{"gene":"LMOD2","run_date":"2026-04-28T18:30:27","timeline":{"discoveries":[{"year":2015,"finding":"Lmod2 promotes actin assembly and dynamics at thin filament pointed ends, functioning to elongate thin filaments in the heart; knockout mice have abnormally short thin filaments, reduced contractile force, and dilated cardiomyopathy, and GFP-Lmod2 viral rescue elongates thin filaments and restores function.","method":"Lmod2 knockout mouse model, micropillar array force measurements, AAV-mediated GFP-Lmod2 rescue, electron microscopy of sarcomere structure","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1–2 — KO phenotype with specific molecular readout (thin filament length), rescue experiment, force measurements; replicated by multiple labs","pmids":["26487682"],"is_preprint":false},{"year":2018,"finding":"Cardiac-specific conditional knockout of Lmod2 in adult mice causes non-uniform, shortened thin filaments, significant decrease in maximum force production, blunted myofilament length-dependent activation, and rapid cardiac failure; Lmod2 levels are directly linked to thin filament length and cardiac function in vivo, with <20% Lmod2 sufficient to maintain cardiac function.","method":"Cardiac-specific conditional Lmod2 knockout mice, isolated cardiac trabeculae force measurements, echocardiography","journal":"Journal of molecular and cellular cardiology","confidence":"High","confidence_rationale":"Tier 2 — clean cardiac-specific KO with quantitative force measurements and dose-response relationship established","pmids":["30102883"],"is_preprint":false},{"year":2019,"finding":"Loss-of-function LMOD2 nonsense variant (p.Trp398*) in humans causes neonatal dilated cardiomyopathy with extraordinarily short cardiac thin filaments and severely reduced maximum calcium-activated force production, confirming LMOD2's essential role in human cardiac thin filament elongation.","method":"Human exome sequencing, explanted heart histology (thin filament length measurement), isolated cardiomyocyte calcium-activated force measurements","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 2 — human disease variant with direct structural and functional cardiac phenotyping, corroborated by mouse model","pmids":["31517052"],"is_preprint":false},{"year":2020,"finding":"In slow skeletal muscle, thin filament length is regulated by dual mechanisms: the length of nebulin strictly controls the nebulin-associated segment, while Lmod2 controls the length of a distal nebulin-free segment; in fast muscle, nebulin alone controls thin filament length.","method":"Nebulin super-repeat targeting mouse models (gene shortening/lengthening), high-resolution structural and functional analysis, comparison with Lmod2 function","journal":"Science advances","confidence":"High","confidence_rationale":"Tier 1–2 — genetic dissection with engineered nebulin length variants and functional readouts establishing pathway epistasis for Lmod2 in slow muscle","pmids":["33177085"],"is_preprint":false},{"year":2021,"finding":"SNX17 interacts with LMOD2 via its C-TERM domain and protects LMOD2 from degradation through the lysosomal pathway; SNX17 deficiency promotes aberrant LMOD2 degradation and worsens doxorubicin-induced cardiac systolic dysfunction.","method":"Co-immunoprecipitation, SNX17 knockdown/knockout in NRVMs and rats, lysosomal inhibitor assays, echocardiography","journal":"Pharmacological research","confidence":"Medium","confidence_rationale":"Tier 3 — single lab Co-IP identifying binding partner plus functional KD phenotype; lysosomal pathway established by inhibitor rescue","pmids":["33933636"],"is_preprint":false},{"year":2025,"finding":"LMOD2 interacts with ACTC1 (cardiac/skeletal actin) and together they regulate myogenic differentiation; MyoG is a transcription factor for LMOD2, and miR-335-3p negatively regulates LMOD2 expression; LMOD2 knockout alters muscle fiber type composition and inhibits myoblast proliferation.","method":"Co-IP confirming LMOD2–ACTC1 interaction, LMOD2 knockout in C2C12 cells, transcriptome analysis, lentivirus-mediated LMOD2 knockdown in vivo","journal":"BMC genomics","confidence":"Medium","confidence_rationale":"Tier 3 — single lab Co-IP for ACTC1 interaction, supported by KO transcriptome and in vivo knockdown phenotype","pmids":["40745266"],"is_preprint":false}],"current_model":"LMOD2 is a striated muscle-specific actin-binding protein that localizes to thin filament pointed ends and promotes actin assembly/dynamics there to elongate cardiac and slow skeletal muscle thin filaments to mature length; its levels directly control thin filament length and contractile force output, it interacts with ACTC1 and is itself stabilized by SNX17 via protection from lysosomal degradation, and loss of LMOD2 in mice or humans causes short thin filaments, impaired force production, and dilated cardiomyopathy."},"narrative":{"teleology":[{"year":2015,"claim":"Establishing that LMOD2 is required for thin filament elongation in the heart answered the fundamental question of what controls cardiac thin filament length at pointed ends, revealing that its loss causes short filaments, reduced force, and dilated cardiomyopathy — and that viral re-expression rescues the phenotype.","evidence":"Lmod2 global knockout mice analyzed by electron microscopy, micropillar force measurements, and AAV-mediated GFP-Lmod2 rescue","pmids":["26487682"],"confidence":"High","gaps":["Mechanism by which LMOD2 nucleates or elongates actin at pointed ends not resolved at atomic level","Whether LMOD2 has additional functions beyond thin filament length regulation not addressed","Relative contributions of LMOD2 versus tropomodulin capping at pointed ends not dissected"]},{"year":2018,"claim":"Conditional adult cardiac knockout demonstrated that LMOD2 is continuously required in the mature heart — not just during development — and established a quantitative dose–response relationship between LMOD2 protein levels, thin filament length, and contractile performance.","evidence":"Cardiac-specific conditional Lmod2 knockout in adult mice with isolated trabeculae force measurements and echocardiography","pmids":["30102883"],"confidence":"High","gaps":["How LMOD2 turnover rate relates to thin filament homeostasis not quantified","Whether LMOD2 dose–response relationship holds in human myocardium not tested"]},{"year":2019,"claim":"Identification of a human LMOD2 loss-of-function variant causing neonatal dilated cardiomyopathy with short thin filaments confirmed the gene's non-redundant role in human cardiac sarcomere assembly and established LMOD2 deficiency as a Mendelian cardiomyopathy.","evidence":"Exome sequencing of affected neonate, explanted heart thin filament length measurement, isolated cardiomyocyte force assays","pmids":["31517052"],"confidence":"High","gaps":["Spectrum of pathogenic LMOD2 variants and genotype–phenotype correlations not established","Whether partial loss-of-function alleles produce milder phenotypes unknown"]},{"year":2020,"claim":"Dissection of thin filament length control in skeletal muscle revealed that LMOD2 specifically governs the nebulin-free distal segment in slow fibers, resolving how pointed-end elongation and nebulin-based templating cooperate in a fiber-type-specific manner.","evidence":"Engineered nebulin super-repeat shortening/lengthening mouse models with structural and functional analysis compared with Lmod2 function","pmids":["33177085"],"confidence":"High","gaps":["Molecular basis for fiber-type specificity of LMOD2 function not defined","Whether LMOD2 and nebulin physically interact at the transition zone not determined"]},{"year":2021,"claim":"Identification of SNX17 as a binding partner that protects LMOD2 from lysosomal degradation provided the first insight into how LMOD2 protein stability is regulated, linking endosomal sorting to thin filament homeostasis.","evidence":"Co-immunoprecipitation of SNX17–LMOD2, SNX17 knockdown/knockout in neonatal rat ventricular myocytes and rats, lysosomal inhibitor rescue","pmids":["33936636"],"confidence":"Medium","gaps":["SNX17–LMOD2 interaction identified by single-lab Co-IP without reciprocal validation or structural mapping","Whether other E3 ligases or degradation pathways also regulate LMOD2 turnover unknown","Physiological relevance of the SNX17–LMOD2 axis in human heart failure not demonstrated"]},{"year":2025,"claim":"Demonstration that LMOD2 physically interacts with ACTC1 and that its loss alters muscle fiber type composition and myoblast proliferation extended LMOD2 function beyond thin filament elongation to include roles in myogenic differentiation and fiber-type specification.","evidence":"Co-IP of LMOD2–ACTC1, LMOD2 knockout in C2C12 cells with transcriptome analysis, lentivirus-mediated knockdown in vivo","pmids":["40745266"],"confidence":"Medium","gaps":["LMOD2–ACTC1 interaction from single-lab Co-IP; stoichiometry and binding interface unresolved","Whether fiber-type changes are a direct consequence of LMOD2 loss or secondary to impaired thin filament function not distinguished","Transcriptional regulation of LMOD2 by MyoG validated only in C2C12 cells"]},{"year":null,"claim":"The atomic-level mechanism by which LMOD2 nucleates or elongates actin at pointed ends, the structural basis of its fiber-type-specific function, and how its protein turnover is coordinated with thin filament dynamics remain unresolved.","evidence":"","pmids":[],"confidence":"High","gaps":["No high-resolution structure of LMOD2 bound to actin pointed ends available","Mechanism distinguishing LMOD2 from tropomodulin at pointed ends not molecularly defined","In vivo dynamics of LMOD2 incorporation and turnover at the sarcomere not measured"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[0,1,3,5]}],"localization":[{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[0,1,3]}],"pathway":[{"term_id":"R-HSA-397014","term_label":"Muscle contraction","supporting_discovery_ids":[0,1,2,3]}],"complexes":[],"partners":["ACTC1","SNX17"],"other_free_text":[]},"mechanistic_narrative":"LMOD2 is a striated muscle-specific actin filament elongation factor that localizes to thin filament pointed ends and is essential for achieving mature thin filament length and normal contractile force in cardiac and slow skeletal muscle. In the heart, LMOD2 promotes actin assembly at pointed ends; its absence causes uniformly short thin filaments, severely reduced calcium-activated force production, blunted length-dependent activation, and dilated cardiomyopathy, with as little as ~20% of normal LMOD2 levels sufficient to maintain cardiac function [PMID:26487682, PMID:30102883]. In slow skeletal muscle, LMOD2 specifically controls the length of the distal nebulin-free segment of thin filaments, whereas nebulin governs the proximal segment [PMID:33177085]. Loss-of-function LMOD2 mutations cause neonatal dilated cardiomyopathy in humans, with extraordinarily short thin filaments and impaired force generation confirming its non-redundant role in human cardiac sarcomere assembly [PMID:31517052]."},"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":36,"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":28,"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":14,"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":3,"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":6139,"output_tokens":1487,"usd":0.020361},"stage2":{"model":"claude-opus-4-6","input_tokens":4729,"output_tokens":1947,"usd":0.10848},"total_usd":0.128841,"stage1_batch_id":"msgbatch_01Mgbec4vM6c9vXht7JVJzss","stage2_batch_id":"msgbatch_01JkuuH5RB2BdJNsgnhjbC6s","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2015,\n      \"finding\": \"Lmod2 promotes actin assembly and dynamics at thin filament pointed ends, functioning to elongate thin filaments in the heart; knockout mice have abnormally short thin filaments, reduced contractile force, and dilated cardiomyopathy, and GFP-Lmod2 viral rescue elongates thin filaments and restores function.\",\n      \"method\": \"Lmod2 knockout mouse model, micropillar array force measurements, AAV-mediated GFP-Lmod2 rescue, electron microscopy of sarcomere structure\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — KO phenotype with specific molecular readout (thin filament length), rescue experiment, force measurements; replicated by 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 causes non-uniform, shortened thin filaments, significant decrease in maximum force production, blunted myofilament length-dependent activation, and rapid cardiac failure; Lmod2 levels are directly linked to thin filament length and cardiac function in vivo, with <20% Lmod2 sufficient to maintain cardiac function.\",\n      \"method\": \"Cardiac-specific conditional Lmod2 knockout mice, isolated cardiac trabeculae force measurements, echocardiography\",\n      \"journal\": \"Journal of molecular and cellular cardiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean cardiac-specific KO with quantitative force measurements and dose-response relationship established\",\n      \"pmids\": [\"30102883\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Loss-of-function LMOD2 nonsense variant (p.Trp398*) in humans causes neonatal dilated cardiomyopathy with extraordinarily short cardiac thin filaments and severely reduced maximum calcium-activated force production, confirming LMOD2's essential role in human cardiac thin filament elongation.\",\n      \"method\": \"Human exome sequencing, explanted heart histology (thin filament length measurement), isolated cardiomyocyte calcium-activated force measurements\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — human disease variant with direct structural and functional cardiac phenotyping, corroborated by mouse model\",\n      \"pmids\": [\"31517052\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"In slow skeletal muscle, thin filament length is regulated by dual mechanisms: the length of nebulin strictly controls the nebulin-associated segment, while Lmod2 controls the length of a distal nebulin-free segment; in fast muscle, nebulin alone controls thin filament length.\",\n      \"method\": \"Nebulin super-repeat targeting mouse models (gene shortening/lengthening), high-resolution structural and functional analysis, comparison with Lmod2 function\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — genetic dissection with engineered nebulin length variants and functional readouts establishing pathway epistasis for Lmod2 in slow muscle\",\n      \"pmids\": [\"33177085\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SNX17 interacts with LMOD2 via its C-TERM domain and protects LMOD2 from degradation through the lysosomal pathway; SNX17 deficiency promotes aberrant LMOD2 degradation and worsens doxorubicin-induced cardiac systolic dysfunction.\",\n      \"method\": \"Co-immunoprecipitation, SNX17 knockdown/knockout in NRVMs and rats, lysosomal inhibitor assays, echocardiography\",\n      \"journal\": \"Pharmacological research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single lab Co-IP identifying binding partner plus functional KD phenotype; lysosomal pathway established by inhibitor rescue\",\n      \"pmids\": [\"33933636\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"LMOD2 interacts with ACTC1 (cardiac/skeletal actin) and together they regulate myogenic differentiation; MyoG is a transcription factor for LMOD2, and miR-335-3p negatively regulates LMOD2 expression; LMOD2 knockout alters muscle fiber type composition and inhibits myoblast proliferation.\",\n      \"method\": \"Co-IP confirming LMOD2–ACTC1 interaction, LMOD2 knockout in C2C12 cells, transcriptome analysis, lentivirus-mediated LMOD2 knockdown in vivo\",\n      \"journal\": \"BMC genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single lab Co-IP for ACTC1 interaction, supported by KO transcriptome and in vivo knockdown phenotype\",\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 and promotes actin assembly/dynamics there to elongate cardiac and slow skeletal muscle thin filaments to mature length; its levels directly control thin filament length and contractile force output, it interacts with ACTC1 and is itself stabilized by SNX17 via protection from lysosomal degradation, and loss of LMOD2 in mice or humans causes short thin filaments, impaired force production, and dilated cardiomyopathy.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"LMOD2 is a striated muscle-specific actin filament elongation factor that localizes to thin filament pointed ends and is essential for achieving mature thin filament length and normal contractile force in cardiac and slow skeletal muscle. In the heart, LMOD2 promotes actin assembly at pointed ends; its absence causes uniformly short thin filaments, severely reduced calcium-activated force production, blunted length-dependent activation, and dilated cardiomyopathy, with as little as ~20% of normal LMOD2 levels sufficient to maintain cardiac function [PMID:26487682, PMID:30102883]. In slow skeletal muscle, LMOD2 specifically controls the length of the distal nebulin-free segment of thin filaments, whereas nebulin governs the proximal segment [PMID:33177085]. Loss-of-function LMOD2 mutations cause neonatal dilated cardiomyopathy in humans, with extraordinarily short thin filaments and impaired force generation confirming its non-redundant role in human cardiac sarcomere assembly [PMID:31517052].\",\n  \"teleology\": [\n    {\n      \"year\": 2015,\n      \"claim\": \"Establishing that LMOD2 is required for thin filament elongation in the heart answered the fundamental question of what controls cardiac thin filament length at pointed ends, revealing that its loss causes short filaments, reduced force, and dilated cardiomyopathy — and that viral re-expression rescues the phenotype.\",\n      \"evidence\": \"Lmod2 global knockout mice analyzed by electron microscopy, micropillar force measurements, and AAV-mediated GFP-Lmod2 rescue\",\n      \"pmids\": [\"26487682\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Mechanism by which LMOD2 nucleates or elongates actin at pointed ends not resolved at atomic level\",\n        \"Whether LMOD2 has additional functions beyond thin filament length regulation not addressed\",\n        \"Relative contributions of LMOD2 versus tropomodulin capping at pointed ends not dissected\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Conditional adult cardiac knockout demonstrated that LMOD2 is continuously required in the mature heart — not just during development — and established a quantitative dose–response relationship between LMOD2 protein levels, thin filament length, and contractile performance.\",\n      \"evidence\": \"Cardiac-specific conditional Lmod2 knockout in adult mice with isolated trabeculae force measurements and echocardiography\",\n      \"pmids\": [\"30102883\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"How LMOD2 turnover rate relates to thin filament homeostasis not quantified\",\n        \"Whether LMOD2 dose–response relationship holds in human myocardium not tested\"\n      ]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identification of a human LMOD2 loss-of-function variant causing neonatal dilated cardiomyopathy with short thin filaments confirmed the gene's non-redundant role in human cardiac sarcomere assembly and established LMOD2 deficiency as a Mendelian cardiomyopathy.\",\n      \"evidence\": \"Exome sequencing of affected neonate, explanted heart thin filament length measurement, isolated cardiomyocyte force assays\",\n      \"pmids\": [\"31517052\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Spectrum of pathogenic LMOD2 variants and genotype–phenotype correlations not established\",\n        \"Whether partial loss-of-function alleles produce milder phenotypes unknown\"\n      ]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Dissection of thin filament length control in skeletal muscle revealed that LMOD2 specifically governs the nebulin-free distal segment in slow fibers, resolving how pointed-end elongation and nebulin-based templating cooperate in a fiber-type-specific manner.\",\n      \"evidence\": \"Engineered nebulin super-repeat shortening/lengthening mouse models with structural and functional analysis compared with Lmod2 function\",\n      \"pmids\": [\"33177085\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Molecular basis for fiber-type specificity of LMOD2 function not defined\",\n        \"Whether LMOD2 and nebulin physically interact at the transition zone not determined\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identification of SNX17 as a binding partner that protects LMOD2 from lysosomal degradation provided the first insight into how LMOD2 protein stability is regulated, linking endosomal sorting to thin filament homeostasis.\",\n      \"evidence\": \"Co-immunoprecipitation of SNX17–LMOD2, SNX17 knockdown/knockout in neonatal rat ventricular myocytes and rats, lysosomal inhibitor rescue\",\n      \"pmids\": [\"33936636\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"SNX17–LMOD2 interaction identified by single-lab Co-IP without reciprocal validation or structural mapping\",\n        \"Whether other E3 ligases or degradation pathways also regulate LMOD2 turnover unknown\",\n        \"Physiological relevance of the SNX17–LMOD2 axis in human heart failure not demonstrated\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Demonstration that LMOD2 physically interacts with ACTC1 and that its loss alters muscle fiber type composition and myoblast proliferation extended LMOD2 function beyond thin filament elongation to include roles in myogenic differentiation and fiber-type specification.\",\n      \"evidence\": \"Co-IP of LMOD2–ACTC1, LMOD2 knockout in C2C12 cells with transcriptome analysis, lentivirus-mediated knockdown in vivo\",\n      \"pmids\": [\"40745266\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"LMOD2–ACTC1 interaction from single-lab Co-IP; stoichiometry and binding interface unresolved\",\n        \"Whether fiber-type changes are a direct consequence of LMOD2 loss or secondary to impaired thin filament function not distinguished\",\n        \"Transcriptional regulation of LMOD2 by MyoG validated only in C2C12 cells\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The atomic-level mechanism by which LMOD2 nucleates or elongates actin at pointed ends, the structural basis of its fiber-type-specific function, and how its protein turnover is coordinated with thin filament dynamics remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No high-resolution structure of LMOD2 bound to actin pointed ends available\",\n        \"Mechanism distinguishing LMOD2 from tropomodulin at pointed ends not molecularly defined\",\n        \"In vivo dynamics of LMOD2 incorporation and turnover at the sarcomere not measured\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0, 1, 3, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [0, 1, 3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-397014\", \"supporting_discovery_ids\": [0, 1, 2, 3]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"ACTC1\",\n      \"SNX17\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}