Affinage

MYH14

Myosin-14 · UniProt Q7Z406

Length
1995 aa
Mass
227.9 kDa
Annotated
2026-06-10
27 papers in source corpus 10 papers cited in narrative 10 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

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).

Mechanistic history

Synthesis pass · year-by-year structured walk · 9 steps
  1. 2004 High

    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)

    PMID:15015131

    Open questions at the time
    • Does not define the molecular mechanism by which loss links to hair cell dysfunction
    • No structural or motor-activity characterization
  2. 2009 High

    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

    PMID:19948655

    Open questions at the time
    • Functional role in slow-tonic/spindle fibres not tested by perturbation
    • Mechanism of fibre-type-selective regulation unknown
  3. 2011 Medium

    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

    PMID:21480433

    Open questions at the time
    • Single pedigree, single lab
    • Did not establish a molecular mechanism for the multisystem phenotype
  4. 2011 High

    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

    PMID:21872659

    Open questions at the time
    • Functional difference between NMHCII-C0 and NMHCII-C1 isoforms not resolved
    • Downstream consequences of isoform shift on contractility not defined
  5. 2016 Medium

    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

    PMID:28101381

    Open questions at the time
    • Molecular basis of protection against trauma not defined
    • Does not explain dominant human DFNA4 mutations mechanistically
  6. 2017 Low

    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

    PMID:28191911 PMID:29208685

    Open questions at the time
    • Localization only, with no functional manipulation of MYH14
    • Causality of MYH14 in anorectal malformation not established
  7. 2019 Medium

    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

    PMID:31231018

    Open questions at the time
    • Single lab
    • How a cortical contractile motor mechanistically executes mitochondrial scission not fully resolved
  8. 2019 High

    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

    PMID:31358530

    Open questions at the time
    • Endogenous signals controlling cortical accumulation not defined
    • Generalizability beyond pancreatic cancer not tested
  9. 2024 Medium

    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

    PMID:38698330

    Open questions at the time
    • Single lab and single cancer context (endometrial)
    • Whether the interaction requires motor activity vs scaffolding not resolved

Open questions

Synthesis pass · forward-looking unresolved questions
  • 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.
  • No unifying biochemical model linking the contractile, fission, and signaling roles
  • Motor activity requirements for each function not dissected

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003774 cytoskeletal motor activity 2 GO:0008092 cytoskeletal protein binding 1
Localization
GO:0005739 mitochondrion 1 GO:0005856 cytoskeleton 1 GO:0005886 plasma membrane 1
Pathway
R-HSA-162582 Signal Transduction 1 R-HSA-8953854 Metabolism of RNA 1
Partners
MYH9

Evidence

Reading pass · 10 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2004 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. Mutational screening of 300 hearing-impaired patients, RT-PCR/expression analysis in mouse cochlea, co-segregation analysis in pedigrees linked to DFNA4 American journal of human genetics High 15015131
2009 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. Immunohistochemistry, RT-PCR, western blotting across developmental stages in rat and mouse tissues The Journal of physiology High 19948655
2011 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. SNP-based linkage mapping, Sanger sequencing of 34 candidate genes, electrodiagnostic and histopathologic studies in a large Korean family Human mutation Medium 21480433
2011 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. RT-PCR splice analysis in DM1 patient muscle biopsies (n=12), minigene splicing assay with MBNL1 modulation, quantitative RT-PCR and western blot Neurobiology of disease High 21872659
2019 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. Confocal microscopy of mitochondrial dynamics in patient fibroblasts and U2OS/M17 cells overexpressing NMIIC; C. elegans modelling of R941L myosin activity EBioMedicine Medium 31231018
2019 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. Deformability cytometry, immunofluorescence, live-cell actin flow imaging, spheroid cortical actin analysis, mouse xenograft model (nude mice) Cancer research High 31358530
2017 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. Immunohistochemistry and subcellular fractionation/localization in mouse kidney sections Physiological reports Low 29208685
2016 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. CRISPR/Cas9 knockout in CBA/CaJ mice, auditory brainstem response (ABR) testing, cochlear hair cell counts after acoustic trauma Neural plasticity Medium 28101381
2017 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. Whole-exome sequencing, immunohistochemistry of mouse embryonic cloacal regions Clinical genetics Low 28191911
2024 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. Co-immunoprecipitation, cellular thermal shift assay (CETSA), cycloheximide chase, luciferase reporter assay, mouse xenograft model Cellular & molecular biology letters Medium 38698330

Source papers

Stage 0 corpus · 27 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2004 Nonmuscle myosin heavy-chain gene MYH14 is expressed in cochlea and mutated in patients affected by autosomal dominant hearing impairment (DFNA4). American journal of human genetics 119 15015131
2009 Two novel/ancient myosins in mammalian skeletal muscles: MYH14/7b and MYH15 are expressed in extraocular muscles and muscle spindles. The Journal of physiology 113 19948655
2011 Carcinoembryonic antigen-related cell adhesion molecule 16 interacts with alpha-tectorin and is mutated in autosomal dominant hearing loss (DFNA4). Proceedings of the National Academy of Sciences of the United States of America 89 21368133
2019 Targeting Mechanoresponsive Proteins in Pancreatic Cancer: 4-Hydroxyacetophenone Blocks Dissemination and Invasion by Activating MYH14. Cancer research 60 31358530
2011 A complex phenotype of peripheral neuropathy, myopathy, hoarseness, and hearing loss is linked to an autosomal dominant mutation in MYH14. Human mutation 46 21480433
2019 The R941L mutation in MYH14 disrupts mitochondrial fission and associates with peripheral neuropathy. EBioMedicine 39 31231018
2005 Genetic heterogeneity of deafness phenotypes linked to DFNA4. American journal of medical genetics. Part A 30 16222661
2017 Discovery of MYH14 as an important and unique deafness gene causing prelingually severe autosomal dominant nonsyndromic hearing loss. The journal of gene medicine 27 28221712
2016 Loss of Myh14 Increases Susceptibility to Noise-Induced Hearing Loss in CBA/CaJ Mice. Neural plasticity 26 28101381
2013 Evolution of the myosin heavy chain gene MYH14 and its intronic microRNA miR-499: muscle-specific miR-499 expression persists in the absence of the ancestral host gene. BMC evolutionary biology 22 24059862
2000 2E4/Kaptin (KPTN)--a candidate gene for the hearing loss locus, DFNA4. Annals of human genetics 19 11409409
2011 Aberrant splicing and expression of the non muscle myosin heavy-chain gene MYH14 in DM1 muscle tissues. Neurobiology of disease 18 21872659
2017 Nonmuscle myosin 2 proteins encoded by Myh9, Myh10, and Myh14 are uniquely distributed in the tubular segments of murine kidney. Physiological reports 17 29208685
2017 Mutations of MYH14 are associated to anorectal malformations with recto-perineal fistulas in a small subset of Chinese population. Clinical genetics 12 28191911
2024 Sesamolin serves as an MYH14 inhibitor to sensitize endometrial cancer to chemotherapy and endocrine therapy via suppressing MYH9/GSK3β/β-catenin signaling. Cellular & molecular biology letters 11 38698330
2017 Variable phenotypic expression and onset in MYH14 distal hereditary motor neuropathy phenotype in a large, multigenerational North American family. Muscle & nerve 11 27875632
2004 Genomic structure, cochlear expression, and mutation screening of KCNK6, a candidate gene for DFNA4. Journal of neuroscience research 11 14689445
2002 Second family with hearing impairment linked to 19q13 and refined DFNA4 localisation. European journal of human genetics : EJHG 11 11938438
2020 A novel MYH14 mutation in a Chinese family with autosomal dominant nonsyndromic hearing loss. BMC medical genetics 6 32711451
2001 Novel coding-region polymorphisms in mitochondrial seryl-tRNA synthetase (SARSM) and mitoribosomal protein S12 (RPMS12) genes in DFNA4 autosomal dominant deafness families. Human mutation 6 11317363
2021 Regulation of the Expression of the Myosin Heavy Chain (MYH) Gene myh14 in Zebrafish Development. Marine biotechnology (New York, N.Y.) 5 34490548
2021 Prevalence and Clinical Characteristics of Hearing Loss Caused by MYH14 Variants. Genes 5 34681017
2010 [c.359T>C mutation of the MYH14 gene in two autosomal dominant non-syndromic hearing impairment families with common ancestor]. Zhonghua yi xue yi chuan xue za zhi = Zhonghua yixue yichuanxue zazhi = Chinese journal of medical genetics 5 20533261
2004 Refinement of the DFNA4 locus to a 1.44 Mb region in 19q13.33. Journal of molecular medicine (Berlin, Germany) 5 15042303
2008 Investigation of MYH14 as a candidate gene in cleft lip with or without cleft palate. European journal of oral sciences 4 18471249
2024 Identification of novel MYH14 variants in families with autosomal dominant sensorineural hearing loss. American journal of medical genetics. Part A 1 38352997
2024 A Novel MYH14 Variant Presenting as a New Phenotype of MYH14-Associated Neuromuscular Disorders-Clinicohistologic Findings and Review of the Literature. Journal of clinical neuromuscular disease 0 39590923

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