{"gene":"MYH14","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":2004,"finding":"MYH14 encodes a heavy chain of class II nonmuscle myosin and is highly expressed in mouse cochlea; nonsense and missense mutations in MYH14 cause autosomal dominant hearing loss (DFNA4), establishing MYH14 as a causative gene for auditory function.","method":"Mutational screening of 300 hearing-impaired patients, RT-PCR/expression analysis in mouse cochlea, co-segregation analysis in pedigrees linked to DFNA4","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple independent pedigrees across three countries, expression confirmed in cochlea, mutations absent in 200 controls, replicated by multiple subsequent studies","pmids":["15015131"],"is_preprint":false},{"year":2009,"finding":"MYH14 protein is selectively expressed in slow-tonic fibres of extraocular muscles and in bag fibres of muscle spindles in rat and mouse; it is transiently expressed in embryonic skeletal muscle but disappears postnatally from most fibre types except slow-tonic fibres.","method":"Immunohistochemistry, RT-PCR, western blotting across developmental stages in rat and mouse tissues","journal":"The Journal of physiology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (protein and mRNA), developmental time series, reproduced across two species","pmids":["19948655"],"is_preprint":false},{"year":2011,"finding":"The R941L (c.2822G>T, p.Arg941Leu) mutation in MYH14 causes a complex autosomal dominant phenotype including peripheral neuropathy, distal myopathy, hoarseness, and hearing loss, expanding the phenotypic spectrum beyond nonsyndromic hearing loss.","method":"SNP-based linkage mapping, Sanger sequencing of 34 candidate genes, electrodiagnostic and histopathologic studies in a large Korean family","journal":"Human mutation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — linkage plus sequencing in large pedigree, electrodiagnostic confirmation, single lab","pmids":["21480433"],"is_preprint":false},{"year":2011,"finding":"In myotonic dystrophy type 1 (DM1) muscle, MBNL1 positively regulates inclusion of MYH14 exon 6 (producing the NMHCII-C1 isoform); loss of MBNL1 in DM1 leads to predominant expression of the NMHCII-C0 isoform and overall reduction of MYH14 mRNA and protein.","method":"RT-PCR splice analysis in DM1 patient muscle biopsies (n=12), minigene splicing assay with MBNL1 modulation, quantitative RT-PCR and western blot","journal":"Neurobiology of disease","confidence":"High","confidence_rationale":"Tier 1 / Moderate — minigene functional assay directly demonstrates MBNL1 regulation of MYH14 exon 6 inclusion, supported by patient tissue data with multiple orthogonal methods","pmids":["21872659"],"is_preprint":false},{"year":2019,"finding":"MYH14 (NMIIC) mediates mitochondrial fission in human cells; the R941L mutation acts in a dominant-negative fashion to inhibit mitochondrial fission, especially in the cell periphery, and disrupts mitochondrial genome organization, providing a mechanism for the peripheral neuropathy phenotype.","method":"Confocal microscopy of mitochondrial dynamics in patient fibroblasts and U2OS/M17 cells overexpressing NMIIC; C. elegans modelling of R941L myosin activity","journal":"EBioMedicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — live-cell imaging with functional consequence, multiple cell types, C. elegans functional model, single lab","pmids":["31231018"],"is_preprint":false},{"year":2019,"finding":"MYH14 (NMIIC) is a mechanoresponsive protein that accumulates at the cell cortex under mechanical stress; pharmacological activation of MYH14 assembly by 4-hydroxyacetophenone (4-HAP) stiffens pancreatic cancer cells, induces cortical actin belts, slows retrograde actin flow, decreases dissemination, and reduces liver metastases in vivo.","method":"Deformability cytometry, immunofluorescence, live-cell actin flow imaging, spheroid cortical actin analysis, mouse xenograft model (nude mice)","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal cellular assays plus in vivo validation, mechanistic link between MYH14 assembly, cortical stiffness and invasion established","pmids":["31358530"],"is_preprint":false},{"year":2017,"finding":"MYH14 (NMIIC) is localized to intercalated cells of the collecting duct and connecting segment in mouse kidney, with isoform-specific subcellular distribution distinct from MYH9 and MYH10, suggesting a role in segment-specific intracellular trafficking.","method":"Immunohistochemistry and subcellular fractionation/localization in mouse kidney sections","journal":"Physiological reports","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single localization study, no functional manipulation of MYH14 specifically, single lab","pmids":["29208685"],"is_preprint":false},{"year":2016,"finding":"Loss of Myh14 in CBA/CaJ mice does not cause significant hearing loss until 5 months of age but increases susceptibility to noise-induced hearing loss, with greater outer hair cell loss after acoustic trauma compared to wild-type controls.","method":"CRISPR/Cas9 knockout in CBA/CaJ mice, auditory brainstem response (ABR) testing, cochlear hair cell counts after acoustic trauma","journal":"Neural plasticity","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean genetic knockout with defined cellular phenotype (OHC loss) and functional hearing measurement, single lab","pmids":["28101381"],"is_preprint":false},{"year":2017,"finding":"MYH14 mutations are associated with anorectal malformations in humans; immunohistochemical analysis in mouse embryos (E11.5–13.5) demonstrated stronger NMHC IIC localization in the epithelium of the embryonic cloaca, urorectal septum, and hindgut compared with the other two NMHC II isoforms, consistent with a role in anorectal development.","method":"Whole-exome sequencing, immunohistochemistry of mouse embryonic cloacal regions","journal":"Clinical genetics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — localization data only without direct functional manipulation of MYH14 in the developmental context, single lab","pmids":["28191911"],"is_preprint":false},{"year":2024,"finding":"MYH14 interacts with MYH9 (non-muscle myosin IIA) in endometrial cancer cells; this interaction impairs GSK3β-mediated β-catenin ubiquitination and degradation, thereby activating Wnt/β-catenin signaling and promoting EMT. The natural compound sesamolin directly binds MYH14, disrupts the MYH14–MYH9 interaction, and suppresses Wnt/β-catenin signaling.","method":"Co-immunoprecipitation, cellular thermal shift assay (CETSA), cycloheximide chase, luciferase reporter assay, mouse xenograft model","journal":"Cellular & molecular biology letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP plus CETSA for direct binding, functional pathway readout with reporter assay and in vivo model, single lab","pmids":["38698330"],"is_preprint":false}],"current_model":"MYH14 encodes the heavy chain of non-muscle myosin IIC (NMIIC), a class II myosin that drives cortical actomyosin contractility and mechanoresponsiveness; it regulates mitochondrial fission (with the R941L mutation acting dominantly-negatively to impair fission and cause peripheral neuropathy), interacts with MYH9 to modulate GSK3β/β-catenin/Wnt signaling, is expressed selectively in cochlear hair cells and slow-tonic/spindle muscle fibres, and its alternative splicing is controlled by MBNL1 such that loss of MBNL1 in myotonic dystrophy shifts isoform balance toward NMHCII-C0."},"narrative":{"mechanistic_narrative":"MYH14 encodes the heavy chain of class II non-muscle myosin IIC (NMIIC), an actomyosin motor that drives cortical contractility and mechanoresponsive cell behaviors [PMID:31358530]. As a mechanoresponsive protein, NMIIC accumulates at the cell cortex under mechanical stress, and pharmacological enhancement of its assembly stiffens cells, builds cortical actin belts, slows retrograde actin flow, and suppresses cancer cell dissemination and metastasis in vivo [PMID:31358530]. Beyond the cortex, NMIIC mediates mitochondrial fission in human cells, with the dominant R941L mutation impairing peripheral fission and disrupting mitochondrial genome organization—a mechanism linked to its peripheral neuropathy phenotype [PMID:31231018]. In endometrial cancer cells NMIIC physically interacts with MYH9 (non-muscle myosin IIA) to impair GSK3β-mediated β-catenin degradation, thereby activating Wnt/β-catenin signaling and promoting EMT [PMID:38698330]. MYH14 is expressed selectively in cochlear hair cells and in slow-tonic and muscle-spindle fibres [PMID:15015131, PMID:19948655], and its exon 6 splicing is controlled by MBNL1, shifting isoform balance toward NMHCII-C0 when MBNL1 is lost in myotonic dystrophy [PMID:21872659]. Clinically, MYH14 mutations cause autosomal dominant hearing loss (DFNA4) [PMID:15015131], and the R941L allele produces a complex dominant syndrome of peripheral neuropathy, distal myopathy, hoarseness, and hearing loss [PMID:21480433].","teleology":[{"year":2004,"claim":"Establishing that MYH14 is a human disease gene answered whether this non-muscle myosin II heavy chain has a non-redundant physiological role, linking it causally to auditory function.","evidence":"Mutational screening of hearing-impaired patients with cochlear expression analysis and pedigree co-segregation (DFNA4)","pmids":["15015131"],"confidence":"High","gaps":["Does not define the molecular mechanism by which loss links to hair cell dysfunction","No structural or motor-activity characterization"]},{"year":2009,"claim":"Mapping MYH14 protein expression to slow-tonic and muscle-spindle fibres established a tissue context beyond the cochlea and a developmentally regulated, fibre-type-selective role.","evidence":"Immunohistochemistry, RT-PCR and western blot across developmental stages in rat and mouse","pmids":["19948655"],"confidence":"High","gaps":["Functional role in slow-tonic/spindle fibres not tested by perturbation","Mechanism of fibre-type-selective regulation unknown"]},{"year":2011,"claim":"Identifying R941L expanded the phenotypic spectrum, showing a single dominant allele can produce neuropathy and myopathy in addition to hearing loss.","evidence":"SNP linkage mapping plus Sanger sequencing with electrodiagnostic and histopathologic study in a large Korean family","pmids":["21480433"],"confidence":"Medium","gaps":["Single pedigree, single lab","Did not establish a molecular mechanism for the multisystem phenotype"]},{"year":2011,"claim":"Defining MBNL1 control of MYH14 exon 6 splicing answered how isoform balance is set and connected MYH14 dysregulation to myotonic dystrophy.","evidence":"RT-PCR splice analysis of DM1 muscle biopsies plus minigene splicing assay with MBNL1 modulation","pmids":["21872659"],"confidence":"High","gaps":["Functional difference between NMHCII-C0 and NMHCII-C1 isoforms not resolved","Downstream consequences of isoform shift on contractility not defined"]},{"year":2016,"claim":"A clean Myh14 knockout addressed whether the gene is required for baseline hearing, revealing it is dispensable until later age but protective against noise-induced damage.","evidence":"CRISPR/Cas9 knockout in CBA/CaJ mice with ABR testing and hair cell counts after acoustic trauma","pmids":["28101381"],"confidence":"Medium","gaps":["Molecular basis of protection against trauma not defined","Does not explain dominant human DFNA4 mutations mechanistically"]},{"year":2017,"claim":"Localization studies in kidney and embryonic cloaca proposed developmental and trafficking roles for NMIIC distinct from other NMII isoforms.","evidence":"Immunohistochemistry and subcellular localization in mouse kidney and embryonic cloacal regions, with human exome data linking MYH14 to anorectal malformations","pmids":["29208685","28191911"],"confidence":"Low","gaps":["Localization only, with no functional manipulation of MYH14","Causality of MYH14 in anorectal malformation not established"]},{"year":2019,"claim":"Demonstrating NMIIC drives mitochondrial fission and that R941L acts dominant-negatively provided a mechanistic basis for the peripheral neuropathy phenotype.","evidence":"Confocal mitochondrial dynamics imaging in patient fibroblasts and cell lines, plus C. elegans modelling of R941L","pmids":["31231018"],"confidence":"Medium","gaps":["Single lab","How a cortical contractile motor mechanistically executes mitochondrial scission not fully resolved"]},{"year":2019,"claim":"Showing NMIIC is mechanoresponsive and that enhancing its assembly stiffens cells and suppresses metastasis established a direct link between MYH14 cortical contractility and cell mechanics/invasion.","evidence":"Deformability cytometry, live-cell actin flow imaging, spheroid analysis and mouse xenograft with 4-HAP activation","pmids":["31358530"],"confidence":"High","gaps":["Endogenous signals controlling cortical accumulation not defined","Generalizability beyond pancreatic cancer not tested"]},{"year":2024,"claim":"Identifying the MYH14–MYH9 interaction as a regulator of GSK3β/β-catenin connected NMIIC to Wnt signaling and EMT in cancer.","evidence":"Reciprocal co-IP, CETSA, cycloheximide chase, luciferase reporter and xenograft with sesamolin disruption","pmids":["38698330"],"confidence":"Medium","gaps":["Single lab and single cancer context (endometrial)","Whether the interaction requires motor activity vs scaffolding not resolved"]},{"year":null,"claim":"It remains unknown how MYH14's distinct functions—cortical mechanoresponse, mitochondrial fission, and Wnt-pathway scaffolding—are coordinated and which depend on its motor ATPase versus assembly/scaffolding properties.","evidence":"","pmids":[],"confidence":"Low","gaps":["No unifying biochemical model linking the contractile, fission, and signaling roles","Motor activity requirements for each function not dissected"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003774","term_label":"cytoskeletal motor activity","supporting_discovery_ids":[4,5]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[5]}],"localization":[{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[5]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[5]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[4]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[9]},{"term_id":"R-HSA-8953854","term_label":"Metabolism of RNA","supporting_discovery_ids":[3]}],"complexes":[],"partners":["MYH9"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q7Z406","full_name":"Myosin-14","aliases":["Myosin heavy chain 14","Myosin heavy chain, non-muscle IIc","Non-muscle myosin heavy chain IIc","NMHC II-C"],"length_aa":1995,"mass_kda":227.9,"function":"Cellular myosin that appears to play a role in cytokinesis, cell shape, and specialized functions such as secretion and capping","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/Q7Z406/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MYH14","classification":"Not 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MYH14","url":"https://www.omim.org/entry/608568"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Nucleoplasm","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"intestine","ntpm":70.3},{"tissue":"skeletal muscle","ntpm":133.3}],"url":"https://www.proteinatlas.org/search/MYH14"},"hgnc":{"alias_symbol":["FLJ13881","KIAA2034","MHC16","MYH17"],"prev_symbol":["DFNA4"]},"alphafold":{"accession":"Q7Z406","domains":[{"cath_id":"2.30.30.360","chopping":"48-100","consensus_level":"high","plddt":81.9772,"start":48,"end":100},{"cath_id":"3.40.850.10","chopping":"119-490_610-661_690-732","consensus_level":"medium","plddt":85.0867,"start":119,"end":732},{"cath_id":"1.20.58.530","chopping":"491-523_535-609","consensus_level":"medium","plddt":84.7788,"start":491,"end":609},{"cath_id":"3.30.70.1590","chopping":"743-841","consensus_level":"medium","plddt":87.5498,"start":743,"end":841},{"cath_id":"-","chopping":"874-935_942-1020","consensus_level":"medium","plddt":74.1017,"start":874,"end":1020}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q7Z406","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q7Z406-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q7Z406-F1-predicted_aligned_error_v6.png","plddt_mean":74.5},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MYH14","jax_strain_url":"https://www.jax.org/strain/search?query=MYH14"},"sequence":{"accession":"Q7Z406","fasta_url":"https://rest.uniprot.org/uniprotkb/Q7Z406.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q7Z406/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q7Z406"}},"corpus_meta":[{"pmid":"15015131","id":"PMC_15015131","title":"Nonmuscle 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Part A","url":"https://pubmed.ncbi.nlm.nih.gov/38352997","citation_count":1,"is_preprint":false},{"pmid":"39590923","id":"PMC_39590923","title":"A Novel MYH14 Variant Presenting as a New Phenotype of MYH14-Associated Neuromuscular Disorders-Clinicohistologic Findings and Review of the Literature.","date":"2024","source":"Journal of clinical neuromuscular disease","url":"https://pubmed.ncbi.nlm.nih.gov/39590923","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.04.14.648628","title":"Transcriptomic profiling of a novel gastric implantation model identifies mechanisms and pathways that drive implantation into explanted human peritoneum","date":"2025-04-18","source":"bioRxiv","url":"https://doi.org/10.1101/2025.04.14.648628","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":15746,"output_tokens":2484,"usd":0.042249,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9664,"output_tokens":3050,"usd":0.062285,"stage2_stop_reason":"end_turn"},"total_usd":0.104534,"stage1_batch_id":"msgbatch_013a8chtv3AWyTqv4z4sEF4C","stage2_batch_id":"msgbatch_01AHsuW63vinsvuTgzmQ3n62","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2004,\n      \"finding\": \"MYH14 encodes a heavy chain of class II nonmuscle myosin and is highly expressed in mouse cochlea; nonsense and missense mutations in MYH14 cause autosomal dominant hearing loss (DFNA4), establishing MYH14 as a causative gene for auditory function.\",\n      \"method\": \"Mutational screening of 300 hearing-impaired patients, RT-PCR/expression analysis in mouse cochlea, co-segregation analysis in pedigrees linked to DFNA4\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple independent pedigrees across three countries, expression confirmed in cochlea, mutations absent in 200 controls, replicated by multiple subsequent studies\",\n      \"pmids\": [\"15015131\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"MYH14 protein is selectively expressed in slow-tonic fibres of extraocular muscles and in bag fibres of muscle spindles in rat and mouse; it is transiently expressed in embryonic skeletal muscle but disappears postnatally from most fibre types except slow-tonic fibres.\",\n      \"method\": \"Immunohistochemistry, RT-PCR, western blotting across developmental stages in rat and mouse tissues\",\n      \"journal\": \"The Journal of physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (protein and mRNA), developmental time series, reproduced across two species\",\n      \"pmids\": [\"19948655\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"The R941L (c.2822G>T, p.Arg941Leu) mutation in MYH14 causes a complex autosomal dominant phenotype including peripheral neuropathy, distal myopathy, hoarseness, and hearing loss, expanding the phenotypic spectrum beyond nonsyndromic hearing loss.\",\n      \"method\": \"SNP-based linkage mapping, Sanger sequencing of 34 candidate genes, electrodiagnostic and histopathologic studies in a large Korean family\",\n      \"journal\": \"Human mutation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — linkage plus sequencing in large pedigree, electrodiagnostic confirmation, single lab\",\n      \"pmids\": [\"21480433\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"In myotonic dystrophy type 1 (DM1) muscle, MBNL1 positively regulates inclusion of MYH14 exon 6 (producing the NMHCII-C1 isoform); loss of MBNL1 in DM1 leads to predominant expression of the NMHCII-C0 isoform and overall reduction of MYH14 mRNA and protein.\",\n      \"method\": \"RT-PCR splice analysis in DM1 patient muscle biopsies (n=12), minigene splicing assay with MBNL1 modulation, quantitative RT-PCR and western blot\",\n      \"journal\": \"Neurobiology of disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — minigene functional assay directly demonstrates MBNL1 regulation of MYH14 exon 6 inclusion, supported by patient tissue data with multiple orthogonal methods\",\n      \"pmids\": [\"21872659\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"MYH14 (NMIIC) mediates mitochondrial fission in human cells; the R941L mutation acts in a dominant-negative fashion to inhibit mitochondrial fission, especially in the cell periphery, and disrupts mitochondrial genome organization, providing a mechanism for the peripheral neuropathy phenotype.\",\n      \"method\": \"Confocal microscopy of mitochondrial dynamics in patient fibroblasts and U2OS/M17 cells overexpressing NMIIC; C. elegans modelling of R941L myosin activity\",\n      \"journal\": \"EBioMedicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — live-cell imaging with functional consequence, multiple cell types, C. elegans functional model, single lab\",\n      \"pmids\": [\"31231018\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"MYH14 (NMIIC) is a mechanoresponsive protein that accumulates at the cell cortex under mechanical stress; pharmacological activation of MYH14 assembly by 4-hydroxyacetophenone (4-HAP) stiffens pancreatic cancer cells, induces cortical actin belts, slows retrograde actin flow, decreases dissemination, and reduces liver metastases in vivo.\",\n      \"method\": \"Deformability cytometry, immunofluorescence, live-cell actin flow imaging, spheroid cortical actin analysis, mouse xenograft model (nude mice)\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal cellular assays plus in vivo validation, mechanistic link between MYH14 assembly, cortical stiffness and invasion established\",\n      \"pmids\": [\"31358530\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"MYH14 (NMIIC) is localized to intercalated cells of the collecting duct and connecting segment in mouse kidney, with isoform-specific subcellular distribution distinct from MYH9 and MYH10, suggesting a role in segment-specific intracellular trafficking.\",\n      \"method\": \"Immunohistochemistry and subcellular fractionation/localization in mouse kidney sections\",\n      \"journal\": \"Physiological reports\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single localization study, no functional manipulation of MYH14 specifically, single lab\",\n      \"pmids\": [\"29208685\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Loss of Myh14 in CBA/CaJ mice does not cause significant hearing loss until 5 months of age but increases susceptibility to noise-induced hearing loss, with greater outer hair cell loss after acoustic trauma compared to wild-type controls.\",\n      \"method\": \"CRISPR/Cas9 knockout in CBA/CaJ mice, auditory brainstem response (ABR) testing, cochlear hair cell counts after acoustic trauma\",\n      \"journal\": \"Neural plasticity\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean genetic knockout with defined cellular phenotype (OHC loss) and functional hearing measurement, single lab\",\n      \"pmids\": [\"28101381\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"MYH14 mutations are associated with anorectal malformations in humans; immunohistochemical analysis in mouse embryos (E11.5–13.5) demonstrated stronger NMHC IIC localization in the epithelium of the embryonic cloaca, urorectal septum, and hindgut compared with the other two NMHC II isoforms, consistent with a role in anorectal development.\",\n      \"method\": \"Whole-exome sequencing, immunohistochemistry of mouse embryonic cloacal regions\",\n      \"journal\": \"Clinical genetics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — localization data only without direct functional manipulation of MYH14 in the developmental context, single lab\",\n      \"pmids\": [\"28191911\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"MYH14 interacts with MYH9 (non-muscle myosin IIA) in endometrial cancer cells; this interaction impairs GSK3β-mediated β-catenin ubiquitination and degradation, thereby activating Wnt/β-catenin signaling and promoting EMT. The natural compound sesamolin directly binds MYH14, disrupts the MYH14–MYH9 interaction, and suppresses Wnt/β-catenin signaling.\",\n      \"method\": \"Co-immunoprecipitation, cellular thermal shift assay (CETSA), cycloheximide chase, luciferase reporter assay, mouse xenograft model\",\n      \"journal\": \"Cellular & molecular biology letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP plus CETSA for direct binding, functional pathway readout with reporter assay and in vivo model, single lab\",\n      \"pmids\": [\"38698330\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MYH14 encodes the heavy chain of non-muscle myosin IIC (NMIIC), a class II myosin that drives cortical actomyosin contractility and mechanoresponsiveness; it regulates mitochondrial fission (with the R941L mutation acting dominantly-negatively to impair fission and cause peripheral neuropathy), interacts with MYH9 to modulate GSK3β/β-catenin/Wnt signaling, is expressed selectively in cochlear hair cells and slow-tonic/spindle muscle fibres, and its alternative splicing is controlled by MBNL1 such that loss of MBNL1 in myotonic dystrophy shifts isoform balance toward NMHCII-C0.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MYH14 encodes the heavy chain of class II non-muscle myosin IIC (NMIIC), an actomyosin motor that drives cortical contractility and mechanoresponsive cell behaviors [#5]. As a mechanoresponsive protein, NMIIC accumulates at the cell cortex under mechanical stress, and pharmacological enhancement of its assembly stiffens cells, builds cortical actin belts, slows retrograde actin flow, and suppresses cancer cell dissemination and metastasis in vivo [#5]. Beyond the cortex, NMIIC mediates mitochondrial fission in human cells, with the dominant R941L mutation impairing peripheral fission and disrupting mitochondrial genome organization—a mechanism linked to its peripheral neuropathy phenotype [#4]. In endometrial cancer cells NMIIC physically interacts with MYH9 (non-muscle myosin IIA) to impair GSK3\\u03b2-mediated \\u03b2-catenin degradation, thereby activating Wnt/\\u03b2-catenin signaling and promoting EMT [#9]. MYH14 is expressed selectively in cochlear hair cells and in slow-tonic and muscle-spindle fibres [#0, #1], and its exon 6 splicing is controlled by MBNL1, shifting isoform balance toward NMHCII-C0 when MBNL1 is lost in myotonic dystrophy [#3]. Clinically, MYH14 mutations cause autosomal dominant hearing loss (DFNA4) [#0], and the R941L allele produces a complex dominant syndrome of peripheral neuropathy, distal myopathy, hoarseness, and hearing loss [#2].\",\n  \"teleology\": [\n    {\n      \"year\": 2004,\n      \"claim\": \"Establishing that MYH14 is a human disease gene answered whether this non-muscle myosin II heavy chain has a non-redundant physiological role, linking it causally to auditory function.\",\n      \"evidence\": \"Mutational screening of hearing-impaired patients with cochlear expression analysis and pedigree co-segregation (DFNA4)\",\n      \"pmids\": [\"15015131\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Does not define the molecular mechanism by which loss links to hair cell dysfunction\", \"No structural or motor-activity characterization\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Mapping MYH14 protein expression to slow-tonic and muscle-spindle fibres established a tissue context beyond the cochlea and a developmentally regulated, fibre-type-selective role.\",\n      \"evidence\": \"Immunohistochemistry, RT-PCR and western blot across developmental stages in rat and mouse\",\n      \"pmids\": [\"19948655\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional role in slow-tonic/spindle fibres not tested by perturbation\", \"Mechanism of fibre-type-selective regulation unknown\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Identifying R941L expanded the phenotypic spectrum, showing a single dominant allele can produce neuropathy and myopathy in addition to hearing loss.\",\n      \"evidence\": \"SNP linkage mapping plus Sanger sequencing with electrodiagnostic and histopathologic study in a large Korean family\",\n      \"pmids\": [\"21480433\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single pedigree, single lab\", \"Did not establish a molecular mechanism for the multisystem phenotype\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Defining MBNL1 control of MYH14 exon 6 splicing answered how isoform balance is set and connected MYH14 dysregulation to myotonic dystrophy.\",\n      \"evidence\": \"RT-PCR splice analysis of DM1 muscle biopsies plus minigene splicing assay with MBNL1 modulation\",\n      \"pmids\": [\"21872659\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Functional difference between NMHCII-C0 and NMHCII-C1 isoforms not resolved\", \"Downstream consequences of isoform shift on contractility not defined\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"A clean Myh14 knockout addressed whether the gene is required for baseline hearing, revealing it is dispensable until later age but protective against noise-induced damage.\",\n      \"evidence\": \"CRISPR/Cas9 knockout in CBA/CaJ mice with ABR testing and hair cell counts after acoustic trauma\",\n      \"pmids\": [\"28101381\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular basis of protection against trauma not defined\", \"Does not explain dominant human DFNA4 mutations mechanistically\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Localization studies in kidney and embryonic cloaca proposed developmental and trafficking roles for NMIIC distinct from other NMII isoforms.\",\n      \"evidence\": \"Immunohistochemistry and subcellular localization in mouse kidney and embryonic cloacal regions, with human exome data linking MYH14 to anorectal malformations\",\n      \"pmids\": [\"29208685\", \"28191911\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Localization only, with no functional manipulation of MYH14\", \"Causality of MYH14 in anorectal malformation not established\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Demonstrating NMIIC drives mitochondrial fission and that R941L acts dominant-negatively provided a mechanistic basis for the peripheral neuropathy phenotype.\",\n      \"evidence\": \"Confocal mitochondrial dynamics imaging in patient fibroblasts and cell lines, plus C. elegans modelling of R941L\",\n      \"pmids\": [\"31231018\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab\", \"How a cortical contractile motor mechanistically executes mitochondrial scission not fully resolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Showing NMIIC is mechanoresponsive and that enhancing its assembly stiffens cells and suppresses metastasis established a direct link between MYH14 cortical contractility and cell mechanics/invasion.\",\n      \"evidence\": \"Deformability cytometry, live-cell actin flow imaging, spheroid analysis and mouse xenograft with 4-HAP activation\",\n      \"pmids\": [\"31358530\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endogenous signals controlling cortical accumulation not defined\", \"Generalizability beyond pancreatic cancer not tested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identifying the MYH14\\u2013MYH9 interaction as a regulator of GSK3\\u03b2/\\u03b2-catenin connected NMIIC to Wnt signaling and EMT in cancer.\",\n      \"evidence\": \"Reciprocal co-IP, CETSA, cycloheximide chase, luciferase reporter and xenograft with sesamolin disruption\",\n      \"pmids\": [\"38698330\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single lab and single cancer context (endometrial)\", \"Whether the interaction requires motor activity vs scaffolding not resolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"It remains unknown how MYH14's distinct functions—cortical mechanoresponse, mitochondrial fission, and Wnt-pathway scaffolding—are coordinated and which depend on its motor ATPase versus assembly/scaffolding properties.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No unifying biochemical model linking the contractile, fission, and signaling roles\", \"Motor activity requirements for each function not dissected\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003774\", \"supporting_discovery_ids\": [4, 5]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [5]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [9]},\n      {\"term_id\": \"R-HSA-8953854\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"MYH9\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}