{"gene":"LMOD2","run_date":"2026-06-10T02:59:50","timeline":{"discoveries":[{"year":2015,"finding":"Lmod2 functions to elongate thin filaments by promoting actin assembly and dynamics at thin filament pointed ends in the heart. Knockout of Lmod2 in mice results in abnormally short thin filaments, reduced contractile force, and dilated cardiomyopathy; AAV-mediated reintroduction of GFP-Lmod2 rescues thin filament length and cardiac function.","method":"Germline knockout mouse model, micropillar array force measurements, AAV transduction rescue experiment","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic KO with defined cellular phenotype (thin filament length, contractile force), mechanistic rescue by reintroduction, replicated across multiple labs","pmids":["26487682"],"is_preprint":false},{"year":2018,"finding":"Cardiac-specific conditional knockout of Lmod2 in adult mice results in non-uniform, substantially shortened thin filaments, a significant decrease in maximum myofilament force production, blunted length-dependent activation, and rapid cardiac failure. As little as <20% of normal Lmod2 levels is sufficient to maintain cardiac function, demonstrating a direct dose-dependent link between Lmod2 levels, thin filament length, and contractile force.","method":"Cardiac-specific conditional knockout mouse, isolated cardiac trabeculae force measurements","journal":"Journal of molecular and cellular cardiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — cardiac-specific conditional KO with quantitative force measurements, dose-response relationship established, consistent with germline KO data","pmids":["30102883"],"is_preprint":false},{"year":2019,"finding":"A homozygous nonsense variant in LMOD2 (p.Trp398*) in a human neonate with DCM causes absence of LMOD2 protein, extraordinarily short cardiac thin filaments, and a large reduction in maximum calcium-activated force production in isolated cardiomyocytes, establishing that LMOD2 is required for normal thin filament length and contractile function in the human heart.","method":"Patient exome sequencing, explanted heart histology, isolated cardiomyocyte force measurements","journal":"Science advances","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — human loss-of-function with direct morphological and functional readout, single case but corroborated by mouse model comparison","pmids":["31517052"],"is_preprint":false},{"year":2020,"finding":"In slow skeletal muscle, thin filament length is dually regulated by nebulin and Lmod2: nebulin strictly controls thin filament length in fast muscles, while in slow muscles a distal nebulin-free thin filament segment exists whose length is specifically regulated by Lmod2.","method":"Nebulin super-repeat targeted gene editing in mice, high-resolution structural and functional analysis of thin filaments","journal":"Science advances","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic manipulation of nebulin combined with structural analysis placing Lmod2 in a specific regulatory pathway, single lab study","pmids":["33177085"],"is_preprint":false},{"year":2016,"finding":"Loss of Lmod2 via piggyBac transposon insertion in mice causes disordered sarcomeres, disarrayed thin filaments, and distorted intercalated discs (ICDs) with decreased convolutions and reduced electron-dense staining, accompanied by downregulation of ICD component genes β-catenin and Connexin43, indicating Lmod2 is required for ICD integrity in addition to thin filament organization.","method":"PiggyBac insertional mouse mutant, electron microscopy, gene expression analysis","journal":"Cell & bioscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic loss-of-function with ultrastructural readout and molecular expression data, single lab","pmids":["27274810"],"is_preprint":false},{"year":2021,"finding":"SNX17 interacts with LMOD2 via its C-TERM domain (confirmed by Co-IP), and SNX17 deficiency promotes aberrant LMOD2 degradation through the lysosomal pathway, exacerbating doxorubicin-induced cardiac systolic dysfunction. This identifies a post-translational regulatory mechanism controlling LMOD2 protein stability.","method":"Co-immunoprecipitation, lysosomal pathway inhibition assays, SNX17 knockdown in NRVMs and rat model","journal":"Pharmacological research","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP interaction plus mechanistic follow-up (lysosomal degradation pathway), functional readout in cells and in vivo, single lab","pmids":["33933636"],"is_preprint":false},{"year":2022,"finding":"A homozygous LMOD2 donor splice-site variant (c.273+1G>A) abolishes canonical LMOD2 mRNA splicing and full-length LMOD2 protein production (confirmed by pre-mRNA splicing studies and western blot), leading to abnormally short actin thin filaments in cardiac tissue and neonatal-lethal DCM.","method":"Pre-mRNA splicing studies, western blot, immunostaining of proband heart tissue, HEK293 transfection with LMOD2 constructs","journal":"European journal of human genetics : EJHG","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal molecular methods (splicing assay, western blot, immunostaining) in patient tissue and cell models, single lab","pmids":["35082396"],"is_preprint":false},{"year":2025,"finding":"LMOD2 interacts with ACTC1 (cardiac/skeletal muscle actin) as confirmed by Co-IP, and together they regulate myogenic differentiation in skeletal muscle. LMOD2 knockout in C2C12 cells alters muscle fiber type composition and inhibits myoblast proliferation. MyoG was identified as a transcription factor for LMOD2.","method":"Co-immunoprecipitation, CRISPR knockout in C2C12 cells, lentivirus-mediated knockdown in vivo, RNA-seq, transcription factor binding analysis","journal":"BMC genomics","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP interaction confirmed, supported by KO phenotype and transcriptome data, single lab with multiple methods","pmids":["40745266"],"is_preprint":false}],"current_model":"LMOD2 is a striated muscle-specific actin-binding protein that localizes to thin filament pointed ends in sarcomeres, where it promotes actin assembly and dynamics to elongate cardiac and slow skeletal muscle thin filaments to their mature length; loss of LMOD2 causes short, non-uniform thin filaments with severely reduced contractile force, and LMOD2 protein stability is regulated post-translationally via SNX17-mediated protection from lysosomal degradation, while LMOD2 also interacts directly with ACTC1 to regulate myogenic differentiation in skeletal muscle."},"narrative":{"mechanistic_narrative":"LMOD2 is a striated muscle actin-binding protein that elongates sarcomeric thin filaments by promoting actin assembly and dynamics at thin filament pointed ends in the heart [PMID:26487682]. Loss of LMOD2 produces abnormally short, non-uniform thin filaments with severely reduced contractile force, and its level is dose-dependently coupled to thin filament length and force output, with rapid cardiac failure upon depletion [PMID:26487682, PMID:30102883]. Homozygous loss-of-function variants in human LMOD2 abolish protein production, yield extraordinarily short cardiac thin filaments, and cause neonatal dilated cardiomyopathy, establishing LMOD2 as a Mendelian DCM gene [PMID:31517052, PMID:35082396]. Beyond the heart, LMOD2 specifically regulates the length of a distal nebulin-free thin filament segment in slow skeletal muscle and, through direct interaction with the actin ACTC1, controls myogenic differentiation, fiber-type composition, and myoblast proliferation [PMID:33177085, PMID:40745266]. LMOD2 abundance is set post-translationally: SNX17 binds LMOD2 and protects it from lysosomal degradation [PMID:33933636].","teleology":[{"year":2015,"claim":"Established the core function of LMOD2 — how cardiac thin filaments reach mature length — by showing it drives actin assembly at pointed ends and that its loss shortens filaments and impairs contraction.","evidence":"Germline knockout mouse with micropillar force measurements and AAV-mediated GFP-Lmod2 rescue","pmids":["26487682"],"confidence":"High","gaps":["Did not resolve the biochemical mechanism of pointed-end actin elongation at atomic detail","Adult versus developmental requirement not separated"]},{"year":2016,"claim":"Extended LMOD2's role beyond thin filaments by linking its loss to intercalated disc integrity, showing sarcomere disorganization coincides with disrupted cell-cell junctional gene expression.","evidence":"PiggyBac insertional mouse mutant with electron microscopy and expression analysis of β-catenin and Connexin43","pmids":["27274810"],"confidence":"Medium","gaps":["Whether ICD defects are direct or secondary to thin filament disarray unresolved","No direct LMOD2 interaction with ICD components shown"]},{"year":2018,"claim":"Resolved whether LMOD2 is needed for ongoing function in mature heart and quantified the relationship between its level and contractile output, demonstrating a steep dose-dependence.","evidence":"Cardiac-specific conditional knockout mouse with isolated trabeculae force measurements","pmids":["30102883"],"confidence":"High","gaps":["Molecular basis of why <20% suffices not explained","Length-dependent activation defect mechanism not dissected"]},{"year":2019,"claim":"Confirmed the mouse-derived mechanism operates in humans by showing a nonsense variant ablates LMOD2 protein, shortens thin filaments, and reduces force in patient cardiomyocytes.","evidence":"Patient exome sequencing with explanted heart histology and isolated cardiomyocyte force measurements","pmids":["31517052"],"confidence":"Medium","gaps":["Single patient case","Genotype-phenotype range across LMOD2 variants not defined"]},{"year":2020,"claim":"Defined the division of labor between LMOD2 and nebulin in skeletal muscle, showing LMOD2 governs a nebulin-free distal thin filament segment specifically in slow muscle.","evidence":"Nebulin super-repeat targeted gene editing in mice with high-resolution thin filament structural analysis","pmids":["33177085"],"confidence":"Medium","gaps":["Single lab","Mechanism of fiber-type-specific LMOD2 dependence not established"]},{"year":2021,"claim":"Identified how LMOD2 protein abundance is controlled, showing SNX17 binds LMOD2 and shields it from lysosomal degradation, with loss of this protection worsening cardiac dysfunction.","evidence":"Co-immunoprecipitation, lysosomal pathway inhibition, and SNX17 knockdown in NRVMs and rat model","pmids":["33933636"],"confidence":"Medium","gaps":["Single Co-IP for the interaction without reciprocal validation","E3 ligase or trafficking route targeting LMOD2 to lysosome unidentified"]},{"year":2022,"claim":"Reinforced human pathogenicity through an independent splice-site variant that abolishes full-length LMOD2 and produces short thin filaments and lethal DCM.","evidence":"Pre-mRNA splicing studies, western blot, and immunostaining of proband heart tissue plus HEK293 construct transfection","pmids":["35082396"],"confidence":"Medium","gaps":["Single family","No therapeutic intervention tested"]},{"year":2025,"claim":"Broadened LMOD2 function into skeletal myogenesis by demonstrating a direct ACTC1 interaction and roles in differentiation, fiber-type composition, and proliferation, with MyoG identified as an upstream transcriptional regulator.","evidence":"Co-IP, CRISPR knockout in C2C12 cells, in vivo lentiviral knockdown, RNA-seq, and transcription factor binding analysis","pmids":["40745266"],"confidence":"Medium","gaps":["Single Co-IP for ACTC1 interaction","Whether myogenic effects reflect thin filament function or a separate role unclear"]},{"year":null,"claim":"The atomic-level mechanism by which LMOD2 nucleates and elongates actin at thin filament pointed ends, and how its filament-length and myogenic differentiation roles are mechanistically connected, remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of LMOD2 on the pointed end","Degradation machinery beyond SNX17 unidentified","Causal link between contractile and differentiation phenotypes untested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[0,7]}],"localization":[{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[0,1]}],"pathway":[{"term_id":"R-HSA-397014","term_label":"Muscle contraction","supporting_discovery_ids":[0,1]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[7]}],"complexes":["sarcomere thin filament"],"partners":["SNX17","ACTC1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q6P5Q4","full_name":"Leiomodin-2","aliases":["Cardiac leiomodin","C-LMOD","Leiomodin"],"length_aa":547,"mass_kda":61.7,"function":"Mediates nucleation of actin filaments and thereby promotes actin polymerization (PubMed:18403713, PubMed:25250574, PubMed:26370058, PubMed:26417072). Plays a role in the regulation of actin filament length (By similarity). Required for normal sarcomere organization in the heart, and for normal heart function (PubMed:18403713)","subcellular_location":"Cytoplasm, myofibril, sarcomere; Cytoplasm, myofibril; Cytoplasm, myofibril, sarcomere, M line; Cytoplasm, cytoskeleton","url":"https://www.uniprot.org/uniprotkb/Q6P5Q4/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/LMOD2","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":[],"url":"https://opencell.sf.czbiohub.org/search/LMOD2","total_profiled":1310},"omim":[{"mim_id":"619897","title":"CARDIOMYOPATHY, DILATED, 2G; CMD2G","url":"https://www.omim.org/entry/619897"},{"mim_id":"616112","title":"LEIOMODIN 3; LMOD3","url":"https://www.omim.org/entry/616112"},{"mim_id":"612254","title":"SYSTEMIC LUPUS ERYTHEMATOSUS, SUSCEPTIBILITY TO, 12; SLEB12","url":"https://www.omim.org/entry/612254"},{"mim_id":"608006","title":"LEIOMODIN 2; LMOD2","url":"https://www.omim.org/entry/608006"},{"mim_id":"602715","title":"LEIOMODIN 1; LMOD1","url":"https://www.omim.org/entry/602715"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Uncertain","locations":[{"location":"Plasma membrane","reliability":"Uncertain"},{"location":"Actin filaments","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"heart muscle","ntpm":728.6},{"tissue":"skeletal muscle","ntpm":874.4},{"tissue":"tongue","ntpm":741.3}],"url":"https://www.proteinatlas.org/search/LMOD2"},"hgnc":{"alias_symbol":["C-Lmod"],"prev_symbol":[]},"alphafold":{"accession":"Q6P5Q4","domains":[{"cath_id":"3.80.10.10","chopping":"200-365","consensus_level":"high","plddt":95.859,"start":200,"end":365}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6P5Q4","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q6P5Q4-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q6P5Q4-F1-predicted_aligned_error_v6.png","plddt_mean":66.94},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=LMOD2","jax_strain_url":"https://www.jax.org/strain/search?query=LMOD2"},"sequence":{"accession":"Q6P5Q4","fasta_url":"https://rest.uniprot.org/uniprotkb/Q6P5Q4.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q6P5Q4/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q6P5Q4"}},"corpus_meta":[{"pmid":"26487682","id":"PMC_26487682","title":"Knockout of Lmod2 results in shorter thin filaments followed by dilated cardiomyopathy and juvenile lethality.","date":"2015","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/26487682","citation_count":76,"is_preprint":false},{"pmid":"31517052","id":"PMC_31517052","title":"Disruption of cardiac thin filament assembly arising from a mutation in LMOD2: A novel mechanism of neonatal dilated cardiomyopathy.","date":"2019","source":"Science advances","url":"https://pubmed.ncbi.nlm.nih.gov/31517052","citation_count":37,"is_preprint":false},{"pmid":"30102883","id":"PMC_30102883","title":"Cardiac-specific knockout of Lmod2 results in a severe reduction in myofilament force production and rapid cardiac failure.","date":"2018","source":"Journal of molecular and cellular cardiology","url":"https://pubmed.ncbi.nlm.nih.gov/30102883","citation_count":32,"is_preprint":false},{"pmid":"33177085","id":"PMC_33177085","title":"Nebulin and Lmod2 are critical for specifying thin-filament length in skeletal muscle.","date":"2020","source":"Science advances","url":"https://pubmed.ncbi.nlm.nih.gov/33177085","citation_count":29,"is_preprint":false},{"pmid":"27274810","id":"PMC_27274810","title":"Lmod2 piggyBac mutant mice exhibit dilated cardiomyopathy.","date":"2016","source":"Cell & bioscience","url":"https://pubmed.ncbi.nlm.nih.gov/27274810","citation_count":19,"is_preprint":false},{"pmid":"35082396","id":"PMC_35082396","title":"Neonatal-lethal dilated cardiomyopathy due to a homozygous LMOD2 donor splice-site variant.","date":"2022","source":"European journal of human genetics : EJHG","url":"https://pubmed.ncbi.nlm.nih.gov/35082396","citation_count":15,"is_preprint":false},{"pmid":"33933636","id":"PMC_33933636","title":"SNX17 protects the heart from doxorubicin-induced cardiotoxicity by modulating LMOD2 degradation.","date":"2021","source":"Pharmacological research","url":"https://pubmed.ncbi.nlm.nih.gov/33933636","citation_count":10,"is_preprint":false},{"pmid":"37296576","id":"PMC_37296576","title":"Whole-Exome Sequencing Identifies Homozygote Nonsense Variants in LMOD2 Gene Causing Infantile Dilated Cardiomyopathy.","date":"2023","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/37296576","citation_count":9,"is_preprint":false},{"pmid":"40745266","id":"PMC_40745266","title":"LMOD2 interaction with ACTC1 regulates myogenic differentiation.","date":"2025","source":"BMC genomics","url":"https://pubmed.ncbi.nlm.nih.gov/40745266","citation_count":4,"is_preprint":false},{"pmid":"39437564","id":"PMC_39437564","title":"Establishment of heterozygous LMOD2 knockout human embryonic stem cell line (ZZUNEUi022-A-1) using CRISPR/Cas9 system.","date":"2024","source":"Stem cell research","url":"https://pubmed.ncbi.nlm.nih.gov/39437564","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":6898,"output_tokens":1996,"usd":0.025317,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9032,"output_tokens":2604,"usd":0.05513,"stage2_stop_reason":"end_turn"},"total_usd":0.080447,"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\": 2015,\n      \"finding\": \"Lmod2 functions to elongate thin filaments by promoting actin assembly and dynamics at thin filament pointed ends in the heart. Knockout of Lmod2 in mice results in abnormally short thin filaments, reduced contractile force, and dilated cardiomyopathy; AAV-mediated reintroduction of GFP-Lmod2 rescues thin filament length and cardiac function.\",\n      \"method\": \"Germline knockout mouse model, micropillar array force measurements, AAV transduction rescue experiment\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic KO with defined cellular phenotype (thin filament length, contractile force), mechanistic rescue by reintroduction, replicated across multiple labs\",\n      \"pmids\": [\"26487682\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Cardiac-specific conditional knockout of Lmod2 in adult mice results in non-uniform, substantially shortened thin filaments, a significant decrease in maximum myofilament force production, blunted length-dependent activation, and rapid cardiac failure. As little as <20% of normal Lmod2 levels is sufficient to maintain cardiac function, demonstrating a direct dose-dependent link between Lmod2 levels, thin filament length, and contractile force.\",\n      \"method\": \"Cardiac-specific conditional knockout mouse, isolated cardiac trabeculae force measurements\",\n      \"journal\": \"Journal of molecular and cellular cardiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — cardiac-specific conditional KO with quantitative force measurements, dose-response relationship established, consistent with germline KO data\",\n      \"pmids\": [\"30102883\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"A homozygous nonsense variant in LMOD2 (p.Trp398*) in a human neonate with DCM causes absence of LMOD2 protein, extraordinarily short cardiac thin filaments, and a large reduction in maximum calcium-activated force production in isolated cardiomyocytes, establishing that LMOD2 is required for normal thin filament length and contractile function in the human heart.\",\n      \"method\": \"Patient exome sequencing, explanted heart histology, isolated cardiomyocyte force measurements\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — human loss-of-function with direct morphological and functional readout, single case but corroborated by mouse model comparison\",\n      \"pmids\": [\"31517052\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"In slow skeletal muscle, thin filament length is dually regulated by nebulin and Lmod2: nebulin strictly controls thin filament length in fast muscles, while in slow muscles a distal nebulin-free thin filament segment exists whose length is specifically regulated by Lmod2.\",\n      \"method\": \"Nebulin super-repeat targeted gene editing in mice, high-resolution structural and functional analysis of thin filaments\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic manipulation of nebulin combined with structural analysis placing Lmod2 in a specific regulatory pathway, single lab study\",\n      \"pmids\": [\"33177085\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Loss of Lmod2 via piggyBac transposon insertion in mice causes disordered sarcomeres, disarrayed thin filaments, and distorted intercalated discs (ICDs) with decreased convolutions and reduced electron-dense staining, accompanied by downregulation of ICD component genes β-catenin and Connexin43, indicating Lmod2 is required for ICD integrity in addition to thin filament organization.\",\n      \"method\": \"PiggyBac insertional mouse mutant, electron microscopy, gene expression analysis\",\n      \"journal\": \"Cell & bioscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic loss-of-function with ultrastructural readout and molecular expression data, single lab\",\n      \"pmids\": [\"27274810\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SNX17 interacts with LMOD2 via its C-TERM domain (confirmed by Co-IP), and SNX17 deficiency promotes aberrant LMOD2 degradation through the lysosomal pathway, exacerbating doxorubicin-induced cardiac systolic dysfunction. This identifies a post-translational regulatory mechanism controlling LMOD2 protein stability.\",\n      \"method\": \"Co-immunoprecipitation, lysosomal pathway inhibition assays, SNX17 knockdown in NRVMs and rat model\",\n      \"journal\": \"Pharmacological research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP interaction plus mechanistic follow-up (lysosomal degradation pathway), functional readout in cells and in vivo, single lab\",\n      \"pmids\": [\"33933636\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"A homozygous LMOD2 donor splice-site variant (c.273+1G>A) abolishes canonical LMOD2 mRNA splicing and full-length LMOD2 protein production (confirmed by pre-mRNA splicing studies and western blot), leading to abnormally short actin thin filaments in cardiac tissue and neonatal-lethal DCM.\",\n      \"method\": \"Pre-mRNA splicing studies, western blot, immunostaining of proband heart tissue, HEK293 transfection with LMOD2 constructs\",\n      \"journal\": \"European journal of human genetics : EJHG\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal molecular methods (splicing assay, western blot, immunostaining) in patient tissue and cell models, single lab\",\n      \"pmids\": [\"35082396\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"LMOD2 interacts with ACTC1 (cardiac/skeletal muscle actin) as confirmed by Co-IP, and together they regulate myogenic differentiation in skeletal muscle. LMOD2 knockout in C2C12 cells alters muscle fiber type composition and inhibits myoblast proliferation. MyoG was identified as a transcription factor for LMOD2.\",\n      \"method\": \"Co-immunoprecipitation, CRISPR knockout in C2C12 cells, lentivirus-mediated knockdown in vivo, RNA-seq, transcription factor binding analysis\",\n      \"journal\": \"BMC genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP interaction confirmed, supported by KO phenotype and transcriptome data, single lab with multiple methods\",\n      \"pmids\": [\"40745266\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"LMOD2 is a striated muscle-specific actin-binding protein that localizes to thin filament pointed ends in sarcomeres, where it promotes actin assembly and dynamics to elongate cardiac and slow skeletal muscle thin filaments to their mature length; loss of LMOD2 causes short, non-uniform thin filaments with severely reduced contractile force, and LMOD2 protein stability is regulated post-translationally via SNX17-mediated protection from lysosomal degradation, while LMOD2 also interacts directly with ACTC1 to regulate myogenic differentiation in skeletal muscle.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"LMOD2 is a striated muscle actin-binding protein that elongates sarcomeric thin filaments by promoting actin assembly and dynamics at thin filament pointed ends in the heart [#0]. Loss of LMOD2 produces abnormally short, non-uniform thin filaments with severely reduced contractile force, and its level is dose-dependently coupled to thin filament length and force output, with rapid cardiac failure upon depletion [#0, #1]. Homozygous loss-of-function variants in human LMOD2 abolish protein production, yield extraordinarily short cardiac thin filaments, and cause neonatal dilated cardiomyopathy, establishing LMOD2 as a Mendelian DCM gene [#2, #6]. Beyond the heart, LMOD2 specifically regulates the length of a distal nebulin-free thin filament segment in slow skeletal muscle and, through direct interaction with the actin ACTC1, controls myogenic differentiation, fiber-type composition, and myoblast proliferation [#3, #7]. LMOD2 abundance is set post-translationally: SNX17 binds LMOD2 and protects it from lysosomal degradation [#5].\",\n  \"teleology\": [\n    {\n      \"year\": 2015,\n      \"claim\": \"Established the core function of LMOD2 — how cardiac thin filaments reach mature length — by showing it drives actin assembly at pointed ends and that its loss shortens filaments and impairs contraction.\",\n      \"evidence\": \"Germline knockout mouse with micropillar force measurements and AAV-mediated GFP-Lmod2 rescue\",\n      \"pmids\": [\"26487682\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve the biochemical mechanism of pointed-end actin elongation at atomic detail\", \"Adult versus developmental requirement not separated\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Extended LMOD2's role beyond thin filaments by linking its loss to intercalated disc integrity, showing sarcomere disorganization coincides with disrupted cell-cell junctional gene expression.\",\n      \"evidence\": \"PiggyBac insertional mouse mutant with electron microscopy and expression analysis of β-catenin and Connexin43\",\n      \"pmids\": [\"27274810\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether ICD defects are direct or secondary to thin filament disarray unresolved\", \"No direct LMOD2 interaction with ICD components shown\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Resolved whether LMOD2 is needed for ongoing function in mature heart and quantified the relationship between its level and contractile output, demonstrating a steep dose-dependence.\",\n      \"evidence\": \"Cardiac-specific conditional knockout mouse with isolated trabeculae force measurements\",\n      \"pmids\": [\"30102883\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of why <20% suffices not explained\", \"Length-dependent activation defect mechanism not dissected\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Confirmed the mouse-derived mechanism operates in humans by showing a nonsense variant ablates LMOD2 protein, shortens thin filaments, and reduces force in patient cardiomyocytes.\",\n      \"evidence\": \"Patient exome sequencing with explanted heart histology and isolated cardiomyocyte force measurements\",\n      \"pmids\": [\"31517052\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single patient case\", \"Genotype-phenotype range across LMOD2 variants not defined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined the division of labor between LMOD2 and nebulin in skeletal muscle, showing LMOD2 governs a nebulin-free distal thin filament segment specifically in slow muscle.\",\n      \"evidence\": \"Nebulin super-repeat targeted gene editing in mice with high-resolution thin filament structural analysis\",\n      \"pmids\": [\"33177085\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"Mechanism of fiber-type-specific LMOD2 dependence not established\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified how LMOD2 protein abundance is controlled, showing SNX17 binds LMOD2 and shields it from lysosomal degradation, with loss of this protection worsening cardiac dysfunction.\",\n      \"evidence\": \"Co-immunoprecipitation, lysosomal pathway inhibition, and SNX17 knockdown in NRVMs and rat model\",\n      \"pmids\": [\"33933636\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single Co-IP for the interaction without reciprocal validation\", \"E3 ligase or trafficking route targeting LMOD2 to lysosome unidentified\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Reinforced human pathogenicity through an independent splice-site variant that abolishes full-length LMOD2 and produces short thin filaments and lethal DCM.\",\n      \"evidence\": \"Pre-mRNA splicing studies, western blot, and immunostaining of proband heart tissue plus HEK293 construct transfection\",\n      \"pmids\": [\"35082396\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single family\", \"No therapeutic intervention tested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Broadened LMOD2 function into skeletal myogenesis by demonstrating a direct ACTC1 interaction and roles in differentiation, fiber-type composition, and proliferation, with MyoG identified as an upstream transcriptional regulator.\",\n      \"evidence\": \"Co-IP, CRISPR knockout in C2C12 cells, in vivo lentiviral knockdown, RNA-seq, and transcription factor binding analysis\",\n      \"pmids\": [\"40745266\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single Co-IP for ACTC1 interaction\", \"Whether myogenic effects reflect thin filament function or a separate role unclear\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The atomic-level mechanism by which LMOD2 nucleates and elongates actin at thin filament pointed ends, and how its filament-length and myogenic differentiation roles are mechanistically connected, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of LMOD2 on the pointed end\", \"Degradation machinery beyond SNX17 unidentified\", \"Causal link between contractile and differentiation phenotypes untested\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0, 7]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005865\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-397014\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"complexes\": [\"sarcomere thin filament\"],\n    \"partners\": [\"SNX17\", \"ACTC1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}