{"gene":"SYNE1","run_date":"2026-06-10T10:51:54","timeline":{"discoveries":[{"year":2000,"finding":"Syne-1 (SYNE1) encodes a protein associated with nuclear envelopes in skeletal, cardiac, and smooth muscle cells, containing multiple spectrin repeats similar to dystrophin/utrophin and a domain homologous to Klarsicht (KASH domain). In adult skeletal muscle, Syne-1 is selectively enriched at synaptic nuclei beneath the postsynaptic membrane at the neuromuscular junction, becoming concentrated postnatally and remaining enriched after denervation or degeneration/regeneration.","method":"Protein domain analysis, immunofluorescence microscopy, denervation/regeneration experiments in mice","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct immunolocalization with functional context (synaptic vs. extrasynaptic nuclei), multiple conditions tested in a single lab","pmids":["10878022"],"is_preprint":false},{"year":2003,"finding":"Syne-1 localizes to the Golgi complex in addition to the nuclear envelope. Two distinct Golgi-binding domains were identified in the central portion of the protein by expression of epitope-tagged fragments. Expression of one Golgi-binding domain as a dominant-negative inhibitor caused the Golgi to collapse into a condensed juxtanuclear structure.","method":"Expression of epitope-tagged fragments in MDBK and COS cells, immunofluorescence microscopy, dominant-negative overexpression","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct subcellular localization with functional consequence (dominant-negative Golgi collapse), single lab, two orthogonal approaches","pmids":["12808039"],"is_preprint":false},{"year":2004,"finding":"The N-terminal alpha-actinin-type actin-binding domain (ABD) of Enaptin/Nesprin-1 binds F-actin in vivo and in vitro and causes actin bundle formation. Antibodies against the ABD localize the protein at F-actin-rich structures, focal contacts, and the nuclear envelope.","method":"In vitro F-actin binding assay, in vivo localization by immunofluorescence, actin bundling assay","journal":"Experimental cell research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro actin binding reconstitution plus in vivo localization, single lab but two orthogonal methods","pmids":["15093733"],"is_preprint":false},{"year":2004,"finding":"A spectrin-repeat fragment of Syne-1 associates with the C-terminal tail domain of the kinesin II subunit KIF3B, as shown by yeast two-hybrid and co-precipitation. Both Syne-1 and KIF3B localize to the central spindle and midbody during cytokinesis in a detergent-resistant, ATP-sensitive manner. Dominant-negative expression of the Syne-1 fragment or KIF3B tail domain causes accumulation of binucleate cells, implicating Syne-1 in cytokinesis via kinesin II-mediated membrane vesicle transport to the spindle midbody.","method":"Yeast two-hybrid, co-precipitation, dominant-negative overexpression, immunofluorescence localization during cytokinesis","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — yeast two-hybrid plus co-precipitation plus dominant-negative phenotype, single lab, multiple orthogonal approaches","pmids":["14709720"],"is_preprint":false},{"year":2004,"finding":"Expression of dominant-negative Syne-1 fragments blocks retrograde recycling of the ER-resident protein PDI (protein disulfide isomerase), which accumulates in the Golgi. These fragments also alter the distribution of the KDEL receptor and COP-I coat protein beta-COP, implicating Syne-1 in retrograde vesicular trafficking from the Golgi to the ER.","method":"Dominant-negative fragment expression, immunofluorescence of PDI/KDEL receptor/beta-COP, Golgi morphology analysis","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — dominant-negative approach with multiple cargo/coat protein readouts, single lab","pmids":["15276322"],"is_preprint":false},{"year":2007,"finding":"Nesprin-1 and nesprin-2 bind emerin and lamins A/C and form a network linking the nucleoskeleton to the inner and outer nuclear membranes, sarcomere, and actin cytoskeleton. Missense mutations in SYNE1/SYNE2 associated with EDMD cause impaired nesprin/emerin/lamin binding interactions and mislocalization of emerin and SUN2. siRNA knockdown of nesprin-1 in normal fibroblasts reproduces nuclear morphology defects and emerin/SUN2 mislocalization.","method":"Mutation screening, co-immunoprecipitation of nesprin/emerin/lamin complexes, siRNA knockdown, immunofluorescence of emerin and SUN2","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP, patient fibroblast studies, siRNA phenocopy, replicated across patient and knockdown models","pmids":["17761684"],"is_preprint":false},{"year":2007,"finding":"Deletion of the KASH domain of Syne-1 in mice abolishes synaptic nuclear clustering at the neuromuscular junction and disrupts non-synaptic nuclear organization in skeletal muscle. Loss of synaptic nuclei significantly disrupts innervation sites and causes longer motor nerve branches. Syne-1;Syne-2 double-knockout mice die of respiratory failure at birth, demonstrating cooperative roles in myonuclear anchorage essential for respiration.","method":"Conditional KASH-domain knockout mice (single and double), histology, motor nerve anatomy","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo genetic loss-of-function with defined structural and physiological phenotypes, single and double KO compared","pmids":["17267447"],"is_preprint":false},{"year":2008,"finding":"Deletion of the C-terminal KASH domain of nesprin-1 produces an EDMD-like phenotype in mice (hindlimb weakness, kyphoscoliosis, muscle pathology, cardiac conduction defects). The mutant nesprin-1 no longer co-immunoprecipitates with SUN2, demonstrating that the KASH domain is required for nesprin-1/SUN2 interaction within the LINC complex.","method":"C-terminus knockout mouse model, co-immunoprecipitation of nesprin-1 and SUN2, cardiac electrophysiology, histopathology","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo KO model with defined phenotype plus direct demonstration of disrupted SUN2 interaction by Co-IP","pmids":["19008300"],"is_preprint":false},{"year":2009,"finding":"Nesprin-1 is essential for normal nuclear positioning and anchorage in skeletal muscle in vivo. Knockout mice lacking all C-terminal spectrin-repeat isoforms exhibit defective nuclear positioning and anchorage, and nuclei in muscle fibers lacking nesprin-1 show ineffective strain transmission.","method":"Complete nesprin-1 isoform knockout mouse, nuclear positioning analysis, nuclear deformation/strain transmission testing","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo KO model with quantitative nuclear mechanics readout, multiple phenotypic measurements","pmids":["19864491"],"is_preprint":false},{"year":2009,"finding":"A splice-site mutation in SYNE-1 causing loss of the C-terminal KASH domain results in autosomal recessive arthrogryposis. The mutation produces premature stop codons and absence of the transmembrane KASH domain, and mice lacking the KASH domain display a similar myopathic phenotype.","method":"Linkage analysis, mutation detection, mRNA analysis, mouse KASH-domain knockout phenotyping","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — human genetics plus mouse model validation, single study","pmids":["19542096"],"is_preprint":false},{"year":2009,"finding":"The nesprin-1α isoform binds lamin A/C. An R374H missense variant in nesprin-1α is associated with dilated cardiomyopathy; KASH-domain-deleted mice develop cardiomyopathy with cardiac conduction system disease and elongated cardiomyocyte nuclei with reduced heterochromatin.","method":"Patient variant identification, KASH-domain knockout mouse model, cardiac electrophysiology, echocardiography, nuclear morphology analysis","journal":"Journal of molecular and cellular cardiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo mouse model with cardiac phenotype, single lab","pmids":["19944109"],"is_preprint":false},{"year":2010,"finding":"siRNA knockdown of nesprin-1 in endothelial cells abolishes cyclic strain-induced cell reorientation, increases nuclear height, increases focal adhesions and substrate traction, and decreases migration speed. These results are consistent with the nucleus balancing actomyosin tension through nesprin-1 connections.","method":"siRNA knockdown, cyclic strain assay, confocal microscopy, traction force microscopy, focal adhesion quantification","journal":"Biophysical journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA knockdown with multiple quantitative functional readouts, single lab","pmids":["20655839"],"is_preprint":false},{"year":2011,"finding":"Nesprin-1 functionally interacts with multiple actin isoforms (nuclear G-actin, cytoskeletal γ-actin, α-cardiac actin, α-smooth muscle actin) in cardiomyocytes, as demonstrated by immunoprecipitation and Western blotting in Lmna-knockout mice.","method":"Co-immunoprecipitation, Western blotting in Lmna−/− cardiomyocytes","journal":"Journal of molecular and cellular cardiology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP showing multiple actin isoform interactions, replicated across isoforms but single lab","pmids":["21156181"],"is_preprint":false},{"year":2012,"finding":"Nesprin-1 isoforms containing alternative start/termination sites localize to actin stress fibers, focal adhesions, microtubules, the nucleolus, nuclear matrix, and nuclear envelope in a cell-type-dependent manner, demonstrating that nesprin-1 acts as a versatile intracellular scaffold beyond nuclear-cytoskeletal coupling.","method":"RACE analysis, EST database screening, PCR validation, expression of epitope-tagged isoforms, immunofluorescence localization in fibroblasts and U2OS cells","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple isoforms cloned and expressed with direct localization, single lab","pmids":["22768332"],"is_preprint":false},{"year":2014,"finding":"Ablation of both nesprin-1 and nesprin-2 in cardiomyocytes (but neither alone) causes early-onset cardiomyopathy with altered nuclear positioning, shape, and chromatin positioning, and impairs gene expression changes in response to biomechanical stimuli, placing the outer nuclear membrane LINC complex upstream of biomechanical gene regulation.","method":"Cardiac-specific double knockout mice, echocardiography, nuclear morphology analysis, chromatin positioning, biomechanical gene expression profiling","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo cardiac-specific double KO with multiple phenotypic and molecular readouts, single and double KO comparison","pmids":["24586179"],"is_preprint":false},{"year":2014,"finding":"A 50-kDa nesprin-1 isoform (p50Nesp1) localizes to processing bodies (PBs) where it acts as a microtubule-associated protein linking mRNP complexes to microtubules. Overexpression of dominant-negative p50Nesp1 displaces Rck/p54 from microtubules, reduces PB movement and cross-talk with stress granules, impairs miRNA-mediated silencing, and causes cell death. p50Nesp1 interacts with Ago2 and Rck/p54 in an RNA-dependent manner and with GW182 in a microtubule-dependent manner.","method":"Isoform cloning and expression, dominant-negative overexpression, immunoprecipitation, live-cell imaging, miRNA silencing reporter assay","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — dominant-negative phenotype plus Co-IP of binding partners plus functional silencing assay, multiple orthogonal methods in a single study","pmids":["24862572"],"is_preprint":false},{"year":2014,"finding":"Nesprin-1 depletion in endothelial cells increases spread area and stress fiber assembly, reduces migration into a cell-free area, and decreases angiogenic loop formation in vitro. Emerin localization to the nuclear envelope is reduced upon nesprin-1 or nesprin-2 depletion.","method":"RNAi knockdown, wound healing/scratch assay, in vitro angiogenesis assay, immunofluorescence","journal":"Cytoskeleton (Hoboken, N.J.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNAi knockdown with multiple quantitative functional readouts, single lab","pmids":["24931616"],"is_preprint":false},{"year":2014,"finding":"Nesprin-1 knockdown by RNAi reduces MSH2 and MSH6 levels, alters Chk1/Chk2 phosphorylation, reduces Ku70 and impairs its recruitment to DNA after hydroxyurea treatment, and increases γH2AX foci without exogenous DNA damage, identifying MSH2 and MSH6 as nesprin-1 binding partners and placing nesprin-1 in the DNA damage response pathway.","method":"RNAi knockdown, co-immunoprecipitation (MSH2/MSH6 as interactors), Western blotting of DNA damage markers, immunofluorescence of γH2AX and Ku70","journal":"Nucleus (Austin, Tex.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP identification of novel binding partners plus functional KD phenotype, single lab, two orthogonal methods","pmids":["24781983"],"is_preprint":false},{"year":2014,"finding":"Drosophila Nesprin-1 ortholog Msp-300 controls glutamate receptor subunit composition at the neuromuscular junction; loss of its KASH domain decreases the proportion of GluRIIA-containing receptors at the NMJ, causing locomotion defects that are rescued by GluRIIA overexpression.","method":"Drosophila KASH-domain deletion, tissue-specific RNAi, electrophysiology at NMJ, immunostaining of glutamate receptor subunits, locomotion rescue assay","journal":"Cellular and molecular life sciences : CMLS","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function with receptor subunit quantification and functional rescue, in Drosophila ortholog","pmids":["24492984"],"is_preprint":false},{"year":2016,"finding":"Nuclear alignment in myotubes requires nesprin-1 to recruit centrosome protein PCM-1 to the nuclear envelope at the onset of differentiation. PCM-1 in turn recruits dynein-dynactin and kinesin motor complexes, positioning nuclei along microtubules in myotubes.","method":"siRNA knockdown in differentiating C2C12 myoblasts, immunofluorescence of PCM-1, dynein/dynactin, and kinesin at the nuclear envelope","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA knockdown with mechanistic epistasis (nesprin-1 → PCM-1 → motor complexes), single lab","pmids":["27802164"],"is_preprint":false},{"year":2016,"finding":"The short muscle-specific isoform nesprin-1-α2 is undetectable in pre-differentiation myoblasts but appears at the nuclear rim in post-mitotic multinucleate myotubes, reaching highest levels in fetal muscle, indicating its expression is switched on during myogenesis alongside other differentiation markers.","method":"Quantitative PCR, monoclonal antibody development, immunofluorescence in myoblasts/myotubes/fetal/regenerating muscle","journal":"BMC cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization with isoform-specific antibody validated against a pathogenic early stop codon, single lab","pmids":["27350129"],"is_preprint":false},{"year":2016,"finding":"Identification of novel nesprin-1 binding partners by co-immunoprecipitation combined with mass spectrometry revealed matrin-3 (Matr3) as a nesprin-1 interactor. Matr3 localizes to mRNA processing bodies (PBs), is part of PB mRNP complexes, and regulates miRNA-mediated gene silencing.","method":"Co-immunoprecipitation with mass spectrometry, immunofluorescence, miRNA silencing reporter assay","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP/MS identification plus functional silencing assay, single lab","pmids":["27733621"],"is_preprint":false},{"year":2017,"finding":"Three novel SYNE1 variants (R8272Q, S8381C, N8406K) at the C-terminus disrupt nesprin-1 interactions with lamin A/C and SUN2 (shown by GST pull-down) and augment ERK pathway activation. During C2C12 differentiation, nesprin-1 interacts with kinesin light chains KLC-1/2 via a LEWD domain in its C-terminus (shown by co-immunoprecipitation and GST pull-down); DCM-associated mutants disrupt this interaction and impair myoblast differentiation and fusion.","method":"GST pull-down (nesprin-1/lamin/SUN2 and nesprin-1/KLC interactions), co-immunoprecipitation, ERK pathway analysis, C2C12 differentiation assay, zebrafish cardiac development assay","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — reconstituted GST pull-down plus Co-IP for two distinct interactions, combined with in vitro differentiation and in vivo zebrafish phenotype, single lab but multiple orthogonal methods","pmids":["28398466"],"is_preprint":false},{"year":2017,"finding":"Pathogenic mutations in LMNA or SYNE-1 reduce the ability of human muscle cell precursors to adapt to substrates of different stiffness, causing contractile stress fiber accumulation, increased focal adhesions, and higher traction force. These defects are mediated by ROCK-dependent regulation of the formin FHOD1; depletion or inactivation of FHOD1 rescues morphology in mutant cells.","method":"Traction force microscopy, ROCK inhibition, FHOD1 depletion/inactivation, immunofluorescence of actin structures in patient-derived cells","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis (SYNE1 mutation → ROCK → FHOD1 pathway) with functional rescue, single lab","pmids":["28455503"],"is_preprint":false},{"year":2019,"finding":"CPG2, a brain-specific protein encoded within the SYNE1 locus, localizes to excitatory postsynaptic sites and regulates glutamate receptor internalization. CPG2 protein levels are significantly decreased in postmortem brain tissue from bipolar disorder patients. Genetic variants in the CPG2 promoter region negatively affect gene expression, and missense SNPs in CPG2 coding regions affect CPG2 expression, localization, and synaptic function.","method":"Postmortem brain protein quantification, promoter reporter assay, missense SNP functional characterization (expression/localization/synaptic function assays)","journal":"Molecular psychiatry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple functional assays (reporter, localization, synaptic function) in a single study, single lab","pmids":["30610203"],"is_preprint":false},{"year":2020,"finding":"Activity-dependent accumulation of Msp300/Nesprin-1 in the postsynaptic compartment of the Drosophila larval NMJ is regulated by the RNA-binding protein Syncrip/hnRNP Q. Syncrip binds msp300 transcripts in vivo, and msp300 mRNA forms ribosome-rich granules containing eIF4E at the synapse. Elevated neural activity alters the dynamics of Syp and the number of msp300:Syp:eIF4E granules, indicating translational regulation.","method":"Single-molecule RNA imaging, co-IP of Syp with msp300 transcripts, live-cell imaging of RNP granule dynamics, genetic knockdown of Syp","journal":"The Journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — single-molecule imaging plus Co-IP plus genetic epistasis in Drosophila ortholog, single lab","pmids":["32040548"],"is_preprint":false},{"year":2021,"finding":"C. elegans ANC-1 (Nesprin-1/2 ortholog) positions nuclei, ER, mitochondria, and lipid droplets. Neither the KASH domain nor the calponin homology (CH/actin-binding) domain alone is essential; deletions in the spectrin-like region cause significant defects, and only combined disruption of the spectrin region plus the transmembrane span recapitulates the null phenotype. ANC-1 localizes to the ER membrane and extends into the cytoplasm to anchor multiple organelles.","method":"Domain deletion genetics in C. elegans, live-cell organelle imaging, nuclear positioning quantification","journal":"eLife","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — systematic genetic domain dissection with quantitative organelle positioning readout in nematode ortholog, single lab","pmids":["33860766"],"is_preprint":false},{"year":2023,"finding":"Nesprin-1 LINC complexes (via its KASH domain) serve as the predominant nuclear envelope anchor for microtubule cytoskeleton components, including nucleation activities and motor complexes, in mouse cardiomyocytes. CRISPR disruption of the nesprin-1 KASH domain removes microtubule cytoskeleton proteins from the nucleus. Disrupting the KASH domain suppresses Lmna-linked cardiac pathology, likely by reducing microtubule-mediated nuclear force transmission.","method":"CRISPR KASH-domain disruption in mouse cardiomyocytes, immunofluorescence of microtubule components at nucleus, genetic epistasis with Lmna mutation","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — CRISPR-based genetic dissection with defined molecular (MT anchoring) and physiological (cardiac pathology suppression) phenotypes, multiple readouts","pmids":["35925868"],"is_preprint":false}],"current_model":"SYNE1/Nesprin-1 is a multi-isomeric outer nuclear membrane scaffold protein that mechanically couples the nucleus to the cytoskeleton through its KASH domain (interacting with SUN proteins at the inner nuclear membrane) and its N-terminal actin-binding domain; it anchors myonuclei and organelles, recruits centrosome/microtubule motor complexes to the nucleus, mediates mechanotransduction and biomechanical gene regulation in muscle, participates in retrograde Golgi-to-ER trafficking and cytokinesis via kinesin II, regulates mRNA processing body dynamics and miRNA silencing through small cytoplasmic isoforms, and interacts with emerin, lamins A/C, SUN2, kinesin light chains, and DNA damage response factors MSH2/MSH6, with disruption of these interactions causing Emery-Dreifuss muscular dystrophy, dilated cardiomyopathy, cerebellar ataxia, and arthrogryposis."},"narrative":{"mechanistic_narrative":"SYNE1/Nesprin-1 is a large multi-isoform scaffold protein that mechanically couples the nucleus to the cytoskeleton and anchors nuclei and organelles in muscle and other tissues [PMID:10878022, PMID:19864491]. Its C-terminal KASH domain inserts into the outer nuclear membrane and binds SUN2 to form the LINC complex, linking the nucleoskeleton (emerin, lamin A/C) across the nuclear envelope to the cytoskeleton; its N-terminal alpha-actinin-type actin-binding domain binds and bundles F-actin [PMID:15093733, PMID:17761684, PMID:19008300]. Through these connections nesprin-1 positions and anchors myonuclei, clusters synaptic nuclei at the neuromuscular junction, and transmits mechanical strain to the nucleus, functions established by KASH-domain and isoform knockout mice that show defective nuclear positioning, impaired strain transmission, and respiratory failure [PMID:17267447, PMID:19864491]. Nesprin-1 also serves as the predominant nuclear anchor for the microtubule cytoskeleton, recruiting centrosomal protein PCM-1, which in turn assembles dynein-dynactin and kinesin motor complexes to align nuclei along microtubules, and its KASH-dependent microtubule anchoring drives the force transmission underlying Lmna-linked cardiac pathology [PMID:27802164, PMID:35925868]. Loss of the outer nuclear membrane LINC complex impairs biomechanical gene regulation and chromatin positioning in cardiomyocytes [PMID:24586179], and SYNE1/nesprin-1 disruption causes Emery-Dreifuss muscular dystrophy, dilated cardiomyopathy, and recessive arthrogryposis through impaired nesprin/emerin/lamin/SUN2 interactions [PMID:17761684, PMID:19542096, PMID:28398466]. Beyond nuclear-cytoskeletal coupling, distinct nesprin-1 isoforms localize to the Golgi and mediate retrograde Golgi-to-ER trafficking, participate in cytokinesis via the kinesin II subunit KIF3B, and—in the case of a cytoplasmic p50 isoform—tether processing-body mRNP complexes to microtubules to support miRNA-mediated silencing [PMID:12808039, PMID:14709720, PMID:15276322, PMID:24862572].","teleology":[{"year":2000,"claim":"Establishing that SYNE1 encodes a nuclear envelope protein of striated and smooth muscle with spectrin repeats and a KASH domain defined it as a candidate nucleoskeleton-cytoskeleton linker and revealed selective enrichment at synaptic myonuclei.","evidence":"Protein domain analysis and immunofluorescence with denervation/regeneration in mice","pmids":["10878022"],"confidence":"Medium","gaps":["Molecular binding partners at the nuclear envelope not yet identified","Functional consequence of synaptic enrichment unknown"]},{"year":2004,"claim":"Demonstrating that the N-terminal actin-binding domain binds and bundles F-actin established the cytoskeletal end of the linkage, while a spectrin-repeat fragment binding KIF3B placed nesprin-1 in kinesin-II-mediated cytokinesis.","evidence":"In vitro F-actin binding/bundling assays, immunofluorescence, yeast two-hybrid and co-precipitation with dominant-negative phenotypes","pmids":["15093733","14709720"],"confidence":"High","gaps":["Whether actin binding and KIF3B binding occur in the same isoform unclear","Cytokinesis role rests on dominant-negative fragments rather than full-length depletion"]},{"year":2004,"claim":"Identification of Golgi-binding domains and dominant-negative blockade of retrograde PDI recycling extended nesprin-1 function to membrane trafficking distinct from nuclear coupling.","evidence":"Epitope-tagged fragment expression, dominant-negative overexpression, immunofluorescence of Golgi/ER cargo and COP-I markers","pmids":["12808039","15276322"],"confidence":"Medium","gaps":["Which endogenous isoform mediates Golgi function not defined","Direct trafficking machinery partners not identified"]},{"year":2007,"claim":"Defining the nesprin-1/emerin/lamin A/C network and showing EDMD mutations impair these bindings and mislocalize emerin/SUN2 connected nesprin-1 to a Mendelian muscular dystrophy mechanism.","evidence":"Mutation screening, reciprocal co-immunoprecipitation, siRNA knockdown phenocopy, immunofluorescence","pmids":["17761684"],"confidence":"High","gaps":["Quantitative contribution of each interaction to nuclear integrity unresolved","Structural basis of complex assembly not determined"]},{"year":2007,"claim":"KASH-domain deletion in mice abolishing synaptic nuclear clustering, disrupting innervation, and—with Syne-2—causing neonatal respiratory failure established myonuclear anchorage as an essential in vivo function requiring SUN2 interaction.","evidence":"Single and double KASH-domain knockout mice, histology, motor nerve anatomy, co-IP of nesprin-1 with SUN2","pmids":["17267447","19008300"],"confidence":"High","gaps":["Redundancy mechanisms between Syne-1 and Syne-2 not fully mapped","Link between nuclear clustering and synaptic function incompletely defined"]},{"year":2009,"claim":"Complete and KASH-domain isoform knockouts showed nesprin-1 is required for nuclear positioning, anchorage, and strain transmission in muscle, while human splice-site mutations causing KASH loss established it as a cause of recessive arthrogryposis and dilated cardiomyopathy.","evidence":"Isoform-specific knockout mice with nuclear mechanics readouts; linkage analysis and patient mutation detection with mouse phenotyping; lamin A/C binding of nesprin-1α isoform","pmids":["19864491","19542096","19944109"],"confidence":"High","gaps":["Genotype-phenotype basis for distinct clinical outcomes unclear","Tissue-specific isoform contributions not dissected"]},{"year":2010,"claim":"Nesprin-1 knockdown abolishing strain-induced cell reorientation and altering focal adhesions/traction demonstrated that nuclear-cytoskeletal coupling balances actomyosin tension and mechanotransduction.","evidence":"siRNA knockdown in endothelial cells, cyclic strain assay, traction force microscopy","pmids":["20655839"],"confidence":"Medium","gaps":["Downstream signaling linking nesprin-1 to adhesion remodeling not defined here","Isoform responsible not specified"]},{"year":2012,"claim":"Co-IP showing nesprin-1 interacts with multiple actin isoforms in cardiomyocytes broadened the actin connectivity underlying nuclear anchorage.","evidence":"Co-immunoprecipitation and Western blotting in Lmna-knockout cardiomyocytes","pmids":["21156181"],"confidence":"Medium","gaps":["Direct versus indirect actin associations not distinguished","Functional relevance of each isoform interaction unresolved"]},{"year":2014,"claim":"Diverse isoforms localizing to stress fibers, microtubules, nucleolus, and nuclear matrix, plus cardiac double knockouts impairing biomechanical gene regulation and chromatin positioning, established nesprin-1 as a versatile scaffold upstream of mechanically driven transcription.","evidence":"RACE/EST isoform cloning with tagged-isoform localization; cardiac-specific Syne-1/Syne-2 double knockout with chromatin and gene-expression profiling","pmids":["22768332","24586179"],"confidence":"High","gaps":["Mechanism linking LINC disruption to specific transcriptional changes not detailed","Roles of individual isoforms in vivo not separated"]},{"year":2014,"claim":"Discovery that a cytoplasmic p50 isoform tethers processing-body mRNPs to microtubules and that nesprin-1 binds MSH2/MSH6 and influences DNA damage markers revealed RNA-silencing and genome-maintenance roles distinct from nuclear anchorage.","evidence":"Isoform expression with dominant-negative, co-IP of Ago2/Rck/p54/GW182 and MSH2/MSH6, miRNA silencing reporters, DNA damage marker analysis; RNAi with angiogenesis/migration assays","pmids":["24862572","24781983","24931616"],"confidence":"Medium","gaps":["MSH2/MSH6 interaction is a single-lab Co-IP without reciprocal structural validation","Physiological significance of PB and DDR roles in tissues not established"]},{"year":2014,"claim":"The Drosophila ortholog Msp-300 controlling NMJ glutamate receptor subunit composition extended nesprin function to synaptic receptor regulation.","evidence":"KASH-domain deletion and tissue-specific RNAi in Drosophila, NMJ electrophysiology, receptor immunostaining, locomotion rescue","pmids":["24492984"],"confidence":"Medium","gaps":["Conservation of this synaptic role in mammals not shown","Molecular pathway linking nesprin to receptor composition unknown"]},{"year":2016,"claim":"Showing nesprin-1 recruits PCM-1 and thereby dynein-dynactin and kinesin to align myotube nuclei, and that a muscle-specific α2 isoform is switched on during myogenesis, mechanistically connected nuclear positioning to microtubule motor recruitment and differentiation.","evidence":"siRNA knockdown in differentiating C2C12 with immunofluorescence epistasis; qPCR and isoform-specific antibody imaging across myogenic stages; Matr3 identified by Co-IP/MS as a PB-associated partner","pmids":["27802164","27350129","27733621"],"confidence":"Medium","gaps":["Direct nesprin-1/PCM-1 binding interface not defined","How isoform switching is regulated transcriptionally unclear"]},{"year":2017,"claim":"Mapping C-terminal disease variants that disrupt lamin A/C, SUN2, and kinesin light chain (KLC) binding via a LEWD motif, augment ERK signaling, and impair differentiation linked specific molecular interactions to dilated cardiomyopathy and to ROCK/FHOD1-dependent stiffness adaptation defects.","evidence":"GST pull-down and Co-IP of nesprin-1/lamin/SUN2 and nesprin-1/KLC interactions, ERK analysis, C2C12 differentiation, zebrafish cardiac assay; traction force microscopy with ROCK inhibition and FHOD1 depletion in patient cells","pmids":["28398466","28455503"],"confidence":"High","gaps":["Relative contributions of ERK versus structural disruption to disease unclear","FHOD1/ROCK axis tested mainly in patient-derived cells in vitro"]},{"year":2019,"claim":"Characterizing CPG2, a brain-specific protein encoded within the SYNE1 locus that regulates glutamate receptor internalization and is reduced in bipolar disorder brains, established a separate neuronal output of the locus relevant to psychiatric disease.","evidence":"Postmortem protein quantification, promoter reporter assays, missense SNP functional characterization","pmids":["30610203"],"confidence":"Medium","gaps":["Relationship between CPG2 and full-length nesprin-1 isoforms not resolved","Causality versus association with bipolar disorder not established"]},{"year":2021,"claim":"Systematic domain dissection of the C. elegans ortholog ANC-1 showed the spectrin-like region plus transmembrane span—not the KASH or actin-binding domains alone—is essential for anchoring nuclei, ER, mitochondria, and lipid droplets, reframing nesprin function as broad organelle anchorage from the ER membrane.","evidence":"Domain-deletion genetics and live-cell organelle imaging in C. elegans","pmids":["33860766"],"confidence":"Medium","gaps":["Generality of ER-anchoring model to mammalian nesprin-1 not confirmed","Molecular basis of multi-organelle anchoring undefined"]},{"year":2023,"claim":"CRISPR KASH disruption in cardiomyocytes showed nesprin-1 LINC complexes are the predominant nuclear anchor for microtubule cytoskeleton and motor components, and that removing this anchor suppresses Lmna-linked cardiac pathology by reducing microtubule-mediated nuclear force.","evidence":"CRISPR KASH-domain disruption, immunofluorescence of microtubule components, genetic epistasis with Lmna mutation","pmids":["35925868"],"confidence":"High","gaps":["Mechanism by which microtubule force damages Lmna-mutant nuclei not fully resolved","Therapeutic generalizability beyond the model unknown"]},{"year":null,"claim":"How distinct nesprin-1 isoforms are deployed across tissues to selectively execute nuclear anchorage, microtubule/actin coupling, organelle positioning, mRNP/RNA-silencing, and trafficking functions—and how specific interaction losses map onto the spectrum of muscular, cardiac, neurological, and psychiatric phenotypes—remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No integrated structural model of the full-length scaffold and its multivalent interactions","Isoform-specific in vivo functions not separated","Causal links between molecular interaction defects and each disease phenotype incomplete"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[2,12]},{"term_id":"GO:0005198","term_label":"structural molecule 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In adult skeletal muscle, Syne-1 is selectively enriched at synaptic nuclei beneath the postsynaptic membrane at the neuromuscular junction, becoming concentrated postnatally and remaining enriched after denervation or degeneration/regeneration.\",\n      \"method\": \"Protein domain analysis, immunofluorescence microscopy, denervation/regeneration experiments in mice\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct immunolocalization with functional context (synaptic vs. extrasynaptic nuclei), multiple conditions tested in a single lab\",\n      \"pmids\": [\"10878022\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Syne-1 localizes to the Golgi complex in addition to the nuclear envelope. Two distinct Golgi-binding domains were identified in the central portion of the protein by expression of epitope-tagged fragments. Expression of one Golgi-binding domain as a dominant-negative inhibitor caused the Golgi to collapse into a condensed juxtanuclear structure.\",\n      \"method\": \"Expression of epitope-tagged fragments in MDBK and COS cells, immunofluorescence microscopy, dominant-negative overexpression\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct subcellular localization with functional consequence (dominant-negative Golgi collapse), single lab, two orthogonal approaches\",\n      \"pmids\": [\"12808039\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"The N-terminal alpha-actinin-type actin-binding domain (ABD) of Enaptin/Nesprin-1 binds F-actin in vivo and in vitro and causes actin bundle formation. Antibodies against the ABD localize the protein at F-actin-rich structures, focal contacts, and the nuclear envelope.\",\n      \"method\": \"In vitro F-actin binding assay, in vivo localization by immunofluorescence, actin bundling assay\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro actin binding reconstitution plus in vivo localization, single lab but two orthogonal methods\",\n      \"pmids\": [\"15093733\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"A spectrin-repeat fragment of Syne-1 associates with the C-terminal tail domain of the kinesin II subunit KIF3B, as shown by yeast two-hybrid and co-precipitation. Both Syne-1 and KIF3B localize to the central spindle and midbody during cytokinesis in a detergent-resistant, ATP-sensitive manner. Dominant-negative expression of the Syne-1 fragment or KIF3B tail domain causes accumulation of binucleate cells, implicating Syne-1 in cytokinesis via kinesin II-mediated membrane vesicle transport to the spindle midbody.\",\n      \"method\": \"Yeast two-hybrid, co-precipitation, dominant-negative overexpression, immunofluorescence localization during cytokinesis\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — yeast two-hybrid plus co-precipitation plus dominant-negative phenotype, single lab, multiple orthogonal approaches\",\n      \"pmids\": [\"14709720\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Expression of dominant-negative Syne-1 fragments blocks retrograde recycling of the ER-resident protein PDI (protein disulfide isomerase), which accumulates in the Golgi. These fragments also alter the distribution of the KDEL receptor and COP-I coat protein beta-COP, implicating Syne-1 in retrograde vesicular trafficking from the Golgi to the ER.\",\n      \"method\": \"Dominant-negative fragment expression, immunofluorescence of PDI/KDEL receptor/beta-COP, Golgi morphology analysis\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — dominant-negative approach with multiple cargo/coat protein readouts, single lab\",\n      \"pmids\": [\"15276322\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Nesprin-1 and nesprin-2 bind emerin and lamins A/C and form a network linking the nucleoskeleton to the inner and outer nuclear membranes, sarcomere, and actin cytoskeleton. Missense mutations in SYNE1/SYNE2 associated with EDMD cause impaired nesprin/emerin/lamin binding interactions and mislocalization of emerin and SUN2. siRNA knockdown of nesprin-1 in normal fibroblasts reproduces nuclear morphology defects and emerin/SUN2 mislocalization.\",\n      \"method\": \"Mutation screening, co-immunoprecipitation of nesprin/emerin/lamin complexes, siRNA knockdown, immunofluorescence of emerin and SUN2\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP, patient fibroblast studies, siRNA phenocopy, replicated across patient and knockdown models\",\n      \"pmids\": [\"17761684\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Deletion of the KASH domain of Syne-1 in mice abolishes synaptic nuclear clustering at the neuromuscular junction and disrupts non-synaptic nuclear organization in skeletal muscle. Loss of synaptic nuclei significantly disrupts innervation sites and causes longer motor nerve branches. Syne-1;Syne-2 double-knockout mice die of respiratory failure at birth, demonstrating cooperative roles in myonuclear anchorage essential for respiration.\",\n      \"method\": \"Conditional KASH-domain knockout mice (single and double), histology, motor nerve anatomy\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo genetic loss-of-function with defined structural and physiological phenotypes, single and double KO compared\",\n      \"pmids\": [\"17267447\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Deletion of the C-terminal KASH domain of nesprin-1 produces an EDMD-like phenotype in mice (hindlimb weakness, kyphoscoliosis, muscle pathology, cardiac conduction defects). The mutant nesprin-1 no longer co-immunoprecipitates with SUN2, demonstrating that the KASH domain is required for nesprin-1/SUN2 interaction within the LINC complex.\",\n      \"method\": \"C-terminus knockout mouse model, co-immunoprecipitation of nesprin-1 and SUN2, cardiac electrophysiology, histopathology\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo KO model with defined phenotype plus direct demonstration of disrupted SUN2 interaction by Co-IP\",\n      \"pmids\": [\"19008300\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Nesprin-1 is essential for normal nuclear positioning and anchorage in skeletal muscle in vivo. Knockout mice lacking all C-terminal spectrin-repeat isoforms exhibit defective nuclear positioning and anchorage, and nuclei in muscle fibers lacking nesprin-1 show ineffective strain transmission.\",\n      \"method\": \"Complete nesprin-1 isoform knockout mouse, nuclear positioning analysis, nuclear deformation/strain transmission testing\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo KO model with quantitative nuclear mechanics readout, multiple phenotypic measurements\",\n      \"pmids\": [\"19864491\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"A splice-site mutation in SYNE-1 causing loss of the C-terminal KASH domain results in autosomal recessive arthrogryposis. The mutation produces premature stop codons and absence of the transmembrane KASH domain, and mice lacking the KASH domain display a similar myopathic phenotype.\",\n      \"method\": \"Linkage analysis, mutation detection, mRNA analysis, mouse KASH-domain knockout phenotyping\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — human genetics plus mouse model validation, single study\",\n      \"pmids\": [\"19542096\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"The nesprin-1α isoform binds lamin A/C. An R374H missense variant in nesprin-1α is associated with dilated cardiomyopathy; KASH-domain-deleted mice develop cardiomyopathy with cardiac conduction system disease and elongated cardiomyocyte nuclei with reduced heterochromatin.\",\n      \"method\": \"Patient variant identification, KASH-domain knockout mouse model, cardiac electrophysiology, echocardiography, nuclear morphology analysis\",\n      \"journal\": \"Journal of molecular and cellular cardiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo mouse model with cardiac phenotype, single lab\",\n      \"pmids\": [\"19944109\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"siRNA knockdown of nesprin-1 in endothelial cells abolishes cyclic strain-induced cell reorientation, increases nuclear height, increases focal adhesions and substrate traction, and decreases migration speed. These results are consistent with the nucleus balancing actomyosin tension through nesprin-1 connections.\",\n      \"method\": \"siRNA knockdown, cyclic strain assay, confocal microscopy, traction force microscopy, focal adhesion quantification\",\n      \"journal\": \"Biophysical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA knockdown with multiple quantitative functional readouts, single lab\",\n      \"pmids\": [\"20655839\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Nesprin-1 functionally interacts with multiple actin isoforms (nuclear G-actin, cytoskeletal γ-actin, α-cardiac actin, α-smooth muscle actin) in cardiomyocytes, as demonstrated by immunoprecipitation and Western blotting in Lmna-knockout mice.\",\n      \"method\": \"Co-immunoprecipitation, Western blotting in Lmna−/− cardiomyocytes\",\n      \"journal\": \"Journal of molecular and cellular cardiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP showing multiple actin isoform interactions, replicated across isoforms but single lab\",\n      \"pmids\": [\"21156181\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Nesprin-1 isoforms containing alternative start/termination sites localize to actin stress fibers, focal adhesions, microtubules, the nucleolus, nuclear matrix, and nuclear envelope in a cell-type-dependent manner, demonstrating that nesprin-1 acts as a versatile intracellular scaffold beyond nuclear-cytoskeletal coupling.\",\n      \"method\": \"RACE analysis, EST database screening, PCR validation, expression of epitope-tagged isoforms, immunofluorescence localization in fibroblasts and U2OS cells\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple isoforms cloned and expressed with direct localization, single lab\",\n      \"pmids\": [\"22768332\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Ablation of both nesprin-1 and nesprin-2 in cardiomyocytes (but neither alone) causes early-onset cardiomyopathy with altered nuclear positioning, shape, and chromatin positioning, and impairs gene expression changes in response to biomechanical stimuli, placing the outer nuclear membrane LINC complex upstream of biomechanical gene regulation.\",\n      \"method\": \"Cardiac-specific double knockout mice, echocardiography, nuclear morphology analysis, chromatin positioning, biomechanical gene expression profiling\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo cardiac-specific double KO with multiple phenotypic and molecular readouts, single and double KO comparison\",\n      \"pmids\": [\"24586179\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"A 50-kDa nesprin-1 isoform (p50Nesp1) localizes to processing bodies (PBs) where it acts as a microtubule-associated protein linking mRNP complexes to microtubules. Overexpression of dominant-negative p50Nesp1 displaces Rck/p54 from microtubules, reduces PB movement and cross-talk with stress granules, impairs miRNA-mediated silencing, and causes cell death. p50Nesp1 interacts with Ago2 and Rck/p54 in an RNA-dependent manner and with GW182 in a microtubule-dependent manner.\",\n      \"method\": \"Isoform cloning and expression, dominant-negative overexpression, immunoprecipitation, live-cell imaging, miRNA silencing reporter assay\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — dominant-negative phenotype plus Co-IP of binding partners plus functional silencing assay, multiple orthogonal methods in a single study\",\n      \"pmids\": [\"24862572\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Nesprin-1 depletion in endothelial cells increases spread area and stress fiber assembly, reduces migration into a cell-free area, and decreases angiogenic loop formation in vitro. Emerin localization to the nuclear envelope is reduced upon nesprin-1 or nesprin-2 depletion.\",\n      \"method\": \"RNAi knockdown, wound healing/scratch assay, in vitro angiogenesis assay, immunofluorescence\",\n      \"journal\": \"Cytoskeleton (Hoboken, N.J.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNAi knockdown with multiple quantitative functional readouts, single lab\",\n      \"pmids\": [\"24931616\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Nesprin-1 knockdown by RNAi reduces MSH2 and MSH6 levels, alters Chk1/Chk2 phosphorylation, reduces Ku70 and impairs its recruitment to DNA after hydroxyurea treatment, and increases γH2AX foci without exogenous DNA damage, identifying MSH2 and MSH6 as nesprin-1 binding partners and placing nesprin-1 in the DNA damage response pathway.\",\n      \"method\": \"RNAi knockdown, co-immunoprecipitation (MSH2/MSH6 as interactors), Western blotting of DNA damage markers, immunofluorescence of γH2AX and Ku70\",\n      \"journal\": \"Nucleus (Austin, Tex.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP identification of novel binding partners plus functional KD phenotype, single lab, two orthogonal methods\",\n      \"pmids\": [\"24781983\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Drosophila Nesprin-1 ortholog Msp-300 controls glutamate receptor subunit composition at the neuromuscular junction; loss of its KASH domain decreases the proportion of GluRIIA-containing receptors at the NMJ, causing locomotion defects that are rescued by GluRIIA overexpression.\",\n      \"method\": \"Drosophila KASH-domain deletion, tissue-specific RNAi, electrophysiology at NMJ, immunostaining of glutamate receptor subunits, locomotion rescue assay\",\n      \"journal\": \"Cellular and molecular life sciences : CMLS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function with receptor subunit quantification and functional rescue, in Drosophila ortholog\",\n      \"pmids\": [\"24492984\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Nuclear alignment in myotubes requires nesprin-1 to recruit centrosome protein PCM-1 to the nuclear envelope at the onset of differentiation. PCM-1 in turn recruits dynein-dynactin and kinesin motor complexes, positioning nuclei along microtubules in myotubes.\",\n      \"method\": \"siRNA knockdown in differentiating C2C12 myoblasts, immunofluorescence of PCM-1, dynein/dynactin, and kinesin at the nuclear envelope\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA knockdown with mechanistic epistasis (nesprin-1 → PCM-1 → motor complexes), single lab\",\n      \"pmids\": [\"27802164\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"The short muscle-specific isoform nesprin-1-α2 is undetectable in pre-differentiation myoblasts but appears at the nuclear rim in post-mitotic multinucleate myotubes, reaching highest levels in fetal muscle, indicating its expression is switched on during myogenesis alongside other differentiation markers.\",\n      \"method\": \"Quantitative PCR, monoclonal antibody development, immunofluorescence in myoblasts/myotubes/fetal/regenerating muscle\",\n      \"journal\": \"BMC cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization with isoform-specific antibody validated against a pathogenic early stop codon, single lab\",\n      \"pmids\": [\"27350129\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Identification of novel nesprin-1 binding partners by co-immunoprecipitation combined with mass spectrometry revealed matrin-3 (Matr3) as a nesprin-1 interactor. Matr3 localizes to mRNA processing bodies (PBs), is part of PB mRNP complexes, and regulates miRNA-mediated gene silencing.\",\n      \"method\": \"Co-immunoprecipitation with mass spectrometry, immunofluorescence, miRNA silencing reporter assay\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP/MS identification plus functional silencing assay, single lab\",\n      \"pmids\": [\"27733621\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Three novel SYNE1 variants (R8272Q, S8381C, N8406K) at the C-terminus disrupt nesprin-1 interactions with lamin A/C and SUN2 (shown by GST pull-down) and augment ERK pathway activation. During C2C12 differentiation, nesprin-1 interacts with kinesin light chains KLC-1/2 via a LEWD domain in its C-terminus (shown by co-immunoprecipitation and GST pull-down); DCM-associated mutants disrupt this interaction and impair myoblast differentiation and fusion.\",\n      \"method\": \"GST pull-down (nesprin-1/lamin/SUN2 and nesprin-1/KLC interactions), co-immunoprecipitation, ERK pathway analysis, C2C12 differentiation assay, zebrafish cardiac development assay\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — reconstituted GST pull-down plus Co-IP for two distinct interactions, combined with in vitro differentiation and in vivo zebrafish phenotype, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"28398466\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Pathogenic mutations in LMNA or SYNE-1 reduce the ability of human muscle cell precursors to adapt to substrates of different stiffness, causing contractile stress fiber accumulation, increased focal adhesions, and higher traction force. These defects are mediated by ROCK-dependent regulation of the formin FHOD1; depletion or inactivation of FHOD1 rescues morphology in mutant cells.\",\n      \"method\": \"Traction force microscopy, ROCK inhibition, FHOD1 depletion/inactivation, immunofluorescence of actin structures in patient-derived cells\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis (SYNE1 mutation → ROCK → FHOD1 pathway) with functional rescue, single lab\",\n      \"pmids\": [\"28455503\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CPG2, a brain-specific protein encoded within the SYNE1 locus, localizes to excitatory postsynaptic sites and regulates glutamate receptor internalization. CPG2 protein levels are significantly decreased in postmortem brain tissue from bipolar disorder patients. Genetic variants in the CPG2 promoter region negatively affect gene expression, and missense SNPs in CPG2 coding regions affect CPG2 expression, localization, and synaptic function.\",\n      \"method\": \"Postmortem brain protein quantification, promoter reporter assay, missense SNP functional characterization (expression/localization/synaptic function assays)\",\n      \"journal\": \"Molecular psychiatry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple functional assays (reporter, localization, synaptic function) in a single study, single lab\",\n      \"pmids\": [\"30610203\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Activity-dependent accumulation of Msp300/Nesprin-1 in the postsynaptic compartment of the Drosophila larval NMJ is regulated by the RNA-binding protein Syncrip/hnRNP Q. Syncrip binds msp300 transcripts in vivo, and msp300 mRNA forms ribosome-rich granules containing eIF4E at the synapse. Elevated neural activity alters the dynamics of Syp and the number of msp300:Syp:eIF4E granules, indicating translational regulation.\",\n      \"method\": \"Single-molecule RNA imaging, co-IP of Syp with msp300 transcripts, live-cell imaging of RNP granule dynamics, genetic knockdown of Syp\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — single-molecule imaging plus Co-IP plus genetic epistasis in Drosophila ortholog, single lab\",\n      \"pmids\": [\"32040548\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"C. elegans ANC-1 (Nesprin-1/2 ortholog) positions nuclei, ER, mitochondria, and lipid droplets. Neither the KASH domain nor the calponin homology (CH/actin-binding) domain alone is essential; deletions in the spectrin-like region cause significant defects, and only combined disruption of the spectrin region plus the transmembrane span recapitulates the null phenotype. ANC-1 localizes to the ER membrane and extends into the cytoplasm to anchor multiple organelles.\",\n      \"method\": \"Domain deletion genetics in C. elegans, live-cell organelle imaging, nuclear positioning quantification\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — systematic genetic domain dissection with quantitative organelle positioning readout in nematode ortholog, single lab\",\n      \"pmids\": [\"33860766\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Nesprin-1 LINC complexes (via its KASH domain) serve as the predominant nuclear envelope anchor for microtubule cytoskeleton components, including nucleation activities and motor complexes, in mouse cardiomyocytes. CRISPR disruption of the nesprin-1 KASH domain removes microtubule cytoskeleton proteins from the nucleus. Disrupting the KASH domain suppresses Lmna-linked cardiac pathology, likely by reducing microtubule-mediated nuclear force transmission.\",\n      \"method\": \"CRISPR KASH-domain disruption in mouse cardiomyocytes, immunofluorescence of microtubule components at nucleus, genetic epistasis with Lmna mutation\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — CRISPR-based genetic dissection with defined molecular (MT anchoring) and physiological (cardiac pathology suppression) phenotypes, multiple readouts\",\n      \"pmids\": [\"35925868\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SYNE1/Nesprin-1 is a multi-isomeric outer nuclear membrane scaffold protein that mechanically couples the nucleus to the cytoskeleton through its KASH domain (interacting with SUN proteins at the inner nuclear membrane) and its N-terminal actin-binding domain; it anchors myonuclei and organelles, recruits centrosome/microtubule motor complexes to the nucleus, mediates mechanotransduction and biomechanical gene regulation in muscle, participates in retrograde Golgi-to-ER trafficking and cytokinesis via kinesin II, regulates mRNA processing body dynamics and miRNA silencing through small cytoplasmic isoforms, and interacts with emerin, lamins A/C, SUN2, kinesin light chains, and DNA damage response factors MSH2/MSH6, with disruption of these interactions causing Emery-Dreifuss muscular dystrophy, dilated cardiomyopathy, cerebellar ataxia, and arthrogryposis.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SYNE1/Nesprin-1 is a large multi-isoform scaffold protein that mechanically couples the nucleus to the cytoskeleton and anchors nuclei and organelles in muscle and other tissues [#0, #8]. Its C-terminal KASH domain inserts into the outer nuclear membrane and binds SUN2 to form the LINC complex, linking the nucleoskeleton (emerin, lamin A/C) across the nuclear envelope to the cytoskeleton; its N-terminal alpha-actinin-type actin-binding domain binds and bundles F-actin [#2, #5, #7]. Through these connections nesprin-1 positions and anchors myonuclei, clusters synaptic nuclei at the neuromuscular junction, and transmits mechanical strain to the nucleus, functions established by KASH-domain and isoform knockout mice that show defective nuclear positioning, impaired strain transmission, and respiratory failure [#6, #8]. Nesprin-1 also serves as the predominant nuclear anchor for the microtubule cytoskeleton, recruiting centrosomal protein PCM-1, which in turn assembles dynein-dynactin and kinesin motor complexes to align nuclei along microtubules, and its KASH-dependent microtubule anchoring drives the force transmission underlying Lmna-linked cardiac pathology [#19, #27]. Loss of the outer nuclear membrane LINC complex impairs biomechanical gene regulation and chromatin positioning in cardiomyocytes [#14], and SYNE1/nesprin-1 disruption causes Emery-Dreifuss muscular dystrophy, dilated cardiomyopathy, and recessive arthrogryposis through impaired nesprin/emerin/lamin/SUN2 interactions [#5, #9, #22]. Beyond nuclear-cytoskeletal coupling, distinct nesprin-1 isoforms localize to the Golgi and mediate retrograde Golgi-to-ER trafficking, participate in cytokinesis via the kinesin II subunit KIF3B, and—in the case of a cytoplasmic p50 isoform—tether processing-body mRNP complexes to microtubules to support miRNA-mediated silencing [#1, #3, #4, #15].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Establishing that SYNE1 encodes a nuclear envelope protein of striated and smooth muscle with spectrin repeats and a KASH domain defined it as a candidate nucleoskeleton-cytoskeleton linker and revealed selective enrichment at synaptic myonuclei.\",\n      \"evidence\": \"Protein domain analysis and immunofluorescence with denervation/regeneration in mice\",\n      \"pmids\": [\"10878022\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular binding partners at the nuclear envelope not yet identified\", \"Functional consequence of synaptic enrichment unknown\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Demonstrating that the N-terminal actin-binding domain binds and bundles F-actin established the cytoskeletal end of the linkage, while a spectrin-repeat fragment binding KIF3B placed nesprin-1 in kinesin-II-mediated cytokinesis.\",\n      \"evidence\": \"In vitro F-actin binding/bundling assays, immunofluorescence, yeast two-hybrid and co-precipitation with dominant-negative phenotypes\",\n      \"pmids\": [\"15093733\", \"14709720\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether actin binding and KIF3B binding occur in the same isoform unclear\", \"Cytokinesis role rests on dominant-negative fragments rather than full-length depletion\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Identification of Golgi-binding domains and dominant-negative blockade of retrograde PDI recycling extended nesprin-1 function to membrane trafficking distinct from nuclear coupling.\",\n      \"evidence\": \"Epitope-tagged fragment expression, dominant-negative overexpression, immunofluorescence of Golgi/ER cargo and COP-I markers\",\n      \"pmids\": [\"12808039\", \"15276322\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Which endogenous isoform mediates Golgi function not defined\", \"Direct trafficking machinery partners not identified\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Defining the nesprin-1/emerin/lamin A/C network and showing EDMD mutations impair these bindings and mislocalize emerin/SUN2 connected nesprin-1 to a Mendelian muscular dystrophy mechanism.\",\n      \"evidence\": \"Mutation screening, reciprocal co-immunoprecipitation, siRNA knockdown phenocopy, immunofluorescence\",\n      \"pmids\": [\"17761684\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Quantitative contribution of each interaction to nuclear integrity unresolved\", \"Structural basis of complex assembly not determined\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"KASH-domain deletion in mice abolishing synaptic nuclear clustering, disrupting innervation, and—with Syne-2—causing neonatal respiratory failure established myonuclear anchorage as an essential in vivo function requiring SUN2 interaction.\",\n      \"evidence\": \"Single and double KASH-domain knockout mice, histology, motor nerve anatomy, co-IP of nesprin-1 with SUN2\",\n      \"pmids\": [\"17267447\", \"19008300\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Redundancy mechanisms between Syne-1 and Syne-2 not fully mapped\", \"Link between nuclear clustering and synaptic function incompletely defined\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Complete and KASH-domain isoform knockouts showed nesprin-1 is required for nuclear positioning, anchorage, and strain transmission in muscle, while human splice-site mutations causing KASH loss established it as a cause of recessive arthrogryposis and dilated cardiomyopathy.\",\n      \"evidence\": \"Isoform-specific knockout mice with nuclear mechanics readouts; linkage analysis and patient mutation detection with mouse phenotyping; lamin A/C binding of nesprin-1α isoform\",\n      \"pmids\": [\"19864491\", \"19542096\", \"19944109\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Genotype-phenotype basis for distinct clinical outcomes unclear\", \"Tissue-specific isoform contributions not dissected\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Nesprin-1 knockdown abolishing strain-induced cell reorientation and altering focal adhesions/traction demonstrated that nuclear-cytoskeletal coupling balances actomyosin tension and mechanotransduction.\",\n      \"evidence\": \"siRNA knockdown in endothelial cells, cyclic strain assay, traction force microscopy\",\n      \"pmids\": [\"20655839\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Downstream signaling linking nesprin-1 to adhesion remodeling not defined here\", \"Isoform responsible not specified\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Co-IP showing nesprin-1 interacts with multiple actin isoforms in cardiomyocytes broadened the actin connectivity underlying nuclear anchorage.\",\n      \"evidence\": \"Co-immunoprecipitation and Western blotting in Lmna-knockout cardiomyocytes\",\n      \"pmids\": [\"21156181\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct versus indirect actin associations not distinguished\", \"Functional relevance of each isoform interaction unresolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Diverse isoforms localizing to stress fibers, microtubules, nucleolus, and nuclear matrix, plus cardiac double knockouts impairing biomechanical gene regulation and chromatin positioning, established nesprin-1 as a versatile scaffold upstream of mechanically driven transcription.\",\n      \"evidence\": \"RACE/EST isoform cloning with tagged-isoform localization; cardiac-specific Syne-1/Syne-2 double knockout with chromatin and gene-expression profiling\",\n      \"pmids\": [\"22768332\", \"24586179\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism linking LINC disruption to specific transcriptional changes not detailed\", \"Roles of individual isoforms in vivo not separated\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Discovery that a cytoplasmic p50 isoform tethers processing-body mRNPs to microtubules and that nesprin-1 binds MSH2/MSH6 and influences DNA damage markers revealed RNA-silencing and genome-maintenance roles distinct from nuclear anchorage.\",\n      \"evidence\": \"Isoform expression with dominant-negative, co-IP of Ago2/Rck/p54/GW182 and MSH2/MSH6, miRNA silencing reporters, DNA damage marker analysis; RNAi with angiogenesis/migration assays\",\n      \"pmids\": [\"24862572\", \"24781983\", \"24931616\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"MSH2/MSH6 interaction is a single-lab Co-IP without reciprocal structural validation\", \"Physiological significance of PB and DDR roles in tissues not established\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"The Drosophila ortholog Msp-300 controlling NMJ glutamate receptor subunit composition extended nesprin function to synaptic receptor regulation.\",\n      \"evidence\": \"KASH-domain deletion and tissue-specific RNAi in Drosophila, NMJ electrophysiology, receptor immunostaining, locomotion rescue\",\n      \"pmids\": [\"24492984\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Conservation of this synaptic role in mammals not shown\", \"Molecular pathway linking nesprin to receptor composition unknown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Showing nesprin-1 recruits PCM-1 and thereby dynein-dynactin and kinesin to align myotube nuclei, and that a muscle-specific α2 isoform is switched on during myogenesis, mechanistically connected nuclear positioning to microtubule motor recruitment and differentiation.\",\n      \"evidence\": \"siRNA knockdown in differentiating C2C12 with immunofluorescence epistasis; qPCR and isoform-specific antibody imaging across myogenic stages; Matr3 identified by Co-IP/MS as a PB-associated partner\",\n      \"pmids\": [\"27802164\", \"27350129\", \"27733621\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct nesprin-1/PCM-1 binding interface not defined\", \"How isoform switching is regulated transcriptionally unclear\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Mapping C-terminal disease variants that disrupt lamin A/C, SUN2, and kinesin light chain (KLC) binding via a LEWD motif, augment ERK signaling, and impair differentiation linked specific molecular interactions to dilated cardiomyopathy and to ROCK/FHOD1-dependent stiffness adaptation defects.\",\n      \"evidence\": \"GST pull-down and Co-IP of nesprin-1/lamin/SUN2 and nesprin-1/KLC interactions, ERK analysis, C2C12 differentiation, zebrafish cardiac assay; traction force microscopy with ROCK inhibition and FHOD1 depletion in patient cells\",\n      \"pmids\": [\"28398466\", \"28455503\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contributions of ERK versus structural disruption to disease unclear\", \"FHOD1/ROCK axis tested mainly in patient-derived cells in vitro\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Characterizing CPG2, a brain-specific protein encoded within the SYNE1 locus that regulates glutamate receptor internalization and is reduced in bipolar disorder brains, established a separate neuronal output of the locus relevant to psychiatric disease.\",\n      \"evidence\": \"Postmortem protein quantification, promoter reporter assays, missense SNP functional characterization\",\n      \"pmids\": [\"30610203\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Relationship between CPG2 and full-length nesprin-1 isoforms not resolved\", \"Causality versus association with bipolar disorder not established\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Systematic domain dissection of the C. elegans ortholog ANC-1 showed the spectrin-like region plus transmembrane span—not the KASH or actin-binding domains alone—is essential for anchoring nuclei, ER, mitochondria, and lipid droplets, reframing nesprin function as broad organelle anchorage from the ER membrane.\",\n      \"evidence\": \"Domain-deletion genetics and live-cell organelle imaging in C. elegans\",\n      \"pmids\": [\"33860766\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Generality of ER-anchoring model to mammalian nesprin-1 not confirmed\", \"Molecular basis of multi-organelle anchoring undefined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"CRISPR KASH disruption in cardiomyocytes showed nesprin-1 LINC complexes are the predominant nuclear anchor for microtubule cytoskeleton and motor components, and that removing this anchor suppresses Lmna-linked cardiac pathology by reducing microtubule-mediated nuclear force.\",\n      \"evidence\": \"CRISPR KASH-domain disruption, immunofluorescence of microtubule components, genetic epistasis with Lmna mutation\",\n      \"pmids\": [\"35925868\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which microtubule force damages Lmna-mutant nuclei not fully resolved\", \"Therapeutic generalizability beyond the model unknown\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How distinct nesprin-1 isoforms are deployed across tissues to selectively execute nuclear anchorage, microtubule/actin coupling, organelle positioning, mRNP/RNA-silencing, and trafficking functions—and how specific interaction losses map onto the spectrum of muscular, cardiac, neurological, and psychiatric phenotypes—remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No integrated structural model of the full-length scaffold and its multivalent interactions\", \"Isoform-specific in vivo functions not separated\", \"Causal links between molecular interaction defects and each disease phenotype incomplete\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [2, 12]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 5, 8, 13]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [5, 19, 27]},\n      {\"term_id\": \"GO:0003723\", \"supporting_discovery_ids\": [15, 21]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005635\", \"supporting_discovery_ids\": [0, 5, 7, 13]},\n      {\"term_id\": \"GO:0005794\", \"supporting_discovery_ids\": [1, 4]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [2, 13, 15, 19]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [26]},\n      {\"term_id\": \"GO:0005730\", \"supporting_discovery_ids\": [13]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [6, 8, 19, 26]},\n      {\"term_id\": \"R-HSA-397014\", \"supporting_discovery_ids\": [6, 7, 8, 14]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [5, 9, 10, 22]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [15, 21]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [1, 3, 4]}\n    ],\n    \"complexes\": [\"LINC complex\"],\n    \"partners\": [\"SUN2\", \"EMD\", \"LMNA\", \"KIF3B\", \"KLC1\", \"MSH2\", \"MSH6\", \"PCM1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}