{"gene":"TMEM43","run_date":"2026-06-10T10:51:55","timeline":{"discoveries":[{"year":2008,"finding":"LUMA (TMEM43) is an integral inner nuclear membrane (INM) protein with four transmembrane domains and a large hydrophilic domain located between membrane spans 1 and 2 exposed to the perinuclear space, with both termini residing cyto- or nucleoplasmically. Nuclear envelope targeting mainly depends on the membrane spans. Transmembrane domains also promote homooligomerization. LUMA binds A- and B-type lamins and depends on A-type lamins for its INM localization. LUMA interacts with emerin, and both downregulation of LUMA and overexpression of dominant-negative LUMA fragments causes redistribution of emerin.","method":"Protease protection assay, antibody epitope accessibility assay, co-immunoprecipitation, dominant-negative overexpression, immunofluorescence","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — topology determined by orthogonal methods (protease protection + epitope accessibility), binding validated by co-IP, functional consequence of downregulation and dominant-negative confirmed by imaging","pmids":["18230648"],"is_preprint":false},{"year":2011,"finding":"TMEM43 (LUMA) interacts with SUN2 (in addition to emerin) at the nuclear membrane. The p.Glu85Lys mutation in TMEM43 causes failure of oligomerization, reduced nuclear staining of LUMA, and redistribution/aggregation of emerin and SUN2, along with a higher proportion of abnormally shaped nuclei. In vivo electroporation of mutant LUMA in mouse tibialis anterior muscles similarly showed decreased staining of emerin and SUN2 on myonuclei.","method":"In vitro transfection, co-immunoprecipitation, immunofluorescence, in vivo electroporation in mouse muscle","journal":"Annals of neurology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal interaction validated by co-IP, functional consequences confirmed in vitro and in vivo with orthogonal methods","pmids":["21391237"],"is_preprint":false},{"year":2014,"finding":"Skin fibroblasts from carriers of the TMEM43 p.S358L mutation exhibit increased nuclear stiffness compared to wild-type controls, as measured by atomic force microscopy, suggesting that the mutation affects nuclear mechanical properties.","method":"Atomic force microscopy on patient-derived skin fibroblasts","journal":"European heart journal","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — direct biophysical measurement on patient cells, but single lab, single method","pmids":["24598986"],"is_preprint":false},{"year":2014,"finding":"In mammalian cells, LUMA (TMEM43) localizes not only at the nuclear envelope but also as a cytoplasmic plaque constituent of zonula adhaerens and punctum adhaerens in diverse epithelia and in composite junctions (CJs) of myocardiac intercalated disks, where it colocalizes with other CJ marker proteins.","method":"Immunolocalization with high-specificity antibodies in diverse mammalian tissues and cell cultures","journal":"Cell and tissue research","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — immunolocalization across multiple cell/tissue types, replicated with multiple antibodies, but no functional perturbation experiments reported","pmids":["24770932"],"is_preprint":false},{"year":2016,"finding":"TMEM43/LUMA is a critical component of the EGFR signaling network that mediates EGFR-induced NF-κB activation. Upon EGF stimulation, EGFR recruits TMEM43, which then interacts with the scaffold protein CARMA3 and its associating complex to induce downstream NF-κB activation. TMEM43 deficiency impairs colony formation, anoikis resistance, migration, invasion, and tumor progression in vivo.","method":"Bimolecular Fluorescence Complementation-based functional genomics screen, co-immunoprecipitation, knockdown studies, in vitro functional assays, in vivo tumor models","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Strong — identified by functional screen, validated by co-IP, confirmed with multiple orthogonal in vitro and in vivo functional assays","pmids":["27991920"],"is_preprint":false},{"year":2018,"finding":"The TMEM43 S358L mutation leads to hyper-activated NF-κB signaling in heart tissues and primary cardiomyocytes, which directly drives expression of pro-fibrotic TGFβ1 and enhances downstream TGFβ signaling, contributing to cardiac fibrosis in ARVC.","method":"TMEM43 S358L knock-in mouse model, NF-κB reporter assays, gene expression analysis in heart tissue and primary cardiomyocytes","journal":"Protein & cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knock-in mouse model with mechanistic pathway characterization, single lab, two orthogonal approaches","pmids":["29980933"],"is_preprint":false},{"year":2018,"finding":"TMEM43 (Luma) is dispensable for murine cardiac development and function; germline null mice are viable with normal cardiac function and normal response to pressure overload. Localization and expression of other LINC complex components in cardiac myocytes and fibroblasts is unaffected by global loss of Luma. Furthermore, Luma S358L knock-in mice display normal cardiac function and morphology.","method":"Germline null mouse generation, Luma S358L knock-in mouse generation, echocardiography, transverse aortic constriction, immunofluorescence, immunoblotting","journal":"Cardiovascular research","confidence":"High","confidence_rationale":"Tier 2 / Strong — rigorous genetic null and knock-in mouse models with multiple cardiac phenotype assessments; negative finding robustly established with orthogonal methods","pmids":["29040414"],"is_preprint":false},{"year":2021,"finding":"Haploinsufficiency of Tmem43 in cardiac myocytes (Myh6-Cre:Tmem43W/F mice) activates the DNA damage response (DDR) and TP53 pathway, leading to increased senescence-associated secretory phenotype (SASP) markers and downstream phospho-SMAD2/phospho-SMAD3 activation, resulting in age-dependent pro-fibrotic cardiomyopathy with fibrosis, adipogenesis, and apoptosis.","method":"Cardiac-specific conditional knockout mouse model (Myh6-Cre x floxed Tmem43), cardiac myocyte transcriptome sequencing, immunoblotting for DDR/TP53/SASP markers, histology","journal":"Cardiovascular research","confidence":"High","confidence_rationale":"Tier 2 / Strong — cardiac-specific KO with defined molecular pathway (DDR→TP53→SASP→fibrosis) validated by transcriptomics and immunoblotting","pmids":["33070193"],"is_preprint":false},{"year":2021,"finding":"A nonsense variant in TMEM43 (p.Arg372Ter) causes auditory neuropathy spectrum disorder (ANSD). TMEM43 physically interacts with Connexin26 and Connexin30 gap junction channels in cochlear glia-like supporting cells (GLSs). The p.Arg372Ter variant disrupts passive conductance current in GLSs in a dominant-negative fashion.","method":"Linkage analysis and exome sequencing, knock-in mouse model, electrophysiology (passive conductance current measurement), co-immunoprecipitation/interaction assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — knock-in mouse recapitulates phenotype, protein interaction validated, electrophysiological functional consequence directly measured","pmids":["34050020"],"is_preprint":false},{"year":2021,"finding":"TMEM43 physically interacts with the KCNK3 (TASK-1) two-pore domain K+ channel in the cochlea. The intracellular loop domain of TMEM43 is responsible for TASK-1 binding. Gene silencing of Task-1 results in significantly reduced passive conductance current in cochlear glia-like supporting cells.","method":"Co-immunoprecipitation, Duolink proximity ligation assay, domain deletion analysis, siRNA knockdown with electrophysiology","journal":"Experimental neurobiology","confidence":"High","confidence_rationale":"Tier 1-2 / Moderate — protein interaction confirmed by two orthogonal binding assays (co-IP + PLA), domain responsible identified, functional consequence of downstream partner knockdown measured electrophysiologically","pmids":["34737237"],"is_preprint":false},{"year":2022,"finding":"TMEM43 overexpression inhibits LPS-induced ferroptosis in cardiomyocytes by suppressing P53 and ferritin levels while enhancing GPX4 and SLC7A11 expression. TMEM43 knockdown aggravates LPS-induced lipid peroxidation and ferroptosis.","method":"AAV9-mediated cardiac overexpression/knockdown in mice, siRNA/adenoviral overexpression in H9c2 cells, ferroptosis markers (MDA, iron density, GPX4, SLC7A11), ferrostatin-1 rescue experiment","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo and in vitro models with mechanistic pathway markers, single lab, multiple methods","pmids":["36230956"],"is_preprint":false},{"year":2022,"finding":"In a zebrafish model, the p.S358L mutant TMEM43 protein is unstable and partially redistributes from the nuclear membrane into the cytoplasm in embryonic and adult hearts. Overexpression of wild-type TMEM43 activates the mTOR pathway and ribosome biogenesis, leading to cardiomyocyte hypertrophy.","method":"Transgenic zebrafish overexpression lines (Tol2-system), CRISPR/Cas9 knockout, immunofluorescence, transcriptomic profiling, electron microscopy","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct imaging of mutant protein mislocalization in vivo, transcriptomic pathway identification, supported by CRISPR knockout phenotype","pmids":["36076925"],"is_preprint":false},{"year":2022,"finding":"TMEM43 promotes pancreatic cancer progression by stabilizing PRPF3 (preventing its degradation) and by regulating the RAP2B/ERK signaling axis, as identified by co-immunoprecipitation followed by mass spectrometry.","method":"Co-immunoprecipitation, protein mass spectrometry, in vitro knockdown/overexpression assays, in vivo tumorigenicity assay","journal":"Cellular & molecular biology letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — protein interaction and pathway identified by co-IP/MS with functional validation in vitro and in vivo, single lab","pmids":["35260078"],"is_preprint":false},{"year":2022,"finding":"In the TMEM43 S358L Drosophila model, the conserved serine at position 333 (homologous to human S358) is critical for physiological function. The S333L substitution causes impaired energy homeostasis and lipid metabolism, cardiac arrhythmias, and premature death. Similar metabolic impairments were confirmed in a murine Tmem43 disease model.","method":"CRISPR/Cas9 CG8111 knockout, transgenic overexpression of CG8111 p.S333L in Drosophila, metabolomic and proteomic analyses, cardiac function assay in flies","journal":"Cellular and molecular life sciences : CMLS","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ortholog model with CRISPR knockout and overexpression, metabolomics/proteomics, cross-validated with murine model","pmids":["35869176"],"is_preprint":false},{"year":2023,"finding":"In the TMEM43 S358L knock-in mouse model, TMEM43 and β-catenin expression are diminished in the heart while junctional plakoglobin (JUP) translocates into nuclei of mutant cardiomyocytes, indicating dysregulation of the WNT-β-catenin pathway. Conversely, in the small intestine of mutants, β-catenin and Ki-67 are overexpressed alongside elongated villi and fatty infiltration, indicating organ-specific pathway alterations.","method":"Knock-in mouse model (heterozygous and homozygous), immunohistochemistry, microarray transcriptome analysis, protein expression analysis, electron microscopy, histology","journal":"American journal of physiology. Heart and circulatory physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knock-in mouse model with multiple orthogonal methods identifying WNT-β-catenin pathway dysregulation, single lab","pmids":["37083466"],"is_preprint":false},{"year":2024,"finding":"USP7 deubiquitinase regulates TMEM43 protein stability through deubiquitination. TMEM43 in turn interacts with and activates VDAC1, promoting hepatocellular carcinoma progression through a USP7/TMEM43/VDAC1 axis.","method":"Co-immunoprecipitation, western blot for ubiquitination, CCK-8, flow cytometry, Transwell assays","journal":"Translational gastroenterology and hepatology","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — co-IP validates protein interactions, ubiquitination assessed by WB, single lab with multiple functional assays","pmids":["38317750"],"is_preprint":false},{"year":2025,"finding":"TMEM43 localizes at the ER/SR membrane and interacts with the outer mitochondrial membrane protein VDAC (Porin) in Drosophila. The p.S333L mutation (analogous to human p.S358L) abolishes this interaction, causing breakdown of mitochondrial membrane potential, increased reactive oxygen species, and severe mitochondrial ultrastructural defects. Similar mitochondrial ultrastructural defects were observed in human right ventricular myocardium from TMEM43 p.S358L carriers, suggesting impaired ER/SR-mitochondrial contact sites as a key pathomechanism.","method":"Immunofluorescence localization, protein interaction assays (Drosophila), mitochondrial membrane potential assay, ROS measurement, ultrastructural electron microscopy (Drosophila and human cardiac tissue)","journal":"Cellular and molecular life sciences : CMLS","confidence":"High","confidence_rationale":"Tier 2 / Strong — TMEM43-VDAC interaction and ER-mitochondrial contact site mechanism established by multiple orthogonal methods, cross-validated between Drosophila and human cardiac tissue","pmids":["41236655"],"is_preprint":false},{"year":2025,"finding":"Proteomic screening by quantitative IP-mass spectrometry identified 166 differential binding partners of TMEM43 vs. TMEM43 p.S358L. VDAC1 and VDAC2 binding to the TMEM43 p.S358L mutant is significantly decreased. Reduced VDAC binding mediates mitochondrial dysfunction in H9c2 cardiac myoblasts expressing TMEM43 p.S358L.","method":"Quantitative immunoprecipitation-mass spectrometry, immunofluorescence, TurboID proximity labeling, mitochondrial functional assays in H9c2 cells","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — IP-MS binding landscape confirmed by proximity labeling, functional consequence in cell model, single lab","pmids":["41411330"],"is_preprint":false},{"year":2025,"finding":"TMEM43 localizes in the endoplasmic reticulum and nuclear lamina. The p.S358L mutation alters interaction with proteins of ER and mitochondrial membranes. Mutant hiPSC-CMs show lipid accumulation, decreased lipid metabolism capacity, lower ATP:ADP ratio, and diminished contraction frequency. Pull-down experiments reveal differential interacting proteins at ER-mitochondrial contact sites, suggesting that the mutation impairs ER-mitochondrial interactions affecting lipid homeostasis and energy supply.","method":"Sucrose-gradient ultracentrifugation, mass spectrometry, HA-tag pull-down, lipidomics, proteomics, ATP/ADP measurement, contractility assay in hiPSC-CMs, metabolomics in human myocardium","journal":"Circulation. Genomic and precision medicine","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — multiple orthogonal methods (pull-down, lipidomics, proteomics, metabolomics, functional assays) in patient-derived hiPSC-CMs and human myocardial tissue, single lab but highly rigorous","pmids":["41919408"],"is_preprint":false},{"year":2025,"finding":"TMEM43 interacts with lamin B2. The TMEM43-P386S mutation induces lamin B2 mislocalization and abnormal nuclear envelope structure in ARVC iPSC-CMs, resulting in decreased chromatin accessibility at promoters of downregulated genes including RYR2. RYR2 proteins are downregulated and grouped into smaller clusters, contributing to enhanced SR Ca2+ leak and arrhythmic phenotype. This phenotype was preventable by flecainide.","method":"iPSC-CMs from mutation carriers, co-immunoprecipitation (TMEM43-lamin B2), Tau-STED super-resolution imaging (RYR2 clusters), chromatin accessibility assay, Ca2+ imaging, knock-in mouse model, flecainide treatment","journal":"Advanced science","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — novel mutation studied in patient iPSC-CMs and knock-in mice, mechanism validated by co-IP, super-resolution imaging, chromatin assay, and functional Ca2+ measurements with orthogonal methods","pmids":["40948388"],"is_preprint":false},{"year":2025,"finding":"Overexpression of wild-type TMEM43 in double transgenic mice (expressing both WT and S358L TMEM43) delays ARVC5 onset, improves cardiac contraction, reduces cardiomyocyte death and myocardial fibrosis, and improves survival. Systemic delivery of AAV9 carrying codon-optimized WT-TMEM43 prevents ventricular dysfunction and ECG abnormalities induced by S358L-TMEM43 in mice.","method":"Double transgenic mouse model (WT + S358L TMEM43), AAV9 gene delivery, echocardiography, ECG, histology, survival analysis","journal":"Circulation research","confidence":"High","confidence_rationale":"Tier 2 / Strong — rigorous transgenic and AAV therapeutic rescue experiments with multiple cardiac phenotype endpoints, establishes WT TMEM43 gain-of-function as dominant over mutant","pmids":["40091736"],"is_preprint":false},{"year":2026,"finding":"In a Drosophila CRISPR/Cas9 knock-in model of Tmem43 p.S333L (equivalent to human p.S358L), flies show reduced lifespan, smaller body size, lipid droplet accumulation, and mitochondrial defects. Proteomic and lipidomic profiling revealed misregulation of energy metabolism, reduced fatty acid synthesis and β-oxidation, altered peroxisomal pathways, elevated phosphatidylethanolamine and phosphatidylinositol levels, and reduced triacylglycerols. Ultrastructural analyses confirmed mitochondrial degradation in muscle tissue.","method":"CRISPR/Cas9 knock-in Drosophila model, lipidomics, proteomics, electron microscopy, fatty acid oxidation assays","journal":"Biology open","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ortholog knock-in model with multi-omics and ultrastructural validation, single lab","pmids":["41873591"],"is_preprint":false}],"current_model":"TMEM43 (LUMA) is a four-transmembrane-domain protein residing at the inner nuclear membrane and ER/SR membrane, where it forms a structural scaffold by binding A- and B-type lamins, emerin, SUN2, and connexins, organizes intercalated disc composite junctions, and stabilizes ER-mitochondrial contact sites through interaction with VDAC1/2; pathogenic mutations (especially p.S358L) disrupt these interactions, impairing nuclear mechanics, mitochondrial energy metabolism and lipid homeostasis, activating NF-κB–TGFβ and DDR–TP53–SASP pro-fibrotic cascades, and causing Ca²⁺ dysregulation via RYR2 downregulation, collectively leading to arrhythmogenic cardiomyopathy; in non-cardiac contexts, TMEM43 mediates EGFR-induced NF-κB activation via CARMA3 and interacts with connexins and TASK-1 channels to maintain passive conductance in cochlear glia-like supporting cells."},"narrative":{"mechanistic_narrative":"TMEM43 (LUMA) is a four-transmembrane-domain integral membrane protein that functions as a structural scaffold at the inner nuclear membrane and the ER/SR membrane, where it organizes nuclear envelope architecture and membrane contact sites [PMID:18230648, PMID:41919408]. At the nuclear envelope it homooligomerizes through its membrane spans, binds A- and B-type lamins (including lamin B2) and depends on A-type lamins for its localization, and tethers emerin and SUN2; loss of TMEM43 or expression of oligomerization-defective mutants redistributes emerin and SUN2 and produces abnormally shaped nuclei [PMID:18230648, PMID:21391237, PMID:40948388]. Beyond the nuclear envelope, TMEM43 localizes to the ER/SR membrane and to cytoplasmic plaques of adhering and composite junctions, including cardiac intercalated disks [PMID:24770932, PMID:41919408], and it bridges the ER/SR to mitochondria by binding the outer-mitochondrial-membrane channels VDAC1/VDAC2 (Porin) to stabilize ER-mitochondrial contact sites [PMID:41236655, PMID:41411330]. The dominant arrhythmogenic cardiomyopathy mutation p.S358L destabilizes the protein and abolishes VDAC binding, collapsing mitochondrial membrane potential, raising ROS, and impairing lipid metabolism and ATP production [PMID:41236655, PMID:41411330, PMID:41919408]; in parallel it mislocalizes lamin B2, closes chromatin at the RYR2 promoter, and downregulates RYR2 to drive SR Ca²⁺ leak and arrhythmia [PMID:40948388]. Loss of TMEM43 in cardiac myocytes activates a DNA-damage-response–TP53–SASP cascade and NF-κB–TGFβ signaling that produces pro-fibrotic cardiomyopathy [PMID:29980933, PMID:33070193], and restoring wild-type TMEM43 by transgene or AAV9 delivery suppresses the S358L disease phenotype [PMID:40091736]. In non-cardiac contexts TMEM43 acts as a signaling scaffold, mediating EGFR-induced NF-κB activation via CARMA3 [PMID:27991920] and maintaining passive conductance in cochlear glia-like supporting cells through interaction with connexins and the KCNK3 (TASK-1) channel, with a nonsense variant causing auditory neuropathy [PMID:34050020, PMID:34737237].","teleology":[{"year":2008,"claim":"Established TMEM43's basic identity and topology — whether it was a bona fide nuclear envelope protein and how it integrated into the lamina — by defining its membrane topology and its physical partners.","evidence":"Protease protection, epitope accessibility, co-IP and dominant-negative imaging in mammalian cells","pmids":["18230648"],"confidence":"High","gaps":["Functional consequence of lamin/emerin binding for nuclear mechanics not measured","Non-nuclear localization not addressed"]},{"year":2011,"claim":"Extended the scaffold model to the LINC complex by showing TMEM43 binds SUN2 and that a disease mutation disrupts oligomerization and mislocalizes partners, linking TMEM43 dysfunction to nuclear shape defects.","evidence":"Co-IP, immunofluorescence and in vivo muscle electroporation of mutant LUMA","pmids":["21391237"],"confidence":"High","gaps":["Mechanical/physiological readout of partner mislocalization not quantified","Tissue specificity of phenotype unresolved"]},{"year":2014,"claim":"Connected genotype to a biophysical phenotype and revealed non-nuclear localization, showing the p.S358L mutation stiffens nuclei and that TMEM43 resides in junctional plaques as well as the nuclear envelope.","evidence":"Atomic force microscopy on patient fibroblasts; immunolocalization across tissues","pmids":["24598986","24770932"],"confidence":"Medium","gaps":["Single-lab AFM measurement","Junction localization lacks functional perturbation"]},{"year":2016,"claim":"Identified an unexpected signaling role: that TMEM43 is a required scaffold in EGFR-induced NF-κB activation, broadening its function beyond a structural envelope protein.","evidence":"BiFC functional genomics screen, co-IP, knockdown and in vivo tumor models","pmids":["27991920"],"confidence":"High","gaps":["Relationship between signaling role and nuclear/junctional functions unclear","Direct EGFR-TMEM43 contact not structurally defined"]},{"year":2018,"claim":"Tested whether TMEM43 is required for the heart and whether S358L is intrinsically pathogenic, yielding conflicting models: a knock-in drove NF-κB–TGFβ fibrosis while an independent null/knock-in showed normal cardiac function.","evidence":"S358L knock-in and germline-null mouse models, NF-κB reporters, echocardiography, pressure overload","pmids":["29980933","29040414"],"confidence":"High","gaps":["Discordant cardiac phenotypes between models unresolved","Genetic background and dosage effects not reconciled"]},{"year":2021,"claim":"Defined a cardiac fibrosis mechanism via loss of function, showing myocyte TMEM43 haploinsufficiency activates a DDR→TP53→SASP axis driving SMAD2/3 and age-dependent cardiomyopathy.","evidence":"Cardiac-specific conditional knockout mouse, transcriptomics, immunoblotting, histology","pmids":["33070193"],"confidence":"High","gaps":["Whether loss-of-function recapitulates the dominant S358L disease mechanism unclear","Trigger linking TMEM43 loss to DNA damage undefined"]},{"year":2021,"claim":"Established a distinct sensory function and a second disease, showing TMEM43 binds connexins and the KCNK3/TASK-1 channel to set passive conductance in cochlear supporting cells, with a nonsense variant causing auditory neuropathy.","evidence":"Linkage/exome sequencing, knock-in mouse, electrophysiology, co-IP/PLA and domain-deletion mapping","pmids":["34050020","34737237"],"confidence":"High","gaps":["Whether TMEM43 itself conducts ions or only scaffolds channels unresolved","Intracellular loop interaction not structurally defined"]},{"year":2022,"claim":"Implicated TMEM43 in metabolism, redox balance and cancer, connecting it to ferroptosis suppression, mTOR-driven hypertrophy, lipid/energy homeostasis, and tumor-promoting partners PRPF3 and RAP2B/ERK.","evidence":"AAV9 cardiac models, zebrafish transgenics/CRISPR, Drosophila ortholog models, co-IP/MS and metabolomics","pmids":["36230956","36076925","35260078","35869176"],"confidence":"Medium","gaps":["Mechanistic link between membrane scaffolding and ferroptosis/mTOR not established","Cancer partner interactions are single-lab co-IP findings"]},{"year":2023,"claim":"Connected the mutation to developmental signaling, showing S358L diminishes cardiac β-catenin while driving nuclear plakoglobin translocation, with organ-specific WNT pathway alterations.","evidence":"S358L knock-in mouse, immunohistochemistry, microarray, electron microscopy","pmids":["37083466"],"confidence":"Medium","gaps":["Causal direction between TMEM43 loss and WNT dysregulation unclear","Single-lab model"]},{"year":2025,"claim":"Converged the field on ER-mitochondrial contact sites as the core pathomechanism, showing TMEM43 binds VDAC1/2 to stabilize these junctions and that S358L abolishes binding, collapsing mitochondrial function, energy and lipid homeostasis across fly, hiPSC-CM and human myocardium.","evidence":"IP-MS, TurboID proximity labeling, Drosophila interaction assays, lipidomics/proteomics/metabolomics, mitochondrial assays in patient-derived cells and tissue","pmids":["41236655","41411330","41919408"],"confidence":"High","gaps":["Structural basis of the TMEM43-VDAC interface not resolved","Quantitative contribution of contact-site loss versus other mechanisms not partitioned"]},{"year":2025,"claim":"Linked the nuclear scaffolding role directly to arrhythmia, showing mutant TMEM43 mislocalizes lamin B2, closes RYR2 promoter chromatin, downregulates RYR2 and produces SR Ca²⁺ leak preventable by flecainide.","evidence":"Patient iPSC-CMs, co-IP, super-resolution imaging, chromatin accessibility assay, Ca²⁺ imaging, knock-in mouse, drug treatment","pmids":["40948388"],"confidence":"High","gaps":["How a single mutation simultaneously disrupts nuclear and ER-mitochondrial functions unresolved","Generalizability beyond P386S/S358L variants"]},{"year":2025,"claim":"Provided proof-of-concept therapy, showing wild-type TMEM43 transgene or AAV9 delivery suppresses the dominant S358L disease, indicating restoration of normal TMEM43 dosage is protective.","evidence":"Double transgenic mice, AAV9 gene delivery, echocardiography, ECG, histology, survival","pmids":["40091736"],"confidence":"High","gaps":["Molecular basis of dominance/rescue not mechanistically dissected","Durability and translational dosing not addressed"]},{"year":null,"claim":"How a single membrane scaffold coordinates nuclear envelope mechanics, junctional integrity, ER-mitochondrial contact, and channel/signaling functions — and which of these is primary in each disease — remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structure of TMEM43 or its complexes","Conflicting cardiac models (fibrosis vs. dispensable) not reconciled","Unified mechanism linking nuclear, mitochondrial and signaling roles absent"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,1,4,16,19]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,3]}],"localization":[{"term_id":"GO:0005635","term_label":"nuclear envelope","supporting_discovery_ids":[0,1,18,19]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[16,18]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[3]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[4,5]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[16,18,21]}],"complexes":["LINC complex"],"partners":["LMNA","EMD","SUN2","LMNB2","VDAC1","VDAC2","CARMA3","KCNK3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9BTV4","full_name":"Transmembrane protein 43","aliases":["Protein LUMA"],"length_aa":400,"mass_kda":44.9,"function":"May have an important role in maintaining nuclear envelope structure by organizing protein complexes at the inner nuclear membrane. Required for retaining emerin at the inner nuclear membrane (By similarity). Plays a role in the modulation of innate immune signaling through the cGAS-STING pathway by interacting with RNF26 (PubMed:32614325). In addition, functions as a critical signaling component in mediating NF-kappa-B activation by acting downstream of EGFR and upstream of CARD10 (PubMed:27991920). Contributes to passive conductance current in cochlear glia-like supporting cells, mediated by gap junctions and necessary for hearing and speech discrimination (PubMed:34050020)","subcellular_location":"Endoplasmic reticulum membrane; Nucleus inner membrane; Cell membrane","url":"https://www.uniprot.org/uniprotkb/Q9BTV4/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TMEM43","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"DAD1","stoichiometry":4.0},{"gene":"DDOST","stoichiometry":4.0},{"gene":"CANX","stoichiometry":0.2},{"gene":"CLTA","stoichiometry":0.2},{"gene":"KRTCAP2","stoichiometry":0.2},{"gene":"OST4","stoichiometry":0.2},{"gene":"RPN1","stoichiometry":0.2},{"gene":"RPN2","stoichiometry":0.2},{"gene":"SEC61B","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/TMEM43","total_profiled":1310},"omim":[{"mim_id":"619832","title":"AUDITORY NEUROPATHY, AUTOSOMAL DOMINANT 3; AUNA3","url":"https://www.omim.org/entry/619832"},{"mim_id":"614302","title":"EMERY-DREIFUSS MUSCULAR DYSTROPHY 7, AUTOSOMAL DOMINANT; EDMD7","url":"https://www.omim.org/entry/614302"},{"mim_id":"612048","title":"TRANSMEMBRANE PROTEIN 43; TMEM43","url":"https://www.omim.org/entry/612048"},{"mim_id":"609129","title":"AUDITORY NEUROPATHY, AUTOSOMAL DOMINANT 1; AUNA1","url":"https://www.omim.org/entry/609129"},{"mim_id":"604400","title":"ARRHYTHMOGENIC RIGHT VENTRICULAR DYSPLASIA, FAMILIAL, 5; ARVD5","url":"https://www.omim.org/entry/604400"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/TMEM43"},"hgnc":{"alias_symbol":["MGC3222","DKFZp586G1919","LUMA"],"prev_symbol":["ARVD5"]},"alphafold":{"accession":"Q9BTV4","domains":[{"cath_id":"-","chopping":"23-60_303-392","consensus_level":"high","plddt":86.8943,"start":23,"end":392},{"cath_id":"-","chopping":"81-269","consensus_level":"medium","plddt":94.904,"start":81,"end":269}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BTV4","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BTV4-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9BTV4-F1-predicted_aligned_error_v6.png","plddt_mean":89.94},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TMEM43","jax_strain_url":"https://www.jax.org/strain/search?query=TMEM43"},"sequence":{"accession":"Q9BTV4","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9BTV4.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9BTV4/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9BTV4"}},"corpus_meta":[{"pmid":"18313022","id":"PMC_18313022","title":"Arrhythmogenic 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Nuclear envelope targeting mainly depends on the membrane spans. Transmembrane domains also promote homooligomerization. LUMA binds A- and B-type lamins and depends on A-type lamins for its INM localization. LUMA interacts with emerin, and both downregulation of LUMA and overexpression of dominant-negative LUMA fragments causes redistribution of emerin.\",\n      \"method\": \"Protease protection assay, antibody epitope accessibility assay, co-immunoprecipitation, dominant-negative overexpression, immunofluorescence\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — topology determined by orthogonal methods (protease protection + epitope accessibility), binding validated by co-IP, functional consequence of downregulation and dominant-negative confirmed by imaging\",\n      \"pmids\": [\"18230648\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"TMEM43 (LUMA) interacts with SUN2 (in addition to emerin) at the nuclear membrane. The p.Glu85Lys mutation in TMEM43 causes failure of oligomerization, reduced nuclear staining of LUMA, and redistribution/aggregation of emerin and SUN2, along with a higher proportion of abnormally shaped nuclei. In vivo electroporation of mutant LUMA in mouse tibialis anterior muscles similarly showed decreased staining of emerin and SUN2 on myonuclei.\",\n      \"method\": \"In vitro transfection, co-immunoprecipitation, immunofluorescence, in vivo electroporation in mouse muscle\",\n      \"journal\": \"Annals of neurology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal interaction validated by co-IP, functional consequences confirmed in vitro and in vivo with orthogonal methods\",\n      \"pmids\": [\"21391237\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Skin fibroblasts from carriers of the TMEM43 p.S358L mutation exhibit increased nuclear stiffness compared to wild-type controls, as measured by atomic force microscopy, suggesting that the mutation affects nuclear mechanical properties.\",\n      \"method\": \"Atomic force microscopy on patient-derived skin fibroblasts\",\n      \"journal\": \"European heart journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — direct biophysical measurement on patient cells, but single lab, single method\",\n      \"pmids\": [\"24598986\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"In mammalian cells, LUMA (TMEM43) localizes not only at the nuclear envelope but also as a cytoplasmic plaque constituent of zonula adhaerens and punctum adhaerens in diverse epithelia and in composite junctions (CJs) of myocardiac intercalated disks, where it colocalizes with other CJ marker proteins.\",\n      \"method\": \"Immunolocalization with high-specificity antibodies in diverse mammalian tissues and cell cultures\",\n      \"journal\": \"Cell and tissue research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — immunolocalization across multiple cell/tissue types, replicated with multiple antibodies, but no functional perturbation experiments reported\",\n      \"pmids\": [\"24770932\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"TMEM43/LUMA is a critical component of the EGFR signaling network that mediates EGFR-induced NF-κB activation. Upon EGF stimulation, EGFR recruits TMEM43, which then interacts with the scaffold protein CARMA3 and its associating complex to induce downstream NF-κB activation. TMEM43 deficiency impairs colony formation, anoikis resistance, migration, invasion, and tumor progression in vivo.\",\n      \"method\": \"Bimolecular Fluorescence Complementation-based functional genomics screen, co-immunoprecipitation, knockdown studies, in vitro functional assays, in vivo tumor models\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — identified by functional screen, validated by co-IP, confirmed with multiple orthogonal in vitro and in vivo functional assays\",\n      \"pmids\": [\"27991920\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"The TMEM43 S358L mutation leads to hyper-activated NF-κB signaling in heart tissues and primary cardiomyocytes, which directly drives expression of pro-fibrotic TGFβ1 and enhances downstream TGFβ signaling, contributing to cardiac fibrosis in ARVC.\",\n      \"method\": \"TMEM43 S358L knock-in mouse model, NF-κB reporter assays, gene expression analysis in heart tissue and primary cardiomyocytes\",\n      \"journal\": \"Protein & cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knock-in mouse model with mechanistic pathway characterization, single lab, two orthogonal approaches\",\n      \"pmids\": [\"29980933\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"TMEM43 (Luma) is dispensable for murine cardiac development and function; germline null mice are viable with normal cardiac function and normal response to pressure overload. Localization and expression of other LINC complex components in cardiac myocytes and fibroblasts is unaffected by global loss of Luma. Furthermore, Luma S358L knock-in mice display normal cardiac function and morphology.\",\n      \"method\": \"Germline null mouse generation, Luma S358L knock-in mouse generation, echocardiography, transverse aortic constriction, immunofluorescence, immunoblotting\",\n      \"journal\": \"Cardiovascular research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — rigorous genetic null and knock-in mouse models with multiple cardiac phenotype assessments; negative finding robustly established with orthogonal methods\",\n      \"pmids\": [\"29040414\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Haploinsufficiency of Tmem43 in cardiac myocytes (Myh6-Cre:Tmem43W/F mice) activates the DNA damage response (DDR) and TP53 pathway, leading to increased senescence-associated secretory phenotype (SASP) markers and downstream phospho-SMAD2/phospho-SMAD3 activation, resulting in age-dependent pro-fibrotic cardiomyopathy with fibrosis, adipogenesis, and apoptosis.\",\n      \"method\": \"Cardiac-specific conditional knockout mouse model (Myh6-Cre x floxed Tmem43), cardiac myocyte transcriptome sequencing, immunoblotting for DDR/TP53/SASP markers, histology\",\n      \"journal\": \"Cardiovascular research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cardiac-specific KO with defined molecular pathway (DDR→TP53→SASP→fibrosis) validated by transcriptomics and immunoblotting\",\n      \"pmids\": [\"33070193\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"A nonsense variant in TMEM43 (p.Arg372Ter) causes auditory neuropathy spectrum disorder (ANSD). TMEM43 physically interacts with Connexin26 and Connexin30 gap junction channels in cochlear glia-like supporting cells (GLSs). The p.Arg372Ter variant disrupts passive conductance current in GLSs in a dominant-negative fashion.\",\n      \"method\": \"Linkage analysis and exome sequencing, knock-in mouse model, electrophysiology (passive conductance current measurement), co-immunoprecipitation/interaction assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — knock-in mouse recapitulates phenotype, protein interaction validated, electrophysiological functional consequence directly measured\",\n      \"pmids\": [\"34050020\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TMEM43 physically interacts with the KCNK3 (TASK-1) two-pore domain K+ channel in the cochlea. The intracellular loop domain of TMEM43 is responsible for TASK-1 binding. Gene silencing of Task-1 results in significantly reduced passive conductance current in cochlear glia-like supporting cells.\",\n      \"method\": \"Co-immunoprecipitation, Duolink proximity ligation assay, domain deletion analysis, siRNA knockdown with electrophysiology\",\n      \"journal\": \"Experimental neurobiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Moderate — protein interaction confirmed by two orthogonal binding assays (co-IP + PLA), domain responsible identified, functional consequence of downstream partner knockdown measured electrophysiologically\",\n      \"pmids\": [\"34737237\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TMEM43 overexpression inhibits LPS-induced ferroptosis in cardiomyocytes by suppressing P53 and ferritin levels while enhancing GPX4 and SLC7A11 expression. TMEM43 knockdown aggravates LPS-induced lipid peroxidation and ferroptosis.\",\n      \"method\": \"AAV9-mediated cardiac overexpression/knockdown in mice, siRNA/adenoviral overexpression in H9c2 cells, ferroptosis markers (MDA, iron density, GPX4, SLC7A11), ferrostatin-1 rescue experiment\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo and in vitro models with mechanistic pathway markers, single lab, multiple methods\",\n      \"pmids\": [\"36230956\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In a zebrafish model, the p.S358L mutant TMEM43 protein is unstable and partially redistributes from the nuclear membrane into the cytoplasm in embryonic and adult hearts. Overexpression of wild-type TMEM43 activates the mTOR pathway and ribosome biogenesis, leading to cardiomyocyte hypertrophy.\",\n      \"method\": \"Transgenic zebrafish overexpression lines (Tol2-system), CRISPR/Cas9 knockout, immunofluorescence, transcriptomic profiling, electron microscopy\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct imaging of mutant protein mislocalization in vivo, transcriptomic pathway identification, supported by CRISPR knockout phenotype\",\n      \"pmids\": [\"36076925\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TMEM43 promotes pancreatic cancer progression by stabilizing PRPF3 (preventing its degradation) and by regulating the RAP2B/ERK signaling axis, as identified by co-immunoprecipitation followed by mass spectrometry.\",\n      \"method\": \"Co-immunoprecipitation, protein mass spectrometry, in vitro knockdown/overexpression assays, in vivo tumorigenicity assay\",\n      \"journal\": \"Cellular & molecular biology letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — protein interaction and pathway identified by co-IP/MS with functional validation in vitro and in vivo, single lab\",\n      \"pmids\": [\"35260078\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"In the TMEM43 S358L Drosophila model, the conserved serine at position 333 (homologous to human S358) is critical for physiological function. The S333L substitution causes impaired energy homeostasis and lipid metabolism, cardiac arrhythmias, and premature death. Similar metabolic impairments were confirmed in a murine Tmem43 disease model.\",\n      \"method\": \"CRISPR/Cas9 CG8111 knockout, transgenic overexpression of CG8111 p.S333L in Drosophila, metabolomic and proteomic analyses, cardiac function assay in flies\",\n      \"journal\": \"Cellular and molecular life sciences : CMLS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ortholog model with CRISPR knockout and overexpression, metabolomics/proteomics, cross-validated with murine model\",\n      \"pmids\": [\"35869176\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"In the TMEM43 S358L knock-in mouse model, TMEM43 and β-catenin expression are diminished in the heart while junctional plakoglobin (JUP) translocates into nuclei of mutant cardiomyocytes, indicating dysregulation of the WNT-β-catenin pathway. Conversely, in the small intestine of mutants, β-catenin and Ki-67 are overexpressed alongside elongated villi and fatty infiltration, indicating organ-specific pathway alterations.\",\n      \"method\": \"Knock-in mouse model (heterozygous and homozygous), immunohistochemistry, microarray transcriptome analysis, protein expression analysis, electron microscopy, histology\",\n      \"journal\": \"American journal of physiology. Heart and circulatory physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knock-in mouse model with multiple orthogonal methods identifying WNT-β-catenin pathway dysregulation, single lab\",\n      \"pmids\": [\"37083466\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"USP7 deubiquitinase regulates TMEM43 protein stability through deubiquitination. TMEM43 in turn interacts with and activates VDAC1, promoting hepatocellular carcinoma progression through a USP7/TMEM43/VDAC1 axis.\",\n      \"method\": \"Co-immunoprecipitation, western blot for ubiquitination, CCK-8, flow cytometry, Transwell assays\",\n      \"journal\": \"Translational gastroenterology and hepatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — co-IP validates protein interactions, ubiquitination assessed by WB, single lab with multiple functional assays\",\n      \"pmids\": [\"38317750\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TMEM43 localizes at the ER/SR membrane and interacts with the outer mitochondrial membrane protein VDAC (Porin) in Drosophila. The p.S333L mutation (analogous to human p.S358L) abolishes this interaction, causing breakdown of mitochondrial membrane potential, increased reactive oxygen species, and severe mitochondrial ultrastructural defects. Similar mitochondrial ultrastructural defects were observed in human right ventricular myocardium from TMEM43 p.S358L carriers, suggesting impaired ER/SR-mitochondrial contact sites as a key pathomechanism.\",\n      \"method\": \"Immunofluorescence localization, protein interaction assays (Drosophila), mitochondrial membrane potential assay, ROS measurement, ultrastructural electron microscopy (Drosophila and human cardiac tissue)\",\n      \"journal\": \"Cellular and molecular life sciences : CMLS\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — TMEM43-VDAC interaction and ER-mitochondrial contact site mechanism established by multiple orthogonal methods, cross-validated between Drosophila and human cardiac tissue\",\n      \"pmids\": [\"41236655\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Proteomic screening by quantitative IP-mass spectrometry identified 166 differential binding partners of TMEM43 vs. TMEM43 p.S358L. VDAC1 and VDAC2 binding to the TMEM43 p.S358L mutant is significantly decreased. Reduced VDAC binding mediates mitochondrial dysfunction in H9c2 cardiac myoblasts expressing TMEM43 p.S358L.\",\n      \"method\": \"Quantitative immunoprecipitation-mass spectrometry, immunofluorescence, TurboID proximity labeling, mitochondrial functional assays in H9c2 cells\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — IP-MS binding landscape confirmed by proximity labeling, functional consequence in cell model, single lab\",\n      \"pmids\": [\"41411330\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TMEM43 localizes in the endoplasmic reticulum and nuclear lamina. The p.S358L mutation alters interaction with proteins of ER and mitochondrial membranes. Mutant hiPSC-CMs show lipid accumulation, decreased lipid metabolism capacity, lower ATP:ADP ratio, and diminished contraction frequency. Pull-down experiments reveal differential interacting proteins at ER-mitochondrial contact sites, suggesting that the mutation impairs ER-mitochondrial interactions affecting lipid homeostasis and energy supply.\",\n      \"method\": \"Sucrose-gradient ultracentrifugation, mass spectrometry, HA-tag pull-down, lipidomics, proteomics, ATP/ADP measurement, contractility assay in hiPSC-CMs, metabolomics in human myocardium\",\n      \"journal\": \"Circulation. Genomic and precision medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — multiple orthogonal methods (pull-down, lipidomics, proteomics, metabolomics, functional assays) in patient-derived hiPSC-CMs and human myocardial tissue, single lab but highly rigorous\",\n      \"pmids\": [\"41919408\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TMEM43 interacts with lamin B2. The TMEM43-P386S mutation induces lamin B2 mislocalization and abnormal nuclear envelope structure in ARVC iPSC-CMs, resulting in decreased chromatin accessibility at promoters of downregulated genes including RYR2. RYR2 proteins are downregulated and grouped into smaller clusters, contributing to enhanced SR Ca2+ leak and arrhythmic phenotype. This phenotype was preventable by flecainide.\",\n      \"method\": \"iPSC-CMs from mutation carriers, co-immunoprecipitation (TMEM43-lamin B2), Tau-STED super-resolution imaging (RYR2 clusters), chromatin accessibility assay, Ca2+ imaging, knock-in mouse model, flecainide treatment\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — novel mutation studied in patient iPSC-CMs and knock-in mice, mechanism validated by co-IP, super-resolution imaging, chromatin assay, and functional Ca2+ measurements with orthogonal methods\",\n      \"pmids\": [\"40948388\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Overexpression of wild-type TMEM43 in double transgenic mice (expressing both WT and S358L TMEM43) delays ARVC5 onset, improves cardiac contraction, reduces cardiomyocyte death and myocardial fibrosis, and improves survival. Systemic delivery of AAV9 carrying codon-optimized WT-TMEM43 prevents ventricular dysfunction and ECG abnormalities induced by S358L-TMEM43 in mice.\",\n      \"method\": \"Double transgenic mouse model (WT + S358L TMEM43), AAV9 gene delivery, echocardiography, ECG, histology, survival analysis\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — rigorous transgenic and AAV therapeutic rescue experiments with multiple cardiac phenotype endpoints, establishes WT TMEM43 gain-of-function as dominant over mutant\",\n      \"pmids\": [\"40091736\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"In a Drosophila CRISPR/Cas9 knock-in model of Tmem43 p.S333L (equivalent to human p.S358L), flies show reduced lifespan, smaller body size, lipid droplet accumulation, and mitochondrial defects. Proteomic and lipidomic profiling revealed misregulation of energy metabolism, reduced fatty acid synthesis and β-oxidation, altered peroxisomal pathways, elevated phosphatidylethanolamine and phosphatidylinositol levels, and reduced triacylglycerols. Ultrastructural analyses confirmed mitochondrial degradation in muscle tissue.\",\n      \"method\": \"CRISPR/Cas9 knock-in Drosophila model, lipidomics, proteomics, electron microscopy, fatty acid oxidation assays\",\n      \"journal\": \"Biology open\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ortholog knock-in model with multi-omics and ultrastructural validation, single lab\",\n      \"pmids\": [\"41873591\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TMEM43 (LUMA) is a four-transmembrane-domain protein residing at the inner nuclear membrane and ER/SR membrane, where it forms a structural scaffold by binding A- and B-type lamins, emerin, SUN2, and connexins, organizes intercalated disc composite junctions, and stabilizes ER-mitochondrial contact sites through interaction with VDAC1/2; pathogenic mutations (especially p.S358L) disrupt these interactions, impairing nuclear mechanics, mitochondrial energy metabolism and lipid homeostasis, activating NF-κB–TGFβ and DDR–TP53–SASP pro-fibrotic cascades, and causing Ca²⁺ dysregulation via RYR2 downregulation, collectively leading to arrhythmogenic cardiomyopathy; in non-cardiac contexts, TMEM43 mediates EGFR-induced NF-κB activation via CARMA3 and interacts with connexins and TASK-1 channels to maintain passive conductance in cochlear glia-like supporting cells.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TMEM43 (LUMA) is a four-transmembrane-domain integral membrane protein that functions as a structural scaffold at the inner nuclear membrane and the ER/SR membrane, where it organizes nuclear envelope architecture and membrane contact sites [#0, #18]. At the nuclear envelope it homooligomerizes through its membrane spans, binds A- and B-type lamins (including lamin B2) and depends on A-type lamins for its localization, and tethers emerin and SUN2; loss of TMEM43 or expression of oligomerization-defective mutants redistributes emerin and SUN2 and produces abnormally shaped nuclei [#0, #1, #19]. Beyond the nuclear envelope, TMEM43 localizes to the ER/SR membrane and to cytoplasmic plaques of adhering and composite junctions, including cardiac intercalated disks [#3, #18], and it bridges the ER/SR to mitochondria by binding the outer-mitochondrial-membrane channels VDAC1/VDAC2 (Porin) to stabilize ER-mitochondrial contact sites [#16, #17]. The dominant arrhythmogenic cardiomyopathy mutation p.S358L destabilizes the protein and abolishes VDAC binding, collapsing mitochondrial membrane potential, raising ROS, and impairing lipid metabolism and ATP production [#16, #17, #18]; in parallel it mislocalizes lamin B2, closes chromatin at the RYR2 promoter, and downregulates RYR2 to drive SR Ca\\u00b2\\u207a leak and arrhythmia [#19]. Loss of TMEM43 in cardiac myocytes activates a DNA-damage-response\\u2013TP53\\u2013SASP cascade and NF-\\u03baB\\u2013TGF\\u03b2 signaling that produces pro-fibrotic cardiomyopathy [#5, #7], and restoring wild-type TMEM43 by transgene or AAV9 delivery suppresses the S358L disease phenotype [#20]. In non-cardiac contexts TMEM43 acts as a signaling scaffold, mediating EGFR-induced NF-\\u03baB activation via CARMA3 [#4] and maintaining passive conductance in cochlear glia-like supporting cells through interaction with connexins and the KCNK3 (TASK-1) channel, with a nonsense variant causing auditory neuropathy [#8, #9].\",\n  \"teleology\": [\n    {\n      \"year\": 2008,\n      \"claim\": \"Established TMEM43's basic identity and topology — whether it was a bona fide nuclear envelope protein and how it integrated into the lamina — by defining its membrane topology and its physical partners.\",\n      \"evidence\": \"Protease protection, epitope accessibility, co-IP and dominant-negative imaging in mammalian cells\",\n      \"pmids\": [\"18230648\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional consequence of lamin/emerin binding for nuclear mechanics not measured\", \"Non-nuclear localization not addressed\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Extended the scaffold model to the LINC complex by showing TMEM43 binds SUN2 and that a disease mutation disrupts oligomerization and mislocalizes partners, linking TMEM43 dysfunction to nuclear shape defects.\",\n      \"evidence\": \"Co-IP, immunofluorescence and in vivo muscle electroporation of mutant LUMA\",\n      \"pmids\": [\"21391237\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanical/physiological readout of partner mislocalization not quantified\", \"Tissue specificity of phenotype unresolved\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Connected genotype to a biophysical phenotype and revealed non-nuclear localization, showing the p.S358L mutation stiffens nuclei and that TMEM43 resides in junctional plaques as well as the nuclear envelope.\",\n      \"evidence\": \"Atomic force microscopy on patient fibroblasts; immunolocalization across tissues\",\n      \"pmids\": [\"24598986\", \"24770932\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab AFM measurement\", \"Junction localization lacks functional perturbation\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identified an unexpected signaling role: that TMEM43 is a required scaffold in EGFR-induced NF-\\u03baB activation, broadening its function beyond a structural envelope protein.\",\n      \"evidence\": \"BiFC functional genomics screen, co-IP, knockdown and in vivo tumor models\",\n      \"pmids\": [\"27991920\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relationship between signaling role and nuclear/junctional functions unclear\", \"Direct EGFR-TMEM43 contact not structurally defined\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Tested whether TMEM43 is required for the heart and whether S358L is intrinsically pathogenic, yielding conflicting models: a knock-in drove NF-\\u03baB\\u2013TGF\\u03b2 fibrosis while an independent null/knock-in showed normal cardiac function.\",\n      \"evidence\": \"S358L knock-in and germline-null mouse models, NF-\\u03baB reporters, echocardiography, pressure overload\",\n      \"pmids\": [\"29980933\", \"29040414\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Discordant cardiac phenotypes between models unresolved\", \"Genetic background and dosage effects not reconciled\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Defined a cardiac fibrosis mechanism via loss of function, showing myocyte TMEM43 haploinsufficiency activates a DDR\\u2192TP53\\u2192SASP axis driving SMAD2/3 and age-dependent cardiomyopathy.\",\n      \"evidence\": \"Cardiac-specific conditional knockout mouse, transcriptomics, immunoblotting, histology\",\n      \"pmids\": [\"33070193\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether loss-of-function recapitulates the dominant S358L disease mechanism unclear\", \"Trigger linking TMEM43 loss to DNA damage undefined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Established a distinct sensory function and a second disease, showing TMEM43 binds connexins and the KCNK3/TASK-1 channel to set passive conductance in cochlear supporting cells, with a nonsense variant causing auditory neuropathy.\",\n      \"evidence\": \"Linkage/exome sequencing, knock-in mouse, electrophysiology, co-IP/PLA and domain-deletion mapping\",\n      \"pmids\": [\"34050020\", \"34737237\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether TMEM43 itself conducts ions or only scaffolds channels unresolved\", \"Intracellular loop interaction not structurally defined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Implicated TMEM43 in metabolism, redox balance and cancer, connecting it to ferroptosis suppression, mTOR-driven hypertrophy, lipid/energy homeostasis, and tumor-promoting partners PRPF3 and RAP2B/ERK.\",\n      \"evidence\": \"AAV9 cardiac models, zebrafish transgenics/CRISPR, Drosophila ortholog models, co-IP/MS and metabolomics\",\n      \"pmids\": [\"36230956\", \"36076925\", \"35260078\", \"35869176\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanistic link between membrane scaffolding and ferroptosis/mTOR not established\", \"Cancer partner interactions are single-lab co-IP findings\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Connected the mutation to developmental signaling, showing S358L diminishes cardiac \\u03b2-catenin while driving nuclear plakoglobin translocation, with organ-specific WNT pathway alterations.\",\n      \"evidence\": \"S358L knock-in mouse, immunohistochemistry, microarray, electron microscopy\",\n      \"pmids\": [\"37083466\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal direction between TMEM43 loss and WNT dysregulation unclear\", \"Single-lab model\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Converged the field on ER-mitochondrial contact sites as the core pathomechanism, showing TMEM43 binds VDAC1/2 to stabilize these junctions and that S358L abolishes binding, collapsing mitochondrial function, energy and lipid homeostasis across fly, hiPSC-CM and human myocardium.\",\n      \"evidence\": \"IP-MS, TurboID proximity labeling, Drosophila interaction assays, lipidomics/proteomics/metabolomics, mitochondrial assays in patient-derived cells and tissue\",\n      \"pmids\": [\"41236655\", \"41411330\", \"41919408\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the TMEM43-VDAC interface not resolved\", \"Quantitative contribution of contact-site loss versus other mechanisms not partitioned\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Linked the nuclear scaffolding role directly to arrhythmia, showing mutant TMEM43 mislocalizes lamin B2, closes RYR2 promoter chromatin, downregulates RYR2 and produces SR Ca\\u00b2\\u207a leak preventable by flecainide.\",\n      \"evidence\": \"Patient iPSC-CMs, co-IP, super-resolution imaging, chromatin accessibility assay, Ca\\u00b2\\u207a imaging, knock-in mouse, drug treatment\",\n      \"pmids\": [\"40948388\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How a single mutation simultaneously disrupts nuclear and ER-mitochondrial functions unresolved\", \"Generalizability beyond P386S/S358L variants\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Provided proof-of-concept therapy, showing wild-type TMEM43 transgene or AAV9 delivery suppresses the dominant S358L disease, indicating restoration of normal TMEM43 dosage is protective.\",\n      \"evidence\": \"Double transgenic mice, AAV9 gene delivery, echocardiography, ECG, histology, survival\",\n      \"pmids\": [\"40091736\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of dominance/rescue not mechanistically dissected\", \"Durability and translational dosing not addressed\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single membrane scaffold coordinates nuclear envelope mechanics, junctional integrity, ER-mitochondrial contact, and channel/signaling functions — and which of these is primary in each disease — remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structure of TMEM43 or its complexes\", \"Conflicting cardiac models (fibrosis vs. dispensable) not reconciled\", \"Unified mechanism linking nuclear, mitochondrial and signaling roles absent\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 1, 4, 16, 19]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005635\", \"supporting_discovery_ids\": [0, 1, 18, 19]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [16, 18]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0162582\", \"supporting_discovery_ids\": [4]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4, 5]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [16, 18, 21]}\n    ],\n    \"complexes\": [\"LINC complex\"],\n    \"partners\": [\"LMNA\", \"EMD\", \"SUN2\", \"LMNB2\", \"VDAC1\", \"VDAC2\", \"CARMA3\", \"KCNK3\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}