": \"shRNA knockdown in cultured neurons, whole-cell patch-clamp electrophysiology, AMPA/IPSC recording, surface AMPA receptor immunostaining and biochemistry\",\n      \"journal\": \"Journal of neurochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — electrophysiology plus surface receptor biochemistry plus rescue; single lab\",\n      \"pmids\": [\"23173741\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Neuronal seipin deficiency causes selective reduction of AMPA receptor expression in hippocampal CA1 pyramidal neurons via decreased ERK-CREB phosphorylation and reduced PPARγ, leading to impaired LTP and spatial memory deficits; PPARγ agonist rosiglitazone rescues AMPAR expression and LTP through ERK-CREB pathway.\",\n      \"method\": \"Neuronal seipin-knockout mice, Morris water maze, LTP recording (hippocampal slices), whole-cell patch-clamp, AMPAR immunostaining, MEK inhibitor experiments\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with electrophysiology plus pharmacological pathway dissection; single lab\",\n      \"pmids\": [\"26818512\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"BSCL2 deletion specifically in brown adipocyte progenitors in mice causes unrestrained cAMP/PKA-mediated lipolysis and premature metabolic activation of differentiating brown adipocytes, ultimately resulting in BAT atrophy via apoptosis; BSCL2 is not required for the core brown adipogenic transcriptional program.\",\n      \"method\": \"Brown adipocyte-specific Bscl2 knockout mice, BAT morphology/function analysis, cAMP/PKA pathway measurement, apoptosis assays, gene expression profiling\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — tissue-specific genetic KO with defined mechanistic pathway (cAMP/PKA); multiple readouts\",\n      \"pmids\": [\"27185876\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Bscl2−/− hearts exhibit increased ATGL protein stability and expression, causing drastic reduction of glycerolipids and excessive fatty acid oxidation; pharmacological or genetic inhibition of ATGL rescues adipocyte differentiation and lipodystrophy in Bscl2−/− cells and mice, placing BSCL2 upstream of ATGL in regulating adipocyte lipid storage.\",\n      \"method\": \"Bscl2−/− mouse model, ATGL inhibitor/genetic deletion rescue, lipidomics, cardiac function measurement, hyperinsulinemic-euglycemic clamp\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis (ATGL deletion rescues seipin KO phenotype) plus mechanistic pathway\",\n      \"pmids\": [\"31185001\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"BSCL2/Seipin knockdown in hepatocytes increases LD number and size and induces SCD1 expression and activity; SCD1 knockdown reverses the LD phenotype associated with Seipin deficiency, placing SCD1 downstream of Seipin in regulating hepatic LD homeostasis.\",\n      \"method\": \"siRNA knockdown in primary and cultured hepatocytes, LD imaging, SCD1 activity assay, double knockdown epistasis\",\n      \"journal\": \"Lipids\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — epistasis via double KD plus enzyme activity assay; single lab\",\n      \"pmids\": [\"27838812\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"SEIPIN interacts with ADRP (adipose differentiation-related protein/perilipin 2) as shown by co-immunoprecipitation; seipin defines ADRP's punctate cytoplasmic localization, and restoration of BSCL2 in patient-derived iPSCs rescues both lipid droplet formation and cytoplasmic punctate ADRP localization.\",\n      \"method\": \"Co-immunoprecipitation, iPSC differentiation model from BSCL2-null patients, rescue with wild-type BSCL2, fluorescence microscopy\",\n      \"journal\": \"Metabolism: clinical and experimental\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single Co-IP plus iPSC rescue; functional consequence tied to localization\",\n      \"pmids\": [\"26975546\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Seipin and GPAT3 associate via direct protein-protein interaction; seipin can simultaneously bind GPAT3 and AGPAT2 in the same complex; loss of GPAT3 in seipin-deficient preadipocytes exacerbates adipogenic failure, indicating GPAT3 has a modest positive role in adipogenesis within the seipin-regulated pathway.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, adipocyte differentiation assays\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2/3 — Co-IP plus functional epistasis; single lab\",\n      \"pmids\": [\"32094408\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Promethin (TMEM159/LDAF1) is a seipin partner protein that forms a complex with seipin; promethin localizes to LD surfaces, and its LD targeting is modulated by seipin expression levels.\",\n      \"method\": \"Co-immunoprecipitation, fluorescence microscopy, modulation of seipin expression levels\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — Co-IP plus localization; functional consequences partially characterized\",\n      \"pmids\": [\"30901948\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"Seipin (BSCL2) is an oligomeric ER integral membrane protein (forming rings/cages of 9–12 subunits) that concentrates at ER-LD junctions, where it clusters neutral lipids (triacylglycerol and diacylglycerol) via its lumenal β-sandwich domain and transmembrane segments to nucleate LD biogenesis, stabilizes ER-LD neck contacts to facilitate lipid and protein cargo delivery from the ER to growing LDs, scaffolds key lipid metabolism enzymes (AGPAT2, lipin 1, GPAT3) during adipogenesis, and restrains cAMP/PKA-mediated lipolysis to permit terminal adipocyte differentiation; additionally, a subset of seipin localizes to ER-mitochondria contact sites where it supports mitochondrial calcium import and TCA cycle metabolism, and dominant N-glycosylation-site mutations (N88S, S90L) cause ER stress and motor neuropathy via protein misfolding and calnexin sequestration.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"Seipin (BSCL2) is an ER-resident integral membrane protein that oligomerizes into ring-shaped assemblies of 9–12 subunits at ER–lipid droplet junctions, where it nucleates lipid droplet (LD) biogenesis by concentrating triacylglycerol and other neutral lipids within its lumenal β-sandwich domain and transmembrane cage, thereby defining LD formation sites, stabilizing ER–LD neck contacts, and preventing aberrant LD ripening [PMID:18093937, PMID:30293840, PMID:35938957, PMID:31178403]. Seipin scaffolds consecutive glycerolipid biosynthetic enzymes—AGPAT2, lipin 1, and GPAT3—at the ER membrane during adipogenesis, and restrains cAMP/PKA-mediated lipolysis and ATGL-dependent lipid mobilization, thereby enabling terminal adipocyte differentiation; loss-of-function mutations cause Berardinelli–Seip congenital generalized lipodystrophy type 2 [PMID:24026679, PMID:25737955, PMID:27806294, PMID:22269949, PMID:31185001]. A subset of seipin localizes to ER–mitochondria contact sites where it facilitates mitochondrial calcium import required for TCA cycle flux and lipogenesis [PMID:30049710, PMID:35021082]. Dominant N-glycosylation-disrupting mutations (N88S, S90L) cause seipin misfolding, ER stress via calnexin sequestration, and motor neuropathy (dHMN-V/Silver syndrome) [PMID:14981520, PMID:17387721].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"The discovery that heterozygous N88S/S90L mutations disrupt seipin N-glycosylation and cause ER aggregation established that BSCL2 mutations can act dominantly through a protein misfolding mechanism, linking seipin to hereditary motor neuropathy.\",\n      \"evidence\": \"Mutation identification in multiple families, glycosylation assays, and aggregate detection in transfected cells\",\n      \"pmids\": [\"14981520\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which aggregates specifically damage motor neurons unknown\", \"Whether aggregation triggers neurodegeneration via gain-of-function toxicity versus loss of seipin function unresolved\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Topology mapping established seipin as a two-pass ER transmembrane protein with a large lumenal loop and cytoplasmic N- and C-termini, defining the structural framework for subsequent functional studies.\",\n      \"evidence\": \"In vitro topology mapping assay\",\n      \"pmids\": [\"16574104\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the lumenal domain not yet resolved\", \"Post-translational modifications beyond N-glycosylation uncharacterized\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Two studies established that seipin concentrates at ER–LD junctions and that its absence causes aberrant LD morphology, while neuropathy-mutant seipin undergoes ERAD and triggers ER stress via stable calnexin binding, separating lipodystrophy from neuropathy mechanisms.\",\n      \"evidence\": \"Yeast seipin-GFP imaging and cross-species complementation (LD phenotype); co-immunoprecipitation with calnexin, ubiquitination, and apoptosis assays in neuronal cells (ER stress)\",\n      \"pmids\": [\"18093937\", \"17387721\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether seipin directly contacts lipid or acts indirectly unknown\", \"Molecular basis of ER–LD junction stabilization unresolved\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Cell-autonomous requirement of seipin for adipocyte differentiation was demonstrated, with seipin knockdown impairing PPARγ/C/EBPα expression and triglyceride synthesis gene induction, while yeast studies showed seipin controls LD size by preventing LD–LD fusion and altering phospholipid composition.\",\n      \"evidence\": \"shRNA knockdown in mesenchymal stem cells with adipogenic readouts; yeast genome-wide screen with LD fusion assays and lipidomics\",\n      \"pmids\": [\"18458148\", \"18250201\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct mechanism linking seipin to PPARγ maintenance unknown\", \"Whether phospholipid changes are cause or consequence of LD defects unclear\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Seipin was shown to form homo-oligomeric toroidal complexes (~9–12-mers), and Bscl2-knockout mouse studies revealed that unrestrained cAMP/PKA-mediated lipolysis—not failure of early adipogenic transcription—causes terminal differentiation failure, rescuable by lipolysis inhibition.\",\n      \"evidence\": \"Purification with sucrose gradients, gel filtration, and negative-stain EM (oligomer); Bscl2−/− MEF differentiation with pharmacological lipolysis rescue (adipogenesis)\",\n      \"pmids\": [\"21062080\", \"22269949\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How seipin restrains cAMP/PKA signaling molecularly unresolved\", \"Whether oligomer stoichiometry is fixed or dynamic unclear\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Seipin was identified as a regulated adaptor for lipin 1 at the ER membrane during adipogenesis; seipin loss decreased lipin 1 membrane association and elevated phosphatidic acid, placing seipin in the glycerolipid biosynthetic pathway.\",\n      \"evidence\": \"Co-immunoprecipitation, PA measurement, and lipin 1 membrane fractionation in differentiating adipocytes; mutant seipin unable to bind lipin 1 fails to reduce PA\",\n      \"pmids\": [\"24024128\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether PA accumulation is the proximal cause of differentiation failure or a secondary effect unknown\", \"Structural basis of seipin–lipin 1 interaction unresolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Atomic force microscopy demonstrated that seipin dodecamers simultaneously bind AGPAT2 and lipin 1, establishing seipin as a physical scaffold organizing consecutive glycerolipid biosynthetic enzymes.\",\n      \"evidence\": \"AFM imaging of direct protein–protein association and co-immunoprecipitation of ternary complex\",\n      \"pmids\": [\"25737955\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry of AGPAT2 and lipin 1 within the dodecameric complex not determined\", \"Whether scaffolding alters enzyme kinetics not tested\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Seipin was shown to physically interact with and regulate GPAT3 activity; GPAT overexpression phenocopied seipin loss, while GPAT3 knockdown partially rescued seipin-deficient adipogenesis, extending the enzyme scaffold to three consecutive glycerolipid pathway steps. Separately, seipin was shown to maintain stable ER–LD contacts, with its absence causing loss of contacts, increased LD mobility, and defective protein/lipid cargo delivery to LDs.\",\n      \"evidence\": \"Co-IP, GPAT kinetics, multi-organism epistasis (yeast/fly/mammalian); live-cell imaging, electron tomography, and patient-cell LD tracking\",\n      \"pmids\": [\"27806294\", \"27879284\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How seipin modulates GPAT catalytic rate mechanistically unclear\", \"Whether ER–LD contact stabilization and enzyme scaffolding are separable functions not tested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Cryo-EM structures of human (undecamer) and Drosophila (dodecamer) seipin revealed lumenal β-sandwich folds with structural similarity to lipid-binding proteins and hydrophobic helices positioned within the bilayer; the lumenal domain binds anionic phospholipids including PA. In parallel, Drosophila studies linked seipin to ER calcium homeostasis via SERCA, with downstream effects on mitochondrial calcium import and TCA-cycle-dependent lipogenesis.\",\n      \"evidence\": \"Cryo-EM at ~3.8–4.0 Å with lipid-binding assays and functional mutagenesis; Drosophila metabolomics with calcium measurements and citrate rescue\",\n      \"pmids\": [\"30293840\", \"30049710\", \"30327422\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Atomic-resolution lipid-binding pose within the lumenal domain not resolved\", \"Whether the calcium-homeostasis function is structurally separable from the LD-biogenesis function unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"LDAF1/TMEM159 was identified as a stoichiometric seipin partner that co-purifies with TAG; LDs form at LDAF1–seipin complexes, and LDAF1 dissociates to the LD surface after budding. Seipin was also shown to mediate uniform ER–LD necks that prevent Ostwald ripening, and its relocalization redirects LD formation sites. Additionally, ATGL was placed downstream of seipin: genetic or pharmacological ATGL inhibition rescued lipodystrophy in Bscl2−/− mice.\",\n      \"evidence\": \"Co-purification with TAG, LDAF1 relocalization assay, auxin-inducible seipin degron, model membranes, ATGL KO rescue of Bscl2−/− mice\",\n      \"pmids\": [\"31708432\", \"31178403\", \"31185001\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of LDAF1 engagement within the seipin ring unresolved\", \"Mechanism by which seipin regulates ATGL protein stability unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Molecular dynamics and the yeast Sei1/Ldb16 cryo-EM structure revealed that seipin concentrates TAG and DAG inside its ring via polar/hydroxyl residues in transmembrane and partner subunits, providing a molecular explanation for neutral lipid nucleation.\",\n      \"evidence\": \"Coarse-grained and all-atom MD simulations with mutagenesis; cryo-EM of Sei1/Ldb16 complex plus biochemical reconstitution\",\n      \"pmids\": [\"33674387\", \"34625558\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct experimental visualization of lipid within the ring at atomic resolution lacking\", \"How opening of the cage permits LD budding in real time not observed\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Yeast seipin cryo-EM revealed a decameric cage with two alternating TM conformations regulated by switch regions; functional mutagenesis showed switch regions are essential, supporting a model in which conformational switching enables TAG phase separation then LD budding. Mammalian studies confirmed seipin at MAMs facilitates mitochondrial calcium import, sustaining Krebs cycle metabolites and ATP.\",\n      \"evidence\": \"Cryo-EM structure with switch-region mutagenesis; proximity ligation, live calcium imaging, and metabolomics upon acute seipin removal in adipocytes\",\n      \"pmids\": [\"35210614\", \"35021082\", \"35938957\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Conformational transition between open and closed states not captured in time-resolved experiments\", \"Whether the MAM-localized pool of seipin is structurally distinct from ER–LD pool unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include how seipin's LD-biogenesis and ER–mitochondria contact functions are structurally partitioned, the atomic mechanism by which seipin cage opening permits LD budding, and how seipin restrains cAMP/PKA lipolytic signaling at the molecular level.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No time-resolved structural data capturing cage conformational dynamics\", \"Molecular link between seipin and cAMP/PKA pathway components unidentified\", \"Whether LDAF1 occupies a defined site within the seipin ring structurally unresolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [13, 17, 20, 21]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [8, 9, 11, 39]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [5, 13, 14, 18]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [0, 1, 12]},\n      {\"term_id\": \"GO:0005811\", \"supporting_discovery_ids\": [0, 12, 16]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [22, 23]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [4, 8, 9, 11, 24, 32]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [3, 7, 35]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [0, 12, 16, 26]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [2, 6]}\n    ],\n    \"complexes\": [\n      \"Seipin oligomeric ring (9-12mer)\",\n      \"Seipin-LDAF1 complex\"\n    ],\n    \"partners\": [\n      \"TMEM159\",\n      \"LPIN1\",\n      \"AGPAT2\",\n      \"GPAT3\",\n      \"CANX\",\n      \"PLIN2\",\n      \"YWHAB\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}