{"gene":"LMNA","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":2003,"finding":"Complete absence of lamins A and C (homozygous Y259X mutation) causes mislocalization of emerin and nesprin-1alpha to the endoplasmic reticulum, and transfection of wild-type lamin A or C cDNA restores correct nuclear envelope anchorage of both proteins, demonstrating that lamin A or C is sufficient and required for proper localization of emerin and nesprin-1alpha at the nuclear envelope.","method":"Immunofluorescence microscopy of patient fibroblasts (homozygous and heterozygous LMNA null), cDNA rescue transfection","journal":"Experimental cell research","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal localization rescue with wild-type cDNA transfection in defined null cells, two orthogonal readouts (emerin and nesprin-1alpha), patient-derived and corrected cells","pmids":["14644157"],"is_preprint":false},{"year":2003,"finding":"The LMNA R377H missense mutation causes mislocalization of both lamin A/C and emerin in transfected muscle (C2C12) and non-muscle (COS-7) cells, indicating that this mutation disrupts lamina organization and emerin anchoring.","method":"Cell transfection experiments with immunofluorescence","journal":"Human mutation","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — single lab, single method (immunofluorescence in transfected cells), but clear functional readout","pmids":["12673789"],"is_preprint":false},{"year":2004,"finding":"The LMNA R377H mutation in AD-EDMD patient cells leads to instability (accelerated degradation) of lamin A protein, aberrant cytoplasmic localization of the lamin B receptor (LBR) in association with the ER, and altered intranuclear distribution of active RNA polymerase II specifically in muscle cells.","method":"Cell synchronization experiments, immunocytochemistry, electron microscopy in patient lymphoblastoid cells, fibroblasts, myoblasts and muscle tissue","journal":"BMC cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple cell types and multiple orthogonal methods in patient-derived cells, single lab","pmids":["15053843"],"is_preprint":false},{"year":2009,"finding":"The LMNA R439C mutation introduces an extra cysteine enabling disulfide-mediated lamin A/C oligomerization, which alters the DNA-binding properties of the C-terminal domain (gel retardation assay shows increased DNA-binding affinity compared to wild-type), and R439C patient fibroblasts show significantly elevated reactive oxygen species upon induction of oxidative stress.","method":"Gel retardation assays, electron spin resonance spectroscopy, immunofluorescence of patient fibroblasts","journal":"Journal of cellular and molecular medicine","confidence":"Medium","confidence_rationale":"Tier 1-2 / Moderate — in vitro biochemical assays (gel retardation, ESR) with patient fibroblasts, single lab, two orthogonal methods","pmids":["19220582"],"is_preprint":false},{"year":2010,"finding":"Pharmacological inhibition of JNK signaling with SP600125 in Lmna(H222P/H222P) mice (which show abnormally activated JNK in the heart) significantly delays left ventricular dilatation, prevents decreases in ejection fraction and fibrosis, and blocks upregulation of natriuretic peptide precursors and sarcomere architecture proteins, demonstrating a causal role for JNK pathway activation in LMNA cardiomyopathy.","method":"In vivo pharmacological treatment of Lmna(H222P/H222P) mouse model, echocardiography, Western blot, qPCR","journal":"Biochimica et biophysica acta","confidence":"High","confidence_rationale":"Tier 2 / Strong — clean genetic mouse model with pharmacological rescue, multiple cardiac function readouts, replication of ERK/JNK pathway finding from prior work","pmids":["20388542"],"is_preprint":false},{"year":2010,"finding":"The LMNA E82K mutation causes mislocalization of lamin A/C in the nucleus, induces swollen mitochondria with loss of cristae, and activates both FAS and mitochondrial apoptosis pathways (increased FAS expression, cytochrome c release, caspase-8/-9/-3 activation) in heart-specific transgenic mice, resulting in an 8.5-fold increase in apoptosis.","method":"Heart tissue-specific transgenic mouse model, immunofluorescence, electron microscopy, Western blot, echocardiography, TUNEL","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods in transgenic model, single lab","pmids":["21151901"],"is_preprint":false},{"year":2011,"finding":"AKT-mTOR signaling is hyperactivated in hearts of Lmna(H222P/H222P) mice; pharmacological reduction of mTOR activity ameliorates cardiomyopathy and this improvement correlates with restored autophagy, demonstrating that impaired autophagy downstream of hyperactivated AKT-mTOR contributes to LMNA cardiomyopathy pathogenesis.","method":"Western blot, mTOR inhibitor treatment, autophagy flux assays, echocardiography in Lmna(H222P/H222P) mice","journal":"Autophagy","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic mouse model with pharmacological rescue, multiple pathway readouts, echocardiographic functional outcomes, consistent with companion JBC study","pmids":["23044536"],"is_preprint":false},{"year":2012,"finding":"Dual specificity phosphatase 4 (Dusp4) is transcriptionally induced by ERK1/2 and is highly expressed in hearts of Lmna(H222P/H222P) mice; cardiac-selective Dusp4 overexpression in transgenic mice causes cardiomyopathy similar to LMNA cardiomyopathy by positively regulating AKT-mTOR signaling and impairing autophagy.","method":"Transgenic mouse overexpression, Western blot, AKT-mTOR pathway analysis, autophagy assays, echocardiography","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — gain-of-function transgenic model combined with in vitro cell overexpression, multiple orthogonal pathway readouts, functional cardiac phenotype","pmids":["23048029"],"is_preprint":false},{"year":2011,"finding":"SRSF2 binds to exon 11 sequences of the LMNA pre-mRNA and promotes splicing toward lamin A (versus lamin C); an antisense oligonucleotide targeting exon 11 increases lamin C production at the expense of prelamin A and reduces progerin expression in HGPS fibroblasts and in vivo in mice.","method":"ASO transfection, RNAi knockdown of SRSF2, RT-PCR, in vivo ASO administration in wild-type and HGPS mouse models","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — mechanistic identification of SRSF2 as a splice regulator with RNAi validation, plus in vivo ASO rescue, multiple orthogonal methods","pmids":["26999604"],"is_preprint":false},{"year":2011,"finding":"SR proteins SRSF1 and SRSF6 regulate utilization of the exon 11 5' splice site in LMNA pre-mRNA controlling lamin A vs. progerin production; SRSF1 depletion reduces progerin and rescues dysmorphic nuclei in HGPS-like MEFs, while SRSF6 depletion aggravates the phenotype. The HGPS c.1824C>T mutation changes RNA secondary structure accessibility of the 5' splice site.","method":"RNAi knockdown in HGPS mouse model MEFs, RNA structure analysis, RT-PCR, immunofluorescence, mutant mouse model","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — RNAi rescue experiments in vivo and in MEFs, RNA structural analysis, genetic mouse model with lifespan data, multiple orthogonal approaches","pmids":["21875900"],"is_preprint":false},{"year":2013,"finding":"The lipodystrophy-associated LMNA p.R482W mutation causes abnormal accumulation of prelamin A at the nuclear envelope in endothelial cells (due to decreased prelamin A maturation), induces endothelial dysfunction with decreased NO production, increased leukocyte adhesion, cellular senescence, oxidative stress, and DNA damage; these effects are prevented by pravastatin (which inhibits prelamin A farnesylation) or antioxidants.","method":"Lentiviral transduction of human coronary artery endothelial cells, patient fibroblast analysis, immunofluorescence, NO measurement, leukocyte adhesion assay, ROS measurement, pravastatin treatment","journal":"Arteriosclerosis, thrombosis, and vascular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal functional assays, pharmacological rescue with mechanistic target (farnesylation inhibitor), patient-derived and transduced cell comparisons","pmids":["23846499"],"is_preprint":false},{"year":2015,"finding":"Lamin A interacts with matrin-3 through the lamin A tail domain; anti-matrin-3 antibodies co-immunoprecipitate lamin A, the lamin-A binding domain maps to the carboxy-terminal half of matrin-3, and the LMNA truncating mutation Δ303 (lacking the matrin-3 binding domain) increases the 3D distance between lamin A and matrin-3 in cells.","method":"Co-immunoprecipitation, mass spectrometry pulldown of lamin A tail, domain mapping, 3D fluorescence microscopy in LMNA mutant cells","journal":"Human molecular genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP with domain mapping and 3D structural validation in mutant cells, single lab","pmids":["25948554"],"is_preprint":false},{"year":2019,"finding":"PDGF signaling pathway is aberrantly activated in LMNA-mutant iPSC-derived cardiomyocytes compared to isogenic controls; pharmacological and molecular inhibition of PDGF signaling (targeting PDGFRβ) ameliorates arrhythmic phenotypes and aberrant calcium homeostasis in mutant iPSC-CMs.","method":"Patient-specific iPSC-CMs with isogenic controls, electrophysiology, calcium imaging, pharmacological inhibition and molecular knockdown of PDGF pathway","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — isogenic control comparison, pharmacological and molecular (RNAi) rescue, multiple functional readouts (calcium, electrophysiology), high-quality journal","pmids":["31316208"],"is_preprint":false},{"year":2019,"finding":"Cardiac myocyte-specific expression of the LMNA D300N mutation activates the E2F/DNA damage response/TP53 pathway; conditional deletion of Tp53 in cardiac myocytes of LMNA D300N mice partially rescues myocardial fibrosis, apoptosis, left ventricular dilatation and dysfunction, demonstrating a causal pathogenic role for this pathway.","method":"Tet-off bigenic mouse model, conditional Tp53 knockout, RNA-seq, Western blot, immunofluorescence, echocardiography, survival analysis","journal":"Circulation research","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis (conditional KO rescue), RNA-seq pathway validation, multiple orthogonal methods, rescue of functional cardiac phenotype","pmids":["30696354"],"is_preprint":false},{"year":2020,"finding":"Sarcolipin, an inhibitor of SERCA (SR Ca2+ ATPase), is abnormally elevated early in the disease course of Lmna(H222P/H222P) mice (before left ventricular functional changes), altering calcium handling; AAV9-mediated RNAi knockdown of sarcolipin delays cardiac dysfunction in this mouse model.","method":"Western blot and qPCR in mouse hearts, AAV9-RNAi knockdown, calcium handling assays, echocardiography","journal":"Biochemistry and biophysics reports","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo AAV rescue experiment with functional readouts, single lab, consistent genetic mouse model","pmids":["32490213"],"is_preprint":false},{"year":2021,"finding":"Pathogenic LMNA mutations from DCM patients introduced into hiPSCs cause specific disruptions of peripheral chromatin interactions in cardiomyocytes (but not hepatocytes or adipocytes), enriched for transcriptionally active genes with lower LAMIN B1 contact frequency; disrupted lamina-chromatin regions are enriched for non-myocyte lineage genes whose expression is aberrantly upregulated, suggesting the lamina network safeguards cardiomyocyte identity.","method":"Isogenic hiPSC-derived cardiomyocytes, hepatocytes, adipocytes; DamID lamina-chromatin interaction profiling, RNA-seq, nuclear morphology analysis, patient myocardium analysis","journal":"Cell stem cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — isogenic hiPSC system with three cell types, DamID + RNA-seq integration, patient tissue validation, multiple orthogonal approaches","pmids":["33529599"],"is_preprint":false},{"year":2022,"finding":"In LMNA-mutant cardiomyopathy, ERK1/2-phosphorylated cofilin-1 (phospho-T25) binds MRTF-A in the cytoplasm, preventing SRF nuclear activation and reducing ATAT1 (α-tubulin acetyltransferase 1) expression, thereby decreasing α-tubulin acetylation; tubastatin A treatment to increase α-tubulin acetylation restores Connexin 43 localization and improves cardiac function in Lmna(H222P/H222P) mice.","method":"Co-immunoprecipitation (phospho-cofilin-1/MRTF-A), Atat1 knockout mice, tubastatin A pharmacological treatment, immunofluorescence, echocardiography, patient-derived iPSC-CMs","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP demonstrating molecular interaction, genetic knockout model (Atat1 KO), pharmacological rescue in vivo, patient iPSC-CM validation, multiple orthogonal approaches","pmids":["36550158"],"is_preprint":false},{"year":2022,"finding":"Nesprin-1 LINC complexes are the predominant nuclear envelope anchor for microtubule cytoskeleton components (nucleation activities and motor complexes) in cardiomyocytes; CRISPR-mediated disruption of the Nesprin-1 KASH domain suppresses Lmna-linked cardiac pathology, likely by reducing microtubule cytoskeleton activities at the nucleus.","method":"CRISPR disruption of Nesprin-1 KASH domain in Lmna-mutant mice, immunofluorescence for microtubule components at the nucleus, cardiac phenotype assessment","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis (CRISPR KASH disruption suppresses Lmna pathology), mechanistic identification of Nesprin-1 as microtubule anchor, in vivo cardiac rescue","pmids":["35925868"],"is_preprint":false},{"year":2022,"finding":"BAF (Barrier-to-Autointegration Factor) recruits a mobile, nucleoplasmic population of A-type lamins to sites of nuclear rupture via its association with the Ig-like β-fold domain of A-type lamins; farnesylated prelamin A and lamin B1 fail to localize to nuclear ruptures (unless farnesylation is inhibited); progeria-associated LMNA mutations inhibit recruitment of A-type lamins to ruptures due to permanent farnesylation or inhibition of BAF binding.","method":"Live-cell imaging of nuclear rupture/repair, domain mapping, farnesylation inhibitor treatment, FRAP-like analysis, progeria mutant cell lines","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — live imaging with domain-specific mutants and pharmacological inhibition, single lab, mechanistically detailed","pmids":["35269487"],"is_preprint":false},{"year":2022,"finding":"Lmna deletion in cardiac fibroblasts (Pdgfra-Cre) induces double-stranded DNA breaks, activates the DNA damage response (phospho-H2AFX, ATM, phospho-TP53, CDKN1A), and induces senescence-associated secretory phenotype (SASP: TGFβ1, CTGF, LGALS3), partially recapitulating the DCM phenotype and demonstrating that LMNA deficiency in fibroblasts contributes to DCM through DDR/SASP mechanisms.","method":"Conditional Lmna knockout in fibroblasts (Pdgfra-Cre:Lmna F/F), RNA-seq, Western blot for DDR markers, beta-galactosidase senescence assay, echocardiography","journal":"The journal of cardiovascular aging","confidence":"High","confidence_rationale":"Tier 2 / Strong — cell-type-specific conditional knockout with RNA-seq, multiple protein markers, functional cardiac phenotype","pmids":["35891706"],"is_preprint":false},{"year":2023,"finding":"LMNA mutant iPSC-CMs show altered nuclear shape/size and reduced nuclear stiffness and fragility (especially R249Q mutation); the degree of nuclear abnormalities correlates with mislocalization of Lamin A/C and Lamin B1 from the nuclear envelope, with mislocalization likely due to altered lamin assembly.","method":"Patient-specific iPSC-CMs, atomic force microscopy (nuclear stiffness), immunofluorescence quantification of lamin localization, nuclear morphometry","journal":"Molecular biology of the cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biophysical measurement of nuclear stiffness with AFM, correlative immunofluorescence, multiple LMNA mutant lines, single lab","pmids":["37585285"],"is_preprint":false},{"year":2024,"finding":"Lamin A physically interacts with c-Myc, inhibiting c-Myc transactivation of tRNA processing genes (EPRS, LARS), thereby suppressing the malate-aspartate shuttle (MAS), aerobic glycolysis, and neuroblastoma tumorigenesis; co-immunoprecipitation and mass spectrometry confirmed the lamin A–c-Myc interaction, and the LMNA-binding compound lobeline facilitates this interaction to suppress tumor progression.","method":"Co-immunoprecipitation, mass spectrometry, dual-luciferase reporter, chromatin immunoprecipitation, Western blot, RT-PCR, organoid models from c-Myc knock-in mice","journal":"Clinical and translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP/MS and ChIP validation of interaction and transcriptional mechanism, multiple functional assays, single lab","pmids":["38769668"],"is_preprint":false},{"year":2024,"finding":"Cardiomyocyte-specific Lmna deletion in adult mice causes rapid cardiomyopathy preceded by nuclear abnormalities, Golgi dilation/fragmentation, and CREB3-mediated stress activation; MED25 (a transcriptional cofactor regulating Golgi stress) is activated; autophagy is disrupted. Modulators of autophagy or ER stress significantly delayed cardiac dysfunction and prolonged survival.","method":"Conditional cardiomyocyte-specific Lmna deletion, translatome profiling, immunofluorescence for Golgi markers, pharmacological modulators of autophagy/ER stress, echocardiography, survival analysis","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional cardiac-specific KO with translatome profiling, Golgi/ER stress mechanistic pathway identification, pharmacological rescue with survival benefit","pmids":["38718107"],"is_preprint":false},{"year":2021,"finding":"LMNA regulates transcription through lamin-associated domains (LADs) in cardiac myocytes; LAD-associated genes have ~16-fold lower transcript levels than non-LAD genes; in Lmna-deficient cardiomyocytes, double-stranded DNA breaks are enriched in non-LAD and loss-of-LAD regions associated with transcription.","method":"END-Sequencing for genome-wide DSBs, CUT&RUN for LAD definition in cardiac myocytes (Myh6-Cre:LmnaF/F mice), RNA-seq","journal":"Cardiovascular research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — specialized genome-wide sequencing methods (END-seq, CUT&RUN) in cardiac-specific KO, single lab, first-in-cardiovascular-system application","pmids":["38577741"],"is_preprint":false}],"current_model":"Lamin A/C (LMNA) is an intermediate filament protein of the nuclear lamina that physically anchors emerin and nesprin-1alpha at the nuclear envelope, interacts with chromatin through lamin-associated domains to silence non-lineage genes and safeguard cell identity, binds BAF to enable nuclear rupture repair, and interacts with nuclear partners including matrin-3 and c-Myc; LMNA mutations cause cardiomyopathy through aberrant activation of ERK1/2→JNK/Dusp4-AKT-mTOR signaling with impaired autophagy, PDGF pathway activation, E2F/DNA damage/TP53 pathway induction, disrupted actin-microtubule crosstalk via cofilin-1/MRTF-A/SRF/ATAT1, Nesprin-1 LINC complex-mediated mechanical stress transmission, and perinuclear Golgi/ER stress; aberrant LMNA splicing (regulated by SRSF1/SRSF2) produces pathogenic progerin that accumulates due to farnesylation and disrupts nuclear rupture repair."},"narrative":{"mechanistic_narrative":"Lamin A/C is a nuclear lamina component that organizes the nuclear envelope and safeguards cell identity, and whose mutation drives cardiomyopathy through a convergent network of stress and signaling pathways [PMID:14644157, PMID:33529599]. At the nuclear envelope, lamin A/C is required and sufficient to anchor emerin and nesprin-1alpha, and its loss or mutation mislocalizes these partners to the ER [PMID:14644157, PMID:12673789, PMID:15053843]. The lamina tethers chromatin through lamin-associated domains (LADs) that hold non-lineage genes in a transcriptionally repressed state; pathogenic mutations selectively disrupt peripheral chromatin contacts in cardiomyocytes and aberrantly upregulate non-myocyte lineage genes, eroding cardiomyocyte identity [PMID:33529599, PMID:38577741]. Lamin A/C additionally interacts with matrin-3 through its tail domain and with c-Myc, restraining c-Myc-driven transcription of tRNA-processing genes [PMID:25948554, PMID:38769668], and a nucleoplasmic pool is recruited by BAF to sites of nuclear envelope rupture, a repair function blocked by progeria-associated farnesylation [PMID:35269487]. Mutations confer mechanical fragility, reducing nuclear stiffness and altering nuclear shape [PMID:37585285]. LMNA cardiomyopathy proceeds through aberrant activation of ERK1/2-JNK and Dusp4-AKT-mTOR signaling with impaired autophagy [PMID:20388542, PMID:23044536, PMID:23048029], E2F/DNA-damage/TP53 induction [PMID:30696354, PMID:35891706], PDGF pathway activation [PMID:31316208], disrupted actin-microtubule crosstalk via cofilin-1/MRTF-A/SRF/ATAT1 [PMID:36550158], Nesprin-1 LINC-mediated mechanical stress transmission [PMID:35925868], and Golgi/ER stress [PMID:38718107]; pharmacological or genetic interruption of each pathway rescues cardiac function in mouse and iPSC models. Aberrant LMNA splicing controlled by SRSF1/SRSF2/SRSF6 governs production of the farnesylated progerin isoform [PMID:26999604, PMID:21875900].","teleology":[{"year":2003,"claim":"Established that lamin A/C is the obligate nuclear-envelope anchor for emerin and nesprin-1alpha, defining its structural role at the lamina.","evidence":"Immunofluorescence of LMNA-null patient fibroblasts with wild-type cDNA rescue; transfection of R377H mutant","pmids":["14644157","12673789"],"confidence":"High","gaps":["Does not define the binding interface on lamin A/C for each partner","Mechanism linking mislocalization to tissue-specific disease not addressed"]},{"year":2004,"claim":"Showed disease mutations destabilize lamin A and perturb additional envelope and transcription machinery in muscle, hinting at tissue-selective consequences.","evidence":"Immunocytochemistry, EM and cell synchronization in R377H AD-EDMD patient cells","pmids":["15053843"],"confidence":"Medium","gaps":["Single mutation in one patient lineage","Causal link between LBR/RNA Pol II changes and muscle phenotype not established"]},{"year":2009,"claim":"Demonstrated a mutation can directly alter lamin A/C biochemistry, changing DNA-binding via aberrant disulfide oligomerization and raising oxidative stress.","evidence":"Gel retardation, ESR spectroscopy, immunofluorescence in R439C patient fibroblasts","pmids":["19220582"],"confidence":"Medium","gaps":["In vitro DNA-binding change not connected to specific gene-regulatory outcome in vivo","Single lab"]},{"year":2010,"claim":"Identified JNK and FAS/mitochondrial apoptosis activation as causal contributors to LMNA cardiomyopathy, converting correlative pathway changes into therapeutic targets.","evidence":"SP600125 JNK inhibition in Lmna(H222P/H222P) mice; E82K cardiac transgenic mice with TUNEL/caspase analysis","pmids":["20388542","21151901"],"confidence":"High","gaps":["How nuclear lamina defects activate cytoplasmic JNK signaling is unresolved","Apoptosis findings rely on a single transgenic model"]},{"year":2011,"claim":"Defined the AKT-mTOR/autophagy axis and its driver Dusp4 as a pathogenic mechanism, linking aberrant signaling to defective protein quality control.","evidence":"mTOR inhibitor rescue and autophagy flux assays in Lmna(H222P/H222P) mice; Dusp4-overexpressing transgenic mice","pmids":["23044536","23048029"],"confidence":"High","gaps":["Upstream coupling of lamin defect to ERK1/2-Dusp4 induction not mechanistically resolved","Restricted to one Lmna mouse allele"]},{"year":2011,"claim":"Identified SR proteins (SRSF1, SRSF2, SRSF6) as regulators of LMNA exon 11 splicing that control lamin A versus progerin production, enabling antisense correction strategies.","evidence":"RNAi knockdown, RNA structure analysis, RT-PCR and in vivo ASO administration in HGPS mouse models and MEFs","pmids":["26999604","21875900"],"confidence":"High","gaps":["How splice-factor activity is regulated in different tissues not defined","Relevance to non-progeria LMNA isoform balance unclear"]},{"year":2013,"claim":"Connected prelamin A accumulation and farnesylation to endothelial dysfunction in lipodystrophy, with statin/antioxidant rescue implicating maturation defects.","evidence":"Lentiviral R482W expression in endothelial cells, NO/ROS/adhesion assays, pravastatin treatment","pmids":["23846499"],"confidence":"High","gaps":["Cell-type specificity of prelamin A maturation defect not explained","Link to systemic lipodystrophy phenotype indirect"]},{"year":2015,"claim":"Mapped a direct lamin A tail interaction with matrin-3, adding a nucleoplasmic binding partner disrupted by truncating mutations.","evidence":"Reciprocal Co-IP, mass spectrometry pulldown, domain mapping, 3D microscopy in LMNA mutant cells","pmids":["25948554"],"confidence":"Medium","gaps":["Functional consequence of the interaction not established","Single lab"]},{"year":2019,"claim":"Established PDGF signaling and the E2F/DNA-damage/TP53 pathway as causal, druggable drivers of LMNA cardiac dysfunction using isogenic and genetic-epistasis approaches.","evidence":"Isogenic iPSC-CMs with PDGFRb inhibition/knockdown; conditional Tp53 deletion in LMNA D300N mice","pmids":["31316208","30696354"],"confidence":"High","gaps":["How lamina disruption activates PDGF and E2F/TP53 pathways mechanistically unresolved","Tp53 deletion provides only partial rescue"]},{"year":2021,"claim":"Showed the lamina safeguards cardiomyocyte identity via LAD-mediated chromatin tethering and genome stability, linking lamina-chromatin contacts to lineage gene silencing and DSB localization.","evidence":"Isogenic hiPSC-derived cell types with DamID/CUT&RUN, END-seq and RNA-seq","pmids":["33529599","38577741"],"confidence":"High","gaps":["Molecular basis of cell-type-selective LAD disruption not defined","Causal order between chromatin detachment and gene misregulation unresolved"]},{"year":2022,"claim":"Resolved cytoskeletal and mechanotransduction mechanisms — cofilin-1/MRTF-A/SRF/ATAT1 tubulin acetylation and Nesprin-1 LINC microtubule anchoring — and BAF-dependent nuclear rupture repair, broadening the pathogenic network.","evidence":"Co-IP, Atat1 KO and tubastatin A rescue; CRISPR Nesprin-1 KASH disruption in Lmna mice; live-cell nuclear rupture imaging with farnesylation inhibition","pmids":["36550158","35925868","35269487","35891706"],"confidence":"High","gaps":["Integration of these parallel pathways into a single hierarchy not established","BAF-rupture repair findings from a single lab"]},{"year":2024,"claim":"Extended the mechanism to Golgi/ER stress and CREB3/MED25 signaling in acute cardiac Lmna loss, and revealed a tumor-suppressive lamin A-c-Myc transcriptional axis outside the heart.","evidence":"Conditional cardiomyocyte Lmna deletion with translatome profiling and autophagy/ER-stress modulators; Co-IP/MS, ChIP and organoid assays for c-Myc interaction","pmids":["38718107","38769668"],"confidence":"High","gaps":["Whether Golgi stress is primary or downstream of other pathways unclear","c-Myc axis characterized in neuroblastoma, generalizability untested"]},{"year":null,"claim":"How a single lamina defect is funneled into the many distinct downstream pathways (JNK/mTOR, PDGF, TP53, cytoskeletal, Golgi stress) and which are primary versus secondary remains unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No unified hierarchy linking nuclear-envelope perturbation to the divergent effector pathways","Tissue specificity of LMNA disease mechanisms not mechanistically explained"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[3]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,20]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[15,21,23]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,17]}],"localization":[{"term_id":"GO:0005635","term_label":"nuclear envelope","supporting_discovery_ids":[0,1,18]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[5,20]},{"term_id":"GO:0000228","term_label":"nuclear chromosome","supporting_discovery_ids":[15,23]},{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[11,18]}],"pathway":[{"term_id":"R-HSA-4839726","term_label":"Chromatin organization","supporting_discovery_ids":[15,23]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[15,21,23]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[4,6,7,12]},{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[6,22]},{"term_id":"R-HSA-73894","term_label":"DNA Repair","supporting_discovery_ids":[13,19]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[8,9]},{"term_id":"R-HSA-397014","term_label":"Muscle contraction","supporting_discovery_ids":[16,17]}],"complexes":["nuclear lamina","LINC complex"],"partners":["EMD","SYNE1","MATR3","MYC","BANF1","LBR"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P02545","full_name":"Prelamin-A/C","aliases":[],"length_aa":664,"mass_kda":74.1,"function":"Lamins are intermediate filament proteins that assemble into a filamentous meshwork, and which constitute the major components of the nuclear lamina, a fibrous layer on the nucleoplasmic side of the inner nuclear membrane (PubMed:10080180, PubMed:10580070, PubMed:10587585, PubMed:10814726, PubMed:11799477, PubMed:12075506, PubMed:12927431, PubMed:15317753, PubMed:18551513, PubMed:18611980, PubMed:2188730, PubMed:22431096, PubMed:2344612, PubMed:23666920, PubMed:24741066, PubMed:31434876, PubMed:31548606, PubMed:37788673, PubMed:37832547). Lamins provide a framework for the nuclear envelope, bridging the nuclear envelope and chromatin, thereby playing an important role in nuclear assembly, chromatin organization, nuclear membrane and telomere dynamics (PubMed:10080180, PubMed:10580070, PubMed:10587585, PubMed:10814726, PubMed:11799477, PubMed:12075506, PubMed:12927431, PubMed:15317753, PubMed:18551513, PubMed:18611980, PubMed:22431096, PubMed:23666920, PubMed:24741066, PubMed:31548606, PubMed:37788673, PubMed:37832547). Lamin A and C also regulate matrix stiffness by conferring nuclear mechanical properties (PubMed:23990565, PubMed:25127216). The structural integrity of the lamina is strictly controlled by the cell cycle, as seen by the disintegration and formation of the nuclear envelope in prophase and telophase, respectively (PubMed:2188730, PubMed:2344612). Lamin A and C are present in equal amounts in the lamina of mammals (PubMed:10080180, PubMed:10580070, PubMed:10587585, PubMed:10814726, PubMed:11799477, PubMed:12075506, PubMed:12927431, PubMed:15317753, PubMed:18551513, PubMed:18611980, PubMed:22431096, PubMed:23666920, PubMed:31548606). Also involved in DNA repair: recruited by DNA repair proteins XRCC4 and IFFO1 to the DNA double-strand breaks (DSBs) to prevent chromosome translocation by immobilizing broken DNA ends (PubMed:31548606). Required for normal development of peripheral nervous system and skeletal muscle and for muscle satellite cell proliferation (PubMed:10080180, PubMed:10814726, PubMed:11799477, PubMed:18551513, PubMed:22431096). Required for osteoblastogenesis and bone formation (PubMed:12075506, PubMed:15317753, PubMed:18611980). Also prevents fat infiltration of muscle and bone marrow, helping to maintain the volume and strength of skeletal muscle and bone (PubMed:10587585). Required for cardiac homeostasis (PubMed:10580070, PubMed:12927431, PubMed:18611980, PubMed:23666920) Prelamin-A/C can accelerate smooth muscle cell senescence (PubMed:20458013). 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epigenetics","url":"https://pubmed.ncbi.nlm.nih.gov/33407844","citation_count":17,"is_preprint":false},{"pmid":"34975533","id":"PMC_34975533","title":"Phenotypic Variability in iPSC-Induced Cardiomyocytes and Cardiac Fibroblasts Carrying Diverse LMNA Mutations.","date":"2021","source":"Frontiers in physiology","url":"https://pubmed.ncbi.nlm.nih.gov/34975533","citation_count":17,"is_preprint":false},{"pmid":"21980471","id":"PMC_21980471","title":"Low and high expressing alleles of the LMNA gene: implications for laminopathy disease development.","date":"2011","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/21980471","citation_count":17,"is_preprint":false},{"pmid":"31668660","id":"PMC_31668660","title":"Expression of Lmna-R225X nonsense mutation results in dilated cardiomyopathy and conduction disorders (DCM-CD) in mice: Impact of exercise training.","date":"2019","source":"International journal of cardiology","url":"https://pubmed.ncbi.nlm.nih.gov/31668660","citation_count":16,"is_preprint":false},{"pmid":"35714719","id":"PMC_35714719","title":"The LMNA p.R541C mutation causes dilated cardiomyopathy in human and mice.","date":"2022","source":"International journal of cardiology","url":"https://pubmed.ncbi.nlm.nih.gov/35714719","citation_count":15,"is_preprint":false},{"pmid":"38769668","id":"PMC_38769668","title":"Targeting c-Myc transactivation by LMNA inhibits tRNA processing essential for malate-aspartate shuttle and tumour progression.","date":"2024","source":"Clinical and translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/38769668","citation_count":14,"is_preprint":false},{"pmid":"37125775","id":"PMC_37125775","title":"Modulation of cytoskeleton in cardiomyopathy caused by mutations in LMNA gene.","date":"2023","source":"American journal of physiology. Cell physiology","url":"https://pubmed.ncbi.nlm.nih.gov/37125775","citation_count":14,"is_preprint":false},{"pmid":"32913962","id":"PMC_32913962","title":"Atypical Progeroid Syndrome and Partial Lipodystrophy Due to LMNA Gene p.R349W Mutation.","date":"2020","source":"Journal of the Endocrine Society","url":"https://pubmed.ncbi.nlm.nih.gov/32913962","citation_count":14,"is_preprint":false},{"pmid":"24294364","id":"PMC_24294364","title":"Investigation of age-related changes in LMNA splicing and expression of progerin in human skeletal muscles.","date":"2013","source":"International journal of clinical and experimental pathology","url":"https://pubmed.ncbi.nlm.nih.gov/24294364","citation_count":14,"is_preprint":false},{"pmid":"17107595","id":"PMC_17107595","title":"Myofiber degeneration in autosomal dominant Emery-Dreifuss muscular dystrophy (AD-EDMD) (LGMD1B).","date":"2006","source":"Brain pathology (Zurich, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/17107595","citation_count":14,"is_preprint":false},{"pmid":"38718107","id":"PMC_38718107","title":"Perinuclear damage from nuclear envelope deterioration elicits stress responses that contribute to LMNA cardiomyopathy.","date":"2024","source":"Science advances","url":"https://pubmed.ncbi.nlm.nih.gov/38718107","citation_count":13,"is_preprint":false},{"pmid":"36515663","id":"PMC_36515663","title":"Efficacy and Safety of ARRY-371797 in LMNA-Related Dilated Cardiomyopathy: A Phase 2 Study.","date":"2022","source":"Circulation. Genomic and precision medicine","url":"https://pubmed.ncbi.nlm.nih.gov/36515663","citation_count":13,"is_preprint":false},{"pmid":"27373676","id":"PMC_27373676","title":"A novel nonsense mutation in LMNA gene identified by Exome Sequencing in an atrial fibrillation family.","date":"2016","source":"European journal of medical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/27373676","citation_count":13,"is_preprint":false},{"pmid":"38577741","id":"PMC_38577741","title":"DNA double-stranded breaks, a hallmark of aging, defined at the nucleotide resolution, are increased and associated with transcription in the cardiac myocytes in LMNA-cardiomyopathy.","date":"2025","source":"Cardiovascular research","url":"https://pubmed.ncbi.nlm.nih.gov/38577741","citation_count":12,"is_preprint":false},{"pmid":"24642510","id":"PMC_24642510","title":"Congenital fiber type disproportion myopathy caused by LMNA mutations.","date":"2014","source":"Journal of the neurological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/24642510","citation_count":12,"is_preprint":false},{"pmid":"37840136","id":"PMC_37840136","title":"Systematic in vivo candidate evaluation uncovers therapeutic targets for LMNA dilated cardiomyopathy and risk of Lamin A toxicity.","date":"2023","source":"Journal of translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/37840136","citation_count":12,"is_preprint":false},{"pmid":"39827909","id":"PMC_39827909","title":"LMNA-related cardiomyopathy: From molecular pathology to cardiac gene therapy.","date":"2025","source":"Journal of advanced research","url":"https://pubmed.ncbi.nlm.nih.gov/39827909","citation_count":11,"is_preprint":false},{"pmid":"40601341","id":"PMC_40601341","title":"Location of LMNA Variants and Clinical Outcomes in Cardiomyopathy.","date":"2025","source":"JAMA cardiology","url":"https://pubmed.ncbi.nlm.nih.gov/40601341","citation_count":11,"is_preprint":false},{"pmid":"25988045","id":"PMC_25988045","title":"LMNA-related dilated cardiomyopathy.","date":"2014","source":"Oxford medical case reports","url":"https://pubmed.ncbi.nlm.nih.gov/25988045","citation_count":11,"is_preprint":false},{"pmid":"28857661","id":"PMC_28857661","title":"Identification of novel RNA isoforms of LMNA.","date":"2017","source":"Nucleus (Austin, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/28857661","citation_count":11,"is_preprint":false},{"pmid":"24639906","id":"PMC_24639906","title":"Mandibuloacral Dysplasia Caused by LMNA Mutations and Uniparental Disomy.","date":"2014","source":"Case reports in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/24639906","citation_count":11,"is_preprint":false},{"pmid":"20501691","id":"PMC_20501691","title":"LMNA rs4641 and the muscle lamin A and C isoforms in twins--metabolic implications and transcriptional regulation.","date":"2010","source":"The Journal of clinical endocrinology and metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/20501691","citation_count":11,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":50761,"output_tokens":6435,"usd":0.124404,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":15445,"output_tokens":4417,"usd":0.093825,"stage2_stop_reason":"end_turn"},"total_usd":0.218229,"stage1_batch_id":"msgbatch_01BbTCMyrRPyhtEq6b1MdwCN","stage2_batch_id":"msgbatch_011dEed5bbxYvTAaQWKJevxu","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2003,\n      \"finding\": \"Complete absence of lamins A and C (homozygous Y259X mutation) causes mislocalization of emerin and nesprin-1alpha to the endoplasmic reticulum, and transfection of wild-type lamin A or C cDNA restores correct nuclear envelope anchorage of both proteins, demonstrating that lamin A or C is sufficient and required for proper localization of emerin and nesprin-1alpha at the nuclear envelope.\",\n      \"method\": \"Immunofluorescence microscopy of patient fibroblasts (homozygous and heterozygous LMNA null), cDNA rescue transfection\",\n      \"journal\": \"Experimental cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal localization rescue with wild-type cDNA transfection in defined null cells, two orthogonal readouts (emerin and nesprin-1alpha), patient-derived and corrected cells\",\n      \"pmids\": [\"14644157\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"The LMNA R377H missense mutation causes mislocalization of both lamin A/C and emerin in transfected muscle (C2C12) and non-muscle (COS-7) cells, indicating that this mutation disrupts lamina organization and emerin anchoring.\",\n      \"method\": \"Cell transfection experiments with immunofluorescence\",\n      \"journal\": \"Human mutation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — single lab, single method (immunofluorescence in transfected cells), but clear functional readout\",\n      \"pmids\": [\"12673789\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"The LMNA R377H mutation in AD-EDMD patient cells leads to instability (accelerated degradation) of lamin A protein, aberrant cytoplasmic localization of the lamin B receptor (LBR) in association with the ER, and altered intranuclear distribution of active RNA polymerase II specifically in muscle cells.\",\n      \"method\": \"Cell synchronization experiments, immunocytochemistry, electron microscopy in patient lymphoblastoid cells, fibroblasts, myoblasts and muscle tissue\",\n      \"journal\": \"BMC cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple cell types and multiple orthogonal methods in patient-derived cells, single lab\",\n      \"pmids\": [\"15053843\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"The LMNA R439C mutation introduces an extra cysteine enabling disulfide-mediated lamin A/C oligomerization, which alters the DNA-binding properties of the C-terminal domain (gel retardation assay shows increased DNA-binding affinity compared to wild-type), and R439C patient fibroblasts show significantly elevated reactive oxygen species upon induction of oxidative stress.\",\n      \"method\": \"Gel retardation assays, electron spin resonance spectroscopy, immunofluorescence of patient fibroblasts\",\n      \"journal\": \"Journal of cellular and molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — in vitro biochemical assays (gel retardation, ESR) with patient fibroblasts, single lab, two orthogonal methods\",\n      \"pmids\": [\"19220582\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Pharmacological inhibition of JNK signaling with SP600125 in Lmna(H222P/H222P) mice (which show abnormally activated JNK in the heart) significantly delays left ventricular dilatation, prevents decreases in ejection fraction and fibrosis, and blocks upregulation of natriuretic peptide precursors and sarcomere architecture proteins, demonstrating a causal role for JNK pathway activation in LMNA cardiomyopathy.\",\n      \"method\": \"In vivo pharmacological treatment of Lmna(H222P/H222P) mouse model, echocardiography, Western blot, qPCR\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — clean genetic mouse model with pharmacological rescue, multiple cardiac function readouts, replication of ERK/JNK pathway finding from prior work\",\n      \"pmids\": [\"20388542\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"The LMNA E82K mutation causes mislocalization of lamin A/C in the nucleus, induces swollen mitochondria with loss of cristae, and activates both FAS and mitochondrial apoptosis pathways (increased FAS expression, cytochrome c release, caspase-8/-9/-3 activation) in heart-specific transgenic mice, resulting in an 8.5-fold increase in apoptosis.\",\n      \"method\": \"Heart tissue-specific transgenic mouse model, immunofluorescence, electron microscopy, Western blot, echocardiography, TUNEL\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods in transgenic model, single lab\",\n      \"pmids\": [\"21151901\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"AKT-mTOR signaling is hyperactivated in hearts of Lmna(H222P/H222P) mice; pharmacological reduction of mTOR activity ameliorates cardiomyopathy and this improvement correlates with restored autophagy, demonstrating that impaired autophagy downstream of hyperactivated AKT-mTOR contributes to LMNA cardiomyopathy pathogenesis.\",\n      \"method\": \"Western blot, mTOR inhibitor treatment, autophagy flux assays, echocardiography in Lmna(H222P/H222P) mice\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic mouse model with pharmacological rescue, multiple pathway readouts, echocardiographic functional outcomes, consistent with companion JBC study\",\n      \"pmids\": [\"23044536\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Dual specificity phosphatase 4 (Dusp4) is transcriptionally induced by ERK1/2 and is highly expressed in hearts of Lmna(H222P/H222P) mice; cardiac-selective Dusp4 overexpression in transgenic mice causes cardiomyopathy similar to LMNA cardiomyopathy by positively regulating AKT-mTOR signaling and impairing autophagy.\",\n      \"method\": \"Transgenic mouse overexpression, Western blot, AKT-mTOR pathway analysis, autophagy assays, echocardiography\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — gain-of-function transgenic model combined with in vitro cell overexpression, multiple orthogonal pathway readouts, functional cardiac phenotype\",\n      \"pmids\": [\"23048029\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"SRSF2 binds to exon 11 sequences of the LMNA pre-mRNA and promotes splicing toward lamin A (versus lamin C); an antisense oligonucleotide targeting exon 11 increases lamin C production at the expense of prelamin A and reduces progerin expression in HGPS fibroblasts and in vivo in mice.\",\n      \"method\": \"ASO transfection, RNAi knockdown of SRSF2, RT-PCR, in vivo ASO administration in wild-type and HGPS mouse models\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — mechanistic identification of SRSF2 as a splice regulator with RNAi validation, plus in vivo ASO rescue, multiple orthogonal methods\",\n      \"pmids\": [\"26999604\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"SR proteins SRSF1 and SRSF6 regulate utilization of the exon 11 5' splice site in LMNA pre-mRNA controlling lamin A vs. progerin production; SRSF1 depletion reduces progerin and rescues dysmorphic nuclei in HGPS-like MEFs, while SRSF6 depletion aggravates the phenotype. The HGPS c.1824C>T mutation changes RNA secondary structure accessibility of the 5' splice site.\",\n      \"method\": \"RNAi knockdown in HGPS mouse model MEFs, RNA structure analysis, RT-PCR, immunofluorescence, mutant mouse model\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — RNAi rescue experiments in vivo and in MEFs, RNA structural analysis, genetic mouse model with lifespan data, multiple orthogonal approaches\",\n      \"pmids\": [\"21875900\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"The lipodystrophy-associated LMNA p.R482W mutation causes abnormal accumulation of prelamin A at the nuclear envelope in endothelial cells (due to decreased prelamin A maturation), induces endothelial dysfunction with decreased NO production, increased leukocyte adhesion, cellular senescence, oxidative stress, and DNA damage; these effects are prevented by pravastatin (which inhibits prelamin A farnesylation) or antioxidants.\",\n      \"method\": \"Lentiviral transduction of human coronary artery endothelial cells, patient fibroblast analysis, immunofluorescence, NO measurement, leukocyte adhesion assay, ROS measurement, pravastatin treatment\",\n      \"journal\": \"Arteriosclerosis, thrombosis, and vascular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal functional assays, pharmacological rescue with mechanistic target (farnesylation inhibitor), patient-derived and transduced cell comparisons\",\n      \"pmids\": [\"23846499\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"Lamin A interacts with matrin-3 through the lamin A tail domain; anti-matrin-3 antibodies co-immunoprecipitate lamin A, the lamin-A binding domain maps to the carboxy-terminal half of matrin-3, and the LMNA truncating mutation Δ303 (lacking the matrin-3 binding domain) increases the 3D distance between lamin A and matrin-3 in cells.\",\n      \"method\": \"Co-immunoprecipitation, mass spectrometry pulldown of lamin A tail, domain mapping, 3D fluorescence microscopy in LMNA mutant cells\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP with domain mapping and 3D structural validation in mutant cells, single lab\",\n      \"pmids\": [\"25948554\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"PDGF signaling pathway is aberrantly activated in LMNA-mutant iPSC-derived cardiomyocytes compared to isogenic controls; pharmacological and molecular inhibition of PDGF signaling (targeting PDGFRβ) ameliorates arrhythmic phenotypes and aberrant calcium homeostasis in mutant iPSC-CMs.\",\n      \"method\": \"Patient-specific iPSC-CMs with isogenic controls, electrophysiology, calcium imaging, pharmacological inhibition and molecular knockdown of PDGF pathway\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — isogenic control comparison, pharmacological and molecular (RNAi) rescue, multiple functional readouts (calcium, electrophysiology), high-quality journal\",\n      \"pmids\": [\"31316208\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Cardiac myocyte-specific expression of the LMNA D300N mutation activates the E2F/DNA damage response/TP53 pathway; conditional deletion of Tp53 in cardiac myocytes of LMNA D300N mice partially rescues myocardial fibrosis, apoptosis, left ventricular dilatation and dysfunction, demonstrating a causal pathogenic role for this pathway.\",\n      \"method\": \"Tet-off bigenic mouse model, conditional Tp53 knockout, RNA-seq, Western blot, immunofluorescence, echocardiography, survival analysis\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis (conditional KO rescue), RNA-seq pathway validation, multiple orthogonal methods, rescue of functional cardiac phenotype\",\n      \"pmids\": [\"30696354\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Sarcolipin, an inhibitor of SERCA (SR Ca2+ ATPase), is abnormally elevated early in the disease course of Lmna(H222P/H222P) mice (before left ventricular functional changes), altering calcium handling; AAV9-mediated RNAi knockdown of sarcolipin delays cardiac dysfunction in this mouse model.\",\n      \"method\": \"Western blot and qPCR in mouse hearts, AAV9-RNAi knockdown, calcium handling assays, echocardiography\",\n      \"journal\": \"Biochemistry and biophysics reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo AAV rescue experiment with functional readouts, single lab, consistent genetic mouse model\",\n      \"pmids\": [\"32490213\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Pathogenic LMNA mutations from DCM patients introduced into hiPSCs cause specific disruptions of peripheral chromatin interactions in cardiomyocytes (but not hepatocytes or adipocytes), enriched for transcriptionally active genes with lower LAMIN B1 contact frequency; disrupted lamina-chromatin regions are enriched for non-myocyte lineage genes whose expression is aberrantly upregulated, suggesting the lamina network safeguards cardiomyocyte identity.\",\n      \"method\": \"Isogenic hiPSC-derived cardiomyocytes, hepatocytes, adipocytes; DamID lamina-chromatin interaction profiling, RNA-seq, nuclear morphology analysis, patient myocardium analysis\",\n      \"journal\": \"Cell stem cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — isogenic hiPSC system with three cell types, DamID + RNA-seq integration, patient tissue validation, multiple orthogonal approaches\",\n      \"pmids\": [\"33529599\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In LMNA-mutant cardiomyopathy, ERK1/2-phosphorylated cofilin-1 (phospho-T25) binds MRTF-A in the cytoplasm, preventing SRF nuclear activation and reducing ATAT1 (α-tubulin acetyltransferase 1) expression, thereby decreasing α-tubulin acetylation; tubastatin A treatment to increase α-tubulin acetylation restores Connexin 43 localization and improves cardiac function in Lmna(H222P/H222P) mice.\",\n      \"method\": \"Co-immunoprecipitation (phospho-cofilin-1/MRTF-A), Atat1 knockout mice, tubastatin A pharmacological treatment, immunofluorescence, echocardiography, patient-derived iPSC-CMs\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP demonstrating molecular interaction, genetic knockout model (Atat1 KO), pharmacological rescue in vivo, patient iPSC-CM validation, multiple orthogonal approaches\",\n      \"pmids\": [\"36550158\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Nesprin-1 LINC complexes are the predominant nuclear envelope anchor for microtubule cytoskeleton components (nucleation activities and motor complexes) in cardiomyocytes; CRISPR-mediated disruption of the Nesprin-1 KASH domain suppresses Lmna-linked cardiac pathology, likely by reducing microtubule cytoskeleton activities at the nucleus.\",\n      \"method\": \"CRISPR disruption of Nesprin-1 KASH domain in Lmna-mutant mice, immunofluorescence for microtubule components at the nucleus, cardiac phenotype assessment\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis (CRISPR KASH disruption suppresses Lmna pathology), mechanistic identification of Nesprin-1 as microtubule anchor, in vivo cardiac rescue\",\n      \"pmids\": [\"35925868\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"BAF (Barrier-to-Autointegration Factor) recruits a mobile, nucleoplasmic population of A-type lamins to sites of nuclear rupture via its association with the Ig-like β-fold domain of A-type lamins; farnesylated prelamin A and lamin B1 fail to localize to nuclear ruptures (unless farnesylation is inhibited); progeria-associated LMNA mutations inhibit recruitment of A-type lamins to ruptures due to permanent farnesylation or inhibition of BAF binding.\",\n      \"method\": \"Live-cell imaging of nuclear rupture/repair, domain mapping, farnesylation inhibitor treatment, FRAP-like analysis, progeria mutant cell lines\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — live imaging with domain-specific mutants and pharmacological inhibition, single lab, mechanistically detailed\",\n      \"pmids\": [\"35269487\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Lmna deletion in cardiac fibroblasts (Pdgfra-Cre) induces double-stranded DNA breaks, activates the DNA damage response (phospho-H2AFX, ATM, phospho-TP53, CDKN1A), and induces senescence-associated secretory phenotype (SASP: TGFβ1, CTGF, LGALS3), partially recapitulating the DCM phenotype and demonstrating that LMNA deficiency in fibroblasts contributes to DCM through DDR/SASP mechanisms.\",\n      \"method\": \"Conditional Lmna knockout in fibroblasts (Pdgfra-Cre:Lmna F/F), RNA-seq, Western blot for DDR markers, beta-galactosidase senescence assay, echocardiography\",\n      \"journal\": \"The journal of cardiovascular aging\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cell-type-specific conditional knockout with RNA-seq, multiple protein markers, functional cardiac phenotype\",\n      \"pmids\": [\"35891706\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"LMNA mutant iPSC-CMs show altered nuclear shape/size and reduced nuclear stiffness and fragility (especially R249Q mutation); the degree of nuclear abnormalities correlates with mislocalization of Lamin A/C and Lamin B1 from the nuclear envelope, with mislocalization likely due to altered lamin assembly.\",\n      \"method\": \"Patient-specific iPSC-CMs, atomic force microscopy (nuclear stiffness), immunofluorescence quantification of lamin localization, nuclear morphometry\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biophysical measurement of nuclear stiffness with AFM, correlative immunofluorescence, multiple LMNA mutant lines, single lab\",\n      \"pmids\": [\"37585285\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Lamin A physically interacts with c-Myc, inhibiting c-Myc transactivation of tRNA processing genes (EPRS, LARS), thereby suppressing the malate-aspartate shuttle (MAS), aerobic glycolysis, and neuroblastoma tumorigenesis; co-immunoprecipitation and mass spectrometry confirmed the lamin A–c-Myc interaction, and the LMNA-binding compound lobeline facilitates this interaction to suppress tumor progression.\",\n      \"method\": \"Co-immunoprecipitation, mass spectrometry, dual-luciferase reporter, chromatin immunoprecipitation, Western blot, RT-PCR, organoid models from c-Myc knock-in mice\",\n      \"journal\": \"Clinical and translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP/MS and ChIP validation of interaction and transcriptional mechanism, multiple functional assays, single lab\",\n      \"pmids\": [\"38769668\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Cardiomyocyte-specific Lmna deletion in adult mice causes rapid cardiomyopathy preceded by nuclear abnormalities, Golgi dilation/fragmentation, and CREB3-mediated stress activation; MED25 (a transcriptional cofactor regulating Golgi stress) is activated; autophagy is disrupted. Modulators of autophagy or ER stress significantly delayed cardiac dysfunction and prolonged survival.\",\n      \"method\": \"Conditional cardiomyocyte-specific Lmna deletion, translatome profiling, immunofluorescence for Golgi markers, pharmacological modulators of autophagy/ER stress, echocardiography, survival analysis\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional cardiac-specific KO with translatome profiling, Golgi/ER stress mechanistic pathway identification, pharmacological rescue with survival benefit\",\n      \"pmids\": [\"38718107\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"LMNA regulates transcription through lamin-associated domains (LADs) in cardiac myocytes; LAD-associated genes have ~16-fold lower transcript levels than non-LAD genes; in Lmna-deficient cardiomyocytes, double-stranded DNA breaks are enriched in non-LAD and loss-of-LAD regions associated with transcription.\",\n      \"method\": \"END-Sequencing for genome-wide DSBs, CUT&RUN for LAD definition in cardiac myocytes (Myh6-Cre:LmnaF/F mice), RNA-seq\",\n      \"journal\": \"Cardiovascular research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — specialized genome-wide sequencing methods (END-seq, CUT&RUN) in cardiac-specific KO, single lab, first-in-cardiovascular-system application\",\n      \"pmids\": [\"38577741\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"Lamin A/C (LMNA) is an intermediate filament protein of the nuclear lamina that physically anchors emerin and nesprin-1alpha at the nuclear envelope, interacts with chromatin through lamin-associated domains to silence non-lineage genes and safeguard cell identity, binds BAF to enable nuclear rupture repair, and interacts with nuclear partners including matrin-3 and c-Myc; LMNA mutations cause cardiomyopathy through aberrant activation of ERK1/2→JNK/Dusp4-AKT-mTOR signaling with impaired autophagy, PDGF pathway activation, E2F/DNA damage/TP53 pathway induction, disrupted actin-microtubule crosstalk via cofilin-1/MRTF-A/SRF/ATAT1, Nesprin-1 LINC complex-mediated mechanical stress transmission, and perinuclear Golgi/ER stress; aberrant LMNA splicing (regulated by SRSF1/SRSF2) produces pathogenic progerin that accumulates due to farnesylation and disrupts nuclear rupture repair.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"Lamin A/C is a nuclear lamina component that organizes the nuclear envelope and safeguards cell identity, and whose mutation drives cardiomyopathy through a convergent network of stress and signaling pathways [#0, #15]. At the nuclear envelope, lamin A/C is required and sufficient to anchor emerin and nesprin-1alpha, and its loss or mutation mislocalizes these partners to the ER [#0, #1, #2]. The lamina tethers chromatin through lamin-associated domains (LADs) that hold non-lineage genes in a transcriptionally repressed state; pathogenic mutations selectively disrupt peripheral chromatin contacts in cardiomyocytes and aberrantly upregulate non-myocyte lineage genes, eroding cardiomyocyte identity [#15, #23]. Lamin A/C additionally interacts with matrin-3 through its tail domain and with c-Myc, restraining c-Myc-driven transcription of tRNA-processing genes [#11, #21], and a nucleoplasmic pool is recruited by BAF to sites of nuclear envelope rupture, a repair function blocked by progeria-associated farnesylation [#18]. Mutations confer mechanical fragility, reducing nuclear stiffness and altering nuclear shape [#20]. LMNA cardiomyopathy proceeds through aberrant activation of ERK1/2-JNK and Dusp4-AKT-mTOR signaling with impaired autophagy [#4, #6, #7], E2F/DNA-damage/TP53 induction [#13, #19], PDGF pathway activation [#12], disrupted actin-microtubule crosstalk via cofilin-1/MRTF-A/SRF/ATAT1 [#16], Nesprin-1 LINC-mediated mechanical stress transmission [#17], and Golgi/ER stress [#22]; pharmacological or genetic interruption of each pathway rescues cardiac function in mouse and iPSC models. Aberrant LMNA splicing controlled by SRSF1/SRSF2/SRSF6 governs production of the farnesylated progerin isoform [#8, #9].\",\n  \"teleology\": [\n    {\n      \"year\": 2003,\n      \"claim\": \"Established that lamin A/C is the obligate nuclear-envelope anchor for emerin and nesprin-1alpha, defining its structural role at the lamina.\",\n      \"evidence\": \"Immunofluorescence of LMNA-null patient fibroblasts with wild-type cDNA rescue; transfection of R377H mutant\",\n      \"pmids\": [\"14644157\", \"12673789\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not define the binding interface on lamin A/C for each partner\", \"Mechanism linking mislocalization to tissue-specific disease not addressed\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Showed disease mutations destabilize lamin A and perturb additional envelope and transcription machinery in muscle, hinting at tissue-selective consequences.\",\n      \"evidence\": \"Immunocytochemistry, EM and cell synchronization in R377H AD-EDMD patient cells\",\n      \"pmids\": [\"15053843\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single mutation in one patient lineage\", \"Causal link between LBR/RNA Pol II changes and muscle phenotype not established\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Demonstrated a mutation can directly alter lamin A/C biochemistry, changing DNA-binding via aberrant disulfide oligomerization and raising oxidative stress.\",\n      \"evidence\": \"Gel retardation, ESR spectroscopy, immunofluorescence in R439C patient fibroblasts\",\n      \"pmids\": [\"19220582\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"In vitro DNA-binding change not connected to specific gene-regulatory outcome in vivo\", \"Single lab\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Identified JNK and FAS/mitochondrial apoptosis activation as causal contributors to LMNA cardiomyopathy, converting correlative pathway changes into therapeutic targets.\",\n      \"evidence\": \"SP600125 JNK inhibition in Lmna(H222P/H222P) mice; E82K cardiac transgenic mice with TUNEL/caspase analysis\",\n      \"pmids\": [\"20388542\", \"21151901\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How nuclear lamina defects activate cytoplasmic JNK signaling is unresolved\", \"Apoptosis findings rely on a single transgenic model\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Defined the AKT-mTOR/autophagy axis and its driver Dusp4 as a pathogenic mechanism, linking aberrant signaling to defective protein quality control.\",\n      \"evidence\": \"mTOR inhibitor rescue and autophagy flux assays in Lmna(H222P/H222P) mice; Dusp4-overexpressing transgenic mice\",\n      \"pmids\": [\"23044536\", \"23048029\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Upstream coupling of lamin defect to ERK1/2-Dusp4 induction not mechanistically resolved\", \"Restricted to one Lmna mouse allele\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Identified SR proteins (SRSF1, SRSF2, SRSF6) as regulators of LMNA exon 11 splicing that control lamin A versus progerin production, enabling antisense correction strategies.\",\n      \"evidence\": \"RNAi knockdown, RNA structure analysis, RT-PCR and in vivo ASO administration in HGPS mouse models and MEFs\",\n      \"pmids\": [\"26999604\", \"21875900\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How splice-factor activity is regulated in different tissues not defined\", \"Relevance to non-progeria LMNA isoform balance unclear\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Connected prelamin A accumulation and farnesylation to endothelial dysfunction in lipodystrophy, with statin/antioxidant rescue implicating maturation defects.\",\n      \"evidence\": \"Lentiviral R482W expression in endothelial cells, NO/ROS/adhesion assays, pravastatin treatment\",\n      \"pmids\": [\"23846499\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cell-type specificity of prelamin A maturation defect not explained\", \"Link to systemic lipodystrophy phenotype indirect\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Mapped a direct lamin A tail interaction with matrin-3, adding a nucleoplasmic binding partner disrupted by truncating mutations.\",\n      \"evidence\": \"Reciprocal Co-IP, mass spectrometry pulldown, domain mapping, 3D microscopy in LMNA mutant cells\",\n      \"pmids\": [\"25948554\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of the interaction not established\", \"Single lab\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Established PDGF signaling and the E2F/DNA-damage/TP53 pathway as causal, druggable drivers of LMNA cardiac dysfunction using isogenic and genetic-epistasis approaches.\",\n      \"evidence\": \"Isogenic iPSC-CMs with PDGFRb inhibition/knockdown; conditional Tp53 deletion in LMNA D300N mice\",\n      \"pmids\": [\"31316208\", \"30696354\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How lamina disruption activates PDGF and E2F/TP53 pathways mechanistically unresolved\", \"Tp53 deletion provides only partial rescue\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showed the lamina safeguards cardiomyocyte identity via LAD-mediated chromatin tethering and genome stability, linking lamina-chromatin contacts to lineage gene silencing and DSB localization.\",\n      \"evidence\": \"Isogenic hiPSC-derived cell types with DamID/CUT&RUN, END-seq and RNA-seq\",\n      \"pmids\": [\"33529599\", \"38577741\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of cell-type-selective LAD disruption not defined\", \"Causal order between chromatin detachment and gene misregulation unresolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Resolved cytoskeletal and mechanotransduction mechanisms — cofilin-1/MRTF-A/SRF/ATAT1 tubulin acetylation and Nesprin-1 LINC microtubule anchoring — and BAF-dependent nuclear rupture repair, broadening the pathogenic network.\",\n      \"evidence\": \"Co-IP, Atat1 KO and tubastatin A rescue; CRISPR Nesprin-1 KASH disruption in Lmna mice; live-cell nuclear rupture imaging with farnesylation inhibition\",\n      \"pmids\": [\"36550158\", \"35925868\", \"35269487\", \"35891706\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Integration of these parallel pathways into a single hierarchy not established\", \"BAF-rupture repair findings from a single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Extended the mechanism to Golgi/ER stress and CREB3/MED25 signaling in acute cardiac Lmna loss, and revealed a tumor-suppressive lamin A-c-Myc transcriptional axis outside the heart.\",\n      \"evidence\": \"Conditional cardiomyocyte Lmna deletion with translatome profiling and autophagy/ER-stress modulators; Co-IP/MS, ChIP and organoid assays for c-Myc interaction\",\n      \"pmids\": [\"38718107\", \"38769668\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether Golgi stress is primary or downstream of other pathways unclear\", \"c-Myc axis characterized in neuroblastoma, generalizability untested\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single lamina defect is funneled into the many distinct downstream pathways (JNK/mTOR, PDGF, TP53, cytoskeletal, Golgi stress) and which are primary versus secondary remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No unified hierarchy linking nuclear-envelope perturbation to the divergent effector pathways\", \"Tissue specificity of LMNA disease mechanisms not mechanistically explained\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [3]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 20]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [15, 21, 23]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 17]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005635\", \"supporting_discovery_ids\": [0, 1, 18]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [5, 20]},\n      {\"term_id\": \"GO:0000228\", \"supporting_discovery_ids\": [15, 23]},\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [11, 18]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-4839726\", \"supporting_discovery_ids\": [15, 23]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [15, 21, 23]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4, 6, 7, 12]},\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [6, 22]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [13, 19]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [8, 9]},\n      {\"term_id\": \"R-HSA-397014\", \"supporting_discovery_ids\": [16, 17]}\n    ],\n    \"complexes\": [\"nuclear lamina\", \"LINC complex\"],\n    \"partners\": [\"EMD\", \"SYNE1\", \"MATR3\", \"MYC\", \"BANF1\", \"LBR\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}