{"gene":"MYO15A","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":1998,"finding":"MYO15 (MYO15A) encodes an unconventional myosin protein; missense and nonsense mutations in MYO15 co-segregate with congenital recessive deafness DFNB3, establishing it as the causative gene for this hereditary hearing loss.","method":"Positional cloning, sequence analysis of exons in affected individuals from three unrelated DFNB3 families","journal":"Science","confidence":"High","confidence_rationale":"Tier 2 / Strong — positional cloning with direct mutation identification, replicated across three unrelated families, foundational paper widely cited","pmids":["9603736"],"is_preprint":false},{"year":1999,"finding":"Full-length myosin XV (MYO15A) transcripts contain 66 exons encoding a ~365 kDa protein with a unique ~1200-aa N-terminal extension preceding the conserved motor domain; the tail region contains two MyTH4 domains, two FERM-like domains, and a putative SH3 domain. Immunostaining of adult mouse organ of Corti showed that myosin XV protein is concentrated within the cuticular plate and stereocilia of cochlear sensory hair cells.","method":"cDNA analysis, genomic sequence comparison, Northern/dot blot, in situ hybridization, immunostaining","journal":"Genomics","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (cDNA analysis, immunostaining, in situ hybridization) establishing domain structure and subcellular localization, replicated in subsequent studies","pmids":["10552926"],"is_preprint":false},{"year":2003,"finding":"Genetic epistasis analysis using double-mutant mice showed that Myo15 function is distinct from Myo6, Myo7a, and the pirouette gene in cochlear stereocilia development; double mutants exhibited superimposition of single-mutant stereocilia phenotypes rather than synergistic or suppressed phenotypes, indicating these myosins act in independent pathways.","method":"Genetic epistasis (double-mutant mouse crosses), hearing assessment, cochlear morphology analysis","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — rigorous double-mutant epistasis analysis with multiple crosses and orthogonal phenotypic readouts (hearing thresholds and morphology)","pmids":["12966030"],"is_preprint":false},{"year":2006,"finding":"BAC transgene containing Myo15a corrects hearing function and cochlear morphology in shaker2 (sh2/sh2) mice for up to 6 months, demonstrating that Myo15a is necessary and sufficient to maintain normal stereocilia structure and hearing; excess Myo15a expression had no deleterious effects on hearing in normal mice.","method":"BAC transgene rescue experiment in Myo15a mutant mice, hearing threshold measurement (ABR), cochlear morphology histology","journal":"Hearing research","confidence":"High","confidence_rationale":"Tier 2 / Strong — transgene rescue with functional hearing measurement and morphological readouts, providing direct causal evidence","pmids":["16580798"],"is_preprint":false},{"year":2007,"finding":"Two homozygous truncating mutations in exon 2 of MYO15A (encoding the large N-terminal extension) are associated with severe-to-profound hearing loss, demonstrating that the long isoform containing the ~1200-aa N-terminal extension (isoform 1) is functionally necessary for normal hearing.","method":"Mutation analysis of consanguineous families, linkage analysis, DNA sequencing of MYO15A exons","journal":"Human mutation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic evidence from multiple families with exon 2 truncating mutations, but no in vitro functional assay; moderate because evidence is genetic/clinical rather than biochemical","pmids":["17546645"],"is_preprint":false},{"year":2007,"finding":"A missense mutation c.5492G>T (p.Gly1831Val) in the MYO15A motor domain disrupts hearing; molecular modeling of the motor head domain predicted that the Gly1831Val mutation inhibits the powerstroke by reducing backbone flexibility and weakening hydrophobic interactions necessary for signal transmission to the converter domain.","method":"Genetic linkage analysis, DNA sequencing, 3D molecular modeling of motor head domain","journal":"American journal of medical genetics. Part A","confidence":"Low","confidence_rationale":"Tier 4 / Weak — molecular mechanism is based on computational modeling only, not experimentally validated in vitro or in vivo","pmids":["17853461"],"is_preprint":false},{"year":2011,"finding":"A missense mutation (T>C, Leu to Pro) in exon 56 of Myo15 within the carboxy-terminal MyTH4 domain in the LEW/Ztm-ci2 rat causes deafness and retinal degeneration (Usher-like syndrome); Myo15 mRNA was detected in the retina by in situ hybridization and PCR, indicating a role beyond the cochlea.","method":"Mutation identification by sequencing, in situ hybridization and RT-PCR for retinal expression, electroretinography, histological analysis","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct identification of causative mutation with multiple phenotypic readouts (ERG, histology) and novel expression data (retina), single lab","pmids":["21479269"],"is_preprint":false},{"year":2016,"finding":"Two distinct MYO15A isoform classes exist: isoform 1 (with exon 2-encoded N-terminal extension) is required for stereocilia development, while loss of this N-terminal extension causes a milder hearing loss phenotype. Studies in Myo15 mouse models revealed two distinct pathogenic mechanisms: myosin 15 is required both for development and for long-term maintenance of stereocilia.","method":"Analysis of mouse models with domain-specific mutations, review of mutational data from human patients with domain-specific genotype-phenotype correlations","journal":"Human mutation","confidence":"High","confidence_rationale":"Tier 2 / Strong — synthesis of multiple mouse models and human mutational data with orthogonal evidence establishing two distinct pathological mechanisms","pmids":["27375115"],"is_preprint":false},{"year":2021,"finding":"The Whirlin–Myosin 15 (Myo15)–Eps8 complex forms tip complex density (TCD)-like condensates through liquid-liquid phase separation driven by specific multivalent interactions among complex components. The reconstituted TCD-like condensates promote actin bundling. A deafness-associated mutation of Myo15 interfered with condensate formation and consequently impaired actin bundling.","method":"Protein reconstitution in vitro, phase separation assays, actin bundling assays, mutagenesis of deafness-associated Myo15 variant","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution of the ternary complex with phase separation assays, mutagenesis showing functional consequence, and actin bundling assay; single lab but multiple orthogonal methods","pmids":["33626355"],"is_preprint":false},{"year":2021,"finding":"The MYO15 motor domain has a moderate duty ratio (~0.5), weak thermodynamic coupling between ADP and actin binding, and ADP release from the actin-attached state is the slowest measured transition (~12 s⁻¹ at 20°C). The kinetic profile is consistent with MYO15 being adapted for processive motility when oligomerized. The ATPase cycle was characterized with major rate constants for ATP/ADP/actin binding, hydrolysis, and phosphate release.","method":"Recombinant minimal motor domain (S1) purification using baculovirus-Sf9 system, stopped-flow and quenched-flow transient kinetic analyses, actin-activated ATPase assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — rigorous in vitro enzymatic characterization with stopped-flow and quenched-flow kinetics, multiple rate constants measured, and appropriate chaperone-assisted folding controls","pmids":["33372036"],"is_preprint":false},{"year":2021,"finding":"A synonymous variant c.9861 C>T in MYO15A causes abnormal splicing confirmed by mini-gene assay, leading to progressive post-lingual hearing loss distinct from the congenital profound deafness caused by biallelic loss-of-function variants.","method":"Mini-gene splicing assay, co-segregation analysis in 10 unrelated families, biallelic variant confirmation","journal":"European journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — mini-gene assay directly demonstrates aberrant splicing, co-segregation across multiple families; single mechanistic assay","pmids":["33398081"],"is_preprint":false},{"year":2024,"finding":"A new MYO15A isoform (MYO15A-3) is expressed in postnatal hair cells as MYO15A-2 wanes. MYO15A-2 initially delivers the elongation-promoting complex (EC) to stereocilia tips; postnatally, MYO15A-3 takes over EC delivery. In Myo15a-3 mutant mice, stereocilia develop normally with correct initial EC targeting but lack the EC postnatally and fail to maintain adult stereocilia architecture, causing progressive hearing loss.","method":"Characterization of new isoform by molecular cloning, conditional mutant mouse (Myo15a-3 mutant) with stereocilia morphology analysis, expression profiling, EC complex localization by immunofluorescence","journal":"bioRxiv","confidence":"High","confidence_rationale":"Tier 2 / Strong — loss-of-function mouse model with specific morphological and functional phenotypic readout, isoform-specific expression analysis, and EC complex localization data; multiple orthogonal methods","pmids":["40027801"],"is_preprint":true},{"year":2024,"finding":"MYO15A isoforms are required for mechanotransduction (MET)-dependent remodeling of the actin cytoskeleton in auditory stereocilia. Hair cells lacking all functional MYO15A isoforms did not exhibit MET-dependent stereocilia cytoskeletal remodeling. Hair cells lacking only the long isoform (MYO15A-1) showed increased MET-dependent remodeling including in non-transducing stereocilia rows, indicating that MYO15A-1 fine-tunes this process.","method":"Electron microscopy of cochlear explants, pharmacological blockade of MET currents, isoform-specific MYO15A mutant mice","journal":"bioRxiv","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct morphological analysis by EM with pharmacological and genetic dissection of isoform contributions; preprint, single lab","pmids":["bio_10.1101_2024.09.04.611210"],"is_preprint":true},{"year":2016,"finding":"iPSC-derived hair cell-like cells from patients carrying compound heterozygous MYO15A mutations (c.4642G>A and c.8374G>A) showed abnormal morphology and dysfunction compared to controls. CRISPR/Cas9 genetic correction of the MYO15A mutation in iPSCs rescued morphology and function of derived hair cell-like cells, demonstrating that the MYO15A mutations directly cause hair cell dysfunction.","method":"iPSC generation from patients, hair cell differentiation, CRISPR/Cas9 gene correction, morphological and functional analysis of derived hair cell-like cells","journal":"Cell death and differentiation","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic correction with matched controls provides causal evidence; iPSC-derived model rather than native tissue; single lab","pmids":["26915297"],"is_preprint":false},{"year":2024,"finding":"A novel MYO15A variant (c.2482C>T) located in the N-terminal domain caused significant differences in morphology and function of iPSC-derived hair cell-like cells compared to controls, without affecting iPSC totipotency, demonstrating that N-terminal domain integrity is required for normal hair cell function.","method":"iPSC generation from proband, hair cell differentiation, morphological and functional comparison between mutant and control iPSC-derived hair cell-like cells","journal":"Molecular genetics & genomic medicine","confidence":"Low","confidence_rationale":"Tier 3 / Weak — iPSC-based functional assay but single lab, single variant, limited mechanistic depth","pmids":["39620501"],"is_preprint":false},{"year":2025,"finding":"Computational analysis predicted that missense SNPs in WHRN destabilize the WHRN–MYO15A protein-protein complex, with molecular docking and dynamics showing altered binding affinity and stability of the complex; however, this is computational only.","method":"In silico SNP pathogenicity prediction, molecular docking (Haddock), molecular dynamics simulation, binding energy calculation (PRODIGY)","journal":"Journal of biomolecular structure & dynamics","confidence":"Low","confidence_rationale":"Tier 4 / Weak — computational modeling only, no experimental validation of WHRN–MYO15A complex disruption","pmids":["40389825"],"is_preprint":false}],"current_model":"MYO15A encodes an unconventional myosin (myosin XVA) that localizes to the stereocilia tips and cuticular plate of cochlear hair cells, where it functions as a molecular motor (moderate duty ratio ~0.5, ATPase rate ~6 s⁻¹) to traffic and deliver an elongation-promoting complex (containing Whirlin/WHRN and Eps8) to stereocilia tips; distinct isoforms mediate stereocilia development (MYO15A-2) versus postnatal maintenance (MYO15A-3/long isoform), and the Whirlin–MYO15A–Eps8 ternary complex assembles into a tip complex density via liquid-liquid phase separation that promotes actin bundling, with loss-of-function mutations causing DFNB3 autosomal recessive non-syndromic deafness through either developmental or maintenance defects in stereocilia architecture."},"narrative":{"mechanistic_narrative":"MYO15A encodes an unconventional myosin (myosin XV) that acts as an actin-based molecular motor concentrated within the stereocilia and cuticular plate of cochlear sensory hair cells, where it builds and maintains the stereocilia actin architecture required for hearing [PMID:9603736, PMID:10552926]. The protein is a ~365 kDa motor with a large N-terminal extension preceding a conserved motor domain and a tail bearing tandem MyTH4, FERM-like, and SH3 domains [PMID:10552926]. Its minimal motor domain has a moderate duty ratio (~0.5) with ADP release from the actin-bound state as the rate-limiting transition, a kinetic profile consistent with processive motility when the motor is oligomerized [PMID:33372036]. MYO15A delivers an elongation-promoting complex to stereocilia tips, and the Whirlin–myosin 15–Eps8 ternary complex assembles into tip-complex-density-like condensates through liquid-liquid phase separation that drives actin bundling; a deafness-associated MYO15A mutation abolishes condensate formation and impairs bundling [PMID:33626355]. Distinct isoforms partition this work temporally: an isoform containing the exon 2–encoded N-terminal extension is required for stereocilia development, while a later-appearing isoform takes over complex delivery postnatally to maintain adult stereocilia, and MYO15A also participates in mechanotransduction-dependent remodeling of the stereocilia cytoskeleton [PMID:27375115, PMID:40027801, PMID:bio_10.1101_2024.09.04.611210]. Loss-of-function and splice-altering mutations in MYO15A cause DFNB3 autosomal recessive non-syndromic deafness through either developmental or maintenance defects, with genotype determining congenital-profound versus progressive post-lingual phenotypes [PMID:9603736, PMID:27375115, PMID:33398081].","teleology":[{"year":1998,"claim":"Established MYO15A as a deafness gene, answering whether an unconventional myosin underlies a defined hereditary hearing loss locus.","evidence":"Positional cloning and exon sequencing in three unrelated DFNB3 families","pmids":["9603736"],"confidence":"High","gaps":["Did not define protein domain architecture","No subcellular localization or cellular mechanism"]},{"year":1999,"claim":"Defined the protein as a ~365 kDa myosin with a unique N-terminal extension and MyTH4/FERM/SH3 tail, and localized it to hair cell stereocilia and cuticular plate, framing where and how it might act.","evidence":"cDNA/genomic analysis, in situ hybridization, and immunostaining of mouse organ of Corti","pmids":["10552926"],"confidence":"High","gaps":["No motor kinetics","Binding partners and cargo unknown","Function of domains not tested"]},{"year":2003,"claim":"Showed Myo15 acts in a pathway distinct from other stereocilia myosins, clarifying that it is not redundant with Myo6, Myo7a, or pirouette.","evidence":"Double-mutant mouse epistasis with hearing and cochlear morphology readouts","pmids":["12966030"],"confidence":"High","gaps":["Did not identify the molecular cargo of the independent pathway"]},{"year":2006,"claim":"Demonstrated Myo15a is necessary and sufficient for normal stereocilia and hearing by rescuing the mutant phenotype, establishing direct causality.","evidence":"BAC transgene rescue in shaker2 mice with ABR and morphology","pmids":["16580798"],"confidence":"High","gaps":["Mechanism of structural maintenance not resolved","Isoform-specific contributions not distinguished"]},{"year":2007,"claim":"Mapped functional requirements to specific regions—the N-terminal extension and the motor domain—linking domain integrity to hearing.","evidence":"Mutation/linkage analysis of consanguineous families plus molecular modeling of a motor-domain missense variant","pmids":["17546645","17853461"],"confidence":"Medium","gaps":["Motor-domain powerstroke effect is computational only","No biochemical validation of the predicted defect"]},{"year":2011,"claim":"Extended Myo15 function beyond the cochlea by tying a MyTH4-domain mutation to retinal degeneration and detecting retinal expression.","evidence":"Mutation identification, retinal in situ/RT-PCR, ERG, and histology in a mutant rat","pmids":["21479269"],"confidence":"Medium","gaps":["Retinal molecular role undefined","No partner or cargo identified in retina"]},{"year":2016,"claim":"Resolved that distinct isoform classes drive two separable processes—stereocilia development versus long-term maintenance—reconciling variable patient phenotypes with genotype.","evidence":"Synthesis of domain-specific mouse models and human genotype-phenotype correlations; CRISPR-corrected patient iPSC hair cell-like cells","pmids":["27375115","26915297"],"confidence":"High","gaps":["Molecular trigger for the developmental-to-maintenance switch not defined","iPSC model is not native cochlear tissue"]},{"year":2021,"claim":"Provided the biochemical basis of motor function and cargo organization: characterized the ATPase cycle as suited to processive oligomeric motility, and showed the Whirlin–Myo15–Eps8 complex phase-separates to bundle actin.","evidence":"Recombinant motor-domain transient kinetics; in vitro ternary-complex reconstitution, phase-separation and actin-bundling assays with deafness-variant mutagenesis","pmids":["33372036","33626355"],"confidence":"High","gaps":["Oligomerization state in vivo not directly shown","Link between motor kinetics and condensate delivery not directly tested in cells"]},{"year":2021,"claim":"Showed a synonymous splice-altering variant produces a milder progressive phenotype, distinguishing splicing defects from biallelic loss-of-function in pathogenesis.","evidence":"Mini-gene splicing assay and co-segregation across 10 families","pmids":["33398081"],"confidence":"Medium","gaps":["Residual protein function from aberrant splicing not quantified"]},{"year":2024,"claim":"Identified an isoform handoff in which a postnatal isoform sustains elongation-complex delivery and adult stereocilia maintenance, and tied MYO15A isoforms to mechanotransduction-dependent cytoskeletal remodeling.","evidence":"Isoform cloning/expression profiling, conditional mutant mice with stereocilia morphology and EC localization; EM with MET blockade in isoform-specific mutants (both preprint)","pmids":["40027801","bio_10.1101_2024.09.04.611210"],"confidence":"High","gaps":["Preprint, single-lab data","Mechanism coordinating MET signaling with isoform activity unresolved"]},{"year":null,"claim":"How motor kinetics, isoform switching, and phase-separated complex delivery are integrated in vivo to specify stereocilia length and maintenance remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No in vivo demonstration of motor oligomerization driving condensate transport","Retinal mechanism uncharacterized","WHRN–MYO15A interface disruption tested only computationally"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[9]},{"term_id":"GO:0003774","term_label":"cytoskeletal motor activity","supporting_discovery_ids":[9,1]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[8,9]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[9]}],"localization":[{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[1,8,12]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[1]}],"pathway":[{"term_id":"R-HSA-9709957","term_label":"Sensory Perception","supporting_discovery_ids":[0,3]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[7,11]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[0,10]}],"complexes":["Whirlin–Myosin 15–Eps8 tip complex (elongation-promoting complex)"],"partners":["WHRN","EPS8"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9UKN7","full_name":"Unconventional myosin-XV","aliases":["Unconventional myosin-15"],"length_aa":3530,"mass_kda":395.3,"function":"Myosins are actin-based motor molecules with ATPase activity. Unconventional myosins serve in intracellular movements. Their highly divergent tails are presumed to bind to membranous compartments, which would be moved relative to actin filaments. Required for the arrangement of stereocilia in mature hair bundles (By similarity)","subcellular_location":"Cell projection, stereocilium; Cytoplasm, cytoskeleton","url":"https://www.uniprot.org/uniprotkb/Q9UKN7/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MYO15A","classification":"Not Classified","n_dependent_lines":52,"n_total_lines":1208,"dependency_fraction":0.04304635761589404},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/MYO15A","total_profiled":1310},"omim":[{"mim_id":"620949","title":"TOG ARRAY REGULATOR OF AXONEMAL MICROTUBULES 2; TOGARAM2","url":"https://www.omim.org/entry/620949"},{"mim_id":"620915","title":"MYOSIN XVB; MYO15B","url":"https://www.omim.org/entry/620915"},{"mim_id":"614988","title":"EPS8-LIKE PROTEIN 2; EPS8L2","url":"https://www.omim.org/entry/614988"},{"mim_id":"613392","title":"DEAFNESS, AUTOSOMAL RECESSIVE 85; DFNB85","url":"https://www.omim.org/entry/613392"},{"mim_id":"611877","title":"BAI1-ASSOCIATED PROTEIN 2-LIKE 1; BAIAP2L1","url":"https://www.omim.org/entry/611877"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"","locations":[],"tissue_specificity":"Tissue enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"pituitary gland","ntpm":40.5}],"url":"https://www.proteinatlas.org/search/MYO15A"},"hgnc":{"alias_symbol":[],"prev_symbol":["DFNB3","MYO15"]},"alphafold":{"accession":"Q9UKN7","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UKN7","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UKN7-2-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UKN7-2-F1-predicted_aligned_error_v6.png","plddt_mean":77.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MYO15A","jax_strain_url":"https://www.jax.org/strain/search?query=MYO15A"},"sequence":{"accession":"Q9UKN7","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9UKN7.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9UKN7/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UKN7"}},"corpus_meta":[{"pmid":"9603736","id":"PMC_9603736","title":"Association of unconventional myosin MYO15 mutations with human nonsyndromic deafness DFNB3.","date":"1998","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/9603736","citation_count":353,"is_preprint":false},{"pmid":"7704031","id":"PMC_7704031","title":"A gene for congenital, recessive deafness DFNB3 maps to the pericentromeric region of chromosome 17.","date":"1995","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/7704031","citation_count":186,"is_preprint":false},{"pmid":"10552926","id":"PMC_10552926","title":"Characterization of the human and mouse unconventional myosin XV genes responsible for hereditary deafness DFNB3 and shaker 2.","date":"1999","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/10552926","citation_count":137,"is_preprint":false},{"pmid":"11735029","id":"PMC_11735029","title":"Novel mutations of MYO15A associated with profound deafness in consanguineous families and moderately severe hearing loss in a patient with Smith-Magenis syndrome.","date":"2001","source":"Human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/11735029","citation_count":96,"is_preprint":false},{"pmid":"26915297","id":"PMC_26915297","title":"Effects of genetic correction on the differentiation of hair cell-like cells from iPSCs with MYO15A mutation.","date":"2016","source":"Cell death and differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/26915297","citation_count":78,"is_preprint":false},{"pmid":"27375115","id":"PMC_27375115","title":"Mutational Spectrum of MYO15A and the Molecular Mechanisms of DFNB3 Human Deafness.","date":"2016","source":"Human mutation","url":"https://pubmed.ncbi.nlm.nih.gov/27375115","citation_count":72,"is_preprint":false},{"pmid":"17546645","id":"PMC_17546645","title":"Mutational spectrum of MYO15A: the large N-terminal extension of myosin XVA is required for hearing.","date":"2007","source":"Human mutation","url":"https://pubmed.ncbi.nlm.nih.gov/17546645","citation_count":72,"is_preprint":false},{"pmid":"22736430","id":"PMC_22736430","title":"Screening for MYO15A gene mutations in autosomal recessive nonsyndromic, GJB2 negative Iranian deaf population.","date":"2012","source":"American journal of medical genetics. 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three unrelated DFNB3 families\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — positional cloning with direct mutation identification, replicated across three unrelated families, foundational paper widely cited\",\n      \"pmids\": [\"9603736\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Full-length myosin XV (MYO15A) transcripts contain 66 exons encoding a ~365 kDa protein with a unique ~1200-aa N-terminal extension preceding the conserved motor domain; the tail region contains two MyTH4 domains, two FERM-like domains, and a putative SH3 domain. Immunostaining of adult mouse organ of Corti showed that myosin XV protein is concentrated within the cuticular plate and stereocilia of cochlear sensory hair cells.\",\n      \"method\": \"cDNA analysis, genomic sequence comparison, Northern/dot blot, in situ hybridization, immunostaining\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (cDNA analysis, immunostaining, in situ hybridization) establishing domain structure and subcellular localization, replicated in subsequent studies\",\n      \"pmids\": [\"10552926\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Genetic epistasis analysis using double-mutant mice showed that Myo15 function is distinct from Myo6, Myo7a, and the pirouette gene in cochlear stereocilia development; double mutants exhibited superimposition of single-mutant stereocilia phenotypes rather than synergistic or suppressed phenotypes, indicating these myosins act in independent pathways.\",\n      \"method\": \"Genetic epistasis (double-mutant mouse crosses), hearing assessment, cochlear morphology analysis\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — rigorous double-mutant epistasis analysis with multiple crosses and orthogonal phenotypic readouts (hearing thresholds and morphology)\",\n      \"pmids\": [\"12966030\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"BAC transgene containing Myo15a corrects hearing function and cochlear morphology in shaker2 (sh2/sh2) mice for up to 6 months, demonstrating that Myo15a is necessary and sufficient to maintain normal stereocilia structure and hearing; excess Myo15a expression had no deleterious effects on hearing in normal mice.\",\n      \"method\": \"BAC transgene rescue experiment in Myo15a mutant mice, hearing threshold measurement (ABR), cochlear morphology histology\",\n      \"journal\": \"Hearing research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — transgene rescue with functional hearing measurement and morphological readouts, providing direct causal evidence\",\n      \"pmids\": [\"16580798\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Two homozygous truncating mutations in exon 2 of MYO15A (encoding the large N-terminal extension) are associated with severe-to-profound hearing loss, demonstrating that the long isoform containing the ~1200-aa N-terminal extension (isoform 1) is functionally necessary for normal hearing.\",\n      \"method\": \"Mutation analysis of consanguineous families, linkage analysis, DNA sequencing of MYO15A exons\",\n      \"journal\": \"Human mutation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic evidence from multiple families with exon 2 truncating mutations, but no in vitro functional assay; moderate because evidence is genetic/clinical rather than biochemical\",\n      \"pmids\": [\"17546645\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"A missense mutation c.5492G>T (p.Gly1831Val) in the MYO15A motor domain disrupts hearing; molecular modeling of the motor head domain predicted that the Gly1831Val mutation inhibits the powerstroke by reducing backbone flexibility and weakening hydrophobic interactions necessary for signal transmission to the converter domain.\",\n      \"method\": \"Genetic linkage analysis, DNA sequencing, 3D molecular modeling of motor head domain\",\n      \"journal\": \"American journal of medical genetics. Part A\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — molecular mechanism is based on computational modeling only, not experimentally validated in vitro or in vivo\",\n      \"pmids\": [\"17853461\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"A missense mutation (T>C, Leu to Pro) in exon 56 of Myo15 within the carboxy-terminal MyTH4 domain in the LEW/Ztm-ci2 rat causes deafness and retinal degeneration (Usher-like syndrome); Myo15 mRNA was detected in the retina by in situ hybridization and PCR, indicating a role beyond the cochlea.\",\n      \"method\": \"Mutation identification by sequencing, in situ hybridization and RT-PCR for retinal expression, electroretinography, histological analysis\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct identification of causative mutation with multiple phenotypic readouts (ERG, histology) and novel expression data (retina), single lab\",\n      \"pmids\": [\"21479269\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Two distinct MYO15A isoform classes exist: isoform 1 (with exon 2-encoded N-terminal extension) is required for stereocilia development, while loss of this N-terminal extension causes a milder hearing loss phenotype. Studies in Myo15 mouse models revealed two distinct pathogenic mechanisms: myosin 15 is required both for development and for long-term maintenance of stereocilia.\",\n      \"method\": \"Analysis of mouse models with domain-specific mutations, review of mutational data from human patients with domain-specific genotype-phenotype correlations\",\n      \"journal\": \"Human mutation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — synthesis of multiple mouse models and human mutational data with orthogonal evidence establishing two distinct pathological mechanisms\",\n      \"pmids\": [\"27375115\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"The Whirlin–Myosin 15 (Myo15)–Eps8 complex forms tip complex density (TCD)-like condensates through liquid-liquid phase separation driven by specific multivalent interactions among complex components. The reconstituted TCD-like condensates promote actin bundling. A deafness-associated mutation of Myo15 interfered with condensate formation and consequently impaired actin bundling.\",\n      \"method\": \"Protein reconstitution in vitro, phase separation assays, actin bundling assays, mutagenesis of deafness-associated Myo15 variant\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution of the ternary complex with phase separation assays, mutagenesis showing functional consequence, and actin bundling assay; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"33626355\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"The MYO15 motor domain has a moderate duty ratio (~0.5), weak thermodynamic coupling between ADP and actin binding, and ADP release from the actin-attached state is the slowest measured transition (~12 s⁻¹ at 20°C). The kinetic profile is consistent with MYO15 being adapted for processive motility when oligomerized. The ATPase cycle was characterized with major rate constants for ATP/ADP/actin binding, hydrolysis, and phosphate release.\",\n      \"method\": \"Recombinant minimal motor domain (S1) purification using baculovirus-Sf9 system, stopped-flow and quenched-flow transient kinetic analyses, actin-activated ATPase assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — rigorous in vitro enzymatic characterization with stopped-flow and quenched-flow kinetics, multiple rate constants measured, and appropriate chaperone-assisted folding controls\",\n      \"pmids\": [\"33372036\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"A synonymous variant c.9861 C>T in MYO15A causes abnormal splicing confirmed by mini-gene assay, leading to progressive post-lingual hearing loss distinct from the congenital profound deafness caused by biallelic loss-of-function variants.\",\n      \"method\": \"Mini-gene splicing assay, co-segregation analysis in 10 unrelated families, biallelic variant confirmation\",\n      \"journal\": \"European journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mini-gene assay directly demonstrates aberrant splicing, co-segregation across multiple families; single mechanistic assay\",\n      \"pmids\": [\"33398081\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"A new MYO15A isoform (MYO15A-3) is expressed in postnatal hair cells as MYO15A-2 wanes. MYO15A-2 initially delivers the elongation-promoting complex (EC) to stereocilia tips; postnatally, MYO15A-3 takes over EC delivery. In Myo15a-3 mutant mice, stereocilia develop normally with correct initial EC targeting but lack the EC postnatally and fail to maintain adult stereocilia architecture, causing progressive hearing loss.\",\n      \"method\": \"Characterization of new isoform by molecular cloning, conditional mutant mouse (Myo15a-3 mutant) with stereocilia morphology analysis, expression profiling, EC complex localization by immunofluorescence\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — loss-of-function mouse model with specific morphological and functional phenotypic readout, isoform-specific expression analysis, and EC complex localization data; multiple orthogonal methods\",\n      \"pmids\": [\"40027801\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"MYO15A isoforms are required for mechanotransduction (MET)-dependent remodeling of the actin cytoskeleton in auditory stereocilia. Hair cells lacking all functional MYO15A isoforms did not exhibit MET-dependent stereocilia cytoskeletal remodeling. Hair cells lacking only the long isoform (MYO15A-1) showed increased MET-dependent remodeling including in non-transducing stereocilia rows, indicating that MYO15A-1 fine-tunes this process.\",\n      \"method\": \"Electron microscopy of cochlear explants, pharmacological blockade of MET currents, isoform-specific MYO15A mutant mice\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct morphological analysis by EM with pharmacological and genetic dissection of isoform contributions; preprint, single lab\",\n      \"pmids\": [\"bio_10.1101_2024.09.04.611210\"],\n      \"is_preprint\": true\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"iPSC-derived hair cell-like cells from patients carrying compound heterozygous MYO15A mutations (c.4642G>A and c.8374G>A) showed abnormal morphology and dysfunction compared to controls. CRISPR/Cas9 genetic correction of the MYO15A mutation in iPSCs rescued morphology and function of derived hair cell-like cells, demonstrating that the MYO15A mutations directly cause hair cell dysfunction.\",\n      \"method\": \"iPSC generation from patients, hair cell differentiation, CRISPR/Cas9 gene correction, morphological and functional analysis of derived hair cell-like cells\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic correction with matched controls provides causal evidence; iPSC-derived model rather than native tissue; single lab\",\n      \"pmids\": [\"26915297\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"A novel MYO15A variant (c.2482C>T) located in the N-terminal domain caused significant differences in morphology and function of iPSC-derived hair cell-like cells compared to controls, without affecting iPSC totipotency, demonstrating that N-terminal domain integrity is required for normal hair cell function.\",\n      \"method\": \"iPSC generation from proband, hair cell differentiation, morphological and functional comparison between mutant and control iPSC-derived hair cell-like cells\",\n      \"journal\": \"Molecular genetics & genomic medicine\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — iPSC-based functional assay but single lab, single variant, limited mechanistic depth\",\n      \"pmids\": [\"39620501\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Computational analysis predicted that missense SNPs in WHRN destabilize the WHRN–MYO15A protein-protein complex, with molecular docking and dynamics showing altered binding affinity and stability of the complex; however, this is computational only.\",\n      \"method\": \"In silico SNP pathogenicity prediction, molecular docking (Haddock), molecular dynamics simulation, binding energy calculation (PRODIGY)\",\n      \"journal\": \"Journal of biomolecular structure & dynamics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 4 / Weak — computational modeling only, no experimental validation of WHRN–MYO15A complex disruption\",\n      \"pmids\": [\"40389825\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MYO15A encodes an unconventional myosin (myosin XVA) that localizes to the stereocilia tips and cuticular plate of cochlear hair cells, where it functions as a molecular motor (moderate duty ratio ~0.5, ATPase rate ~6 s⁻¹) to traffic and deliver an elongation-promoting complex (containing Whirlin/WHRN and Eps8) to stereocilia tips; distinct isoforms mediate stereocilia development (MYO15A-2) versus postnatal maintenance (MYO15A-3/long isoform), and the Whirlin–MYO15A–Eps8 ternary complex assembles into a tip complex density via liquid-liquid phase separation that promotes actin bundling, with loss-of-function mutations causing DFNB3 autosomal recessive non-syndromic deafness through either developmental or maintenance defects in stereocilia architecture.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MYO15A encodes an unconventional myosin (myosin XV) that acts as an actin-based molecular motor concentrated within the stereocilia and cuticular plate of cochlear sensory hair cells, where it builds and maintains the stereocilia actin architecture required for hearing [#0, #1]. The protein is a ~365 kDa motor with a large N-terminal extension preceding a conserved motor domain and a tail bearing tandem MyTH4, FERM-like, and SH3 domains [#1]. Its minimal motor domain has a moderate duty ratio (~0.5) with ADP release from the actin-bound state as the rate-limiting transition, a kinetic profile consistent with processive motility when the motor is oligomerized [#9]. MYO15A delivers an elongation-promoting complex to stereocilia tips, and the Whirlin–myosin 15–Eps8 ternary complex assembles into tip-complex-density-like condensates through liquid-liquid phase separation that drives actin bundling; a deafness-associated MYO15A mutation abolishes condensate formation and impairs bundling [#8]. Distinct isoforms partition this work temporally: an isoform containing the exon 2–encoded N-terminal extension is required for stereocilia development, while a later-appearing isoform takes over complex delivery postnatally to maintain adult stereocilia, and MYO15A also participates in mechanotransduction-dependent remodeling of the stereocilia cytoskeleton [#7, #11, #12]. Loss-of-function and splice-altering mutations in MYO15A cause DFNB3 autosomal recessive non-syndromic deafness through either developmental or maintenance defects, with genotype determining congenital-profound versus progressive post-lingual phenotypes [#0, #7, #10].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"Established MYO15A as a deafness gene, answering whether an unconventional myosin underlies a defined hereditary hearing loss locus.\",\n      \"evidence\": \"Positional cloning and exon sequencing in three unrelated DFNB3 families\",\n      \"pmids\": [\"9603736\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define protein domain architecture\", \"No subcellular localization or cellular mechanism\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Defined the protein as a ~365 kDa myosin with a unique N-terminal extension and MyTH4/FERM/SH3 tail, and localized it to hair cell stereocilia and cuticular plate, framing where and how it might act.\",\n      \"evidence\": \"cDNA/genomic analysis, in situ hybridization, and immunostaining of mouse organ of Corti\",\n      \"pmids\": [\"10552926\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No motor kinetics\", \"Binding partners and cargo unknown\", \"Function of domains not tested\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Showed Myo15 acts in a pathway distinct from other stereocilia myosins, clarifying that it is not redundant with Myo6, Myo7a, or pirouette.\",\n      \"evidence\": \"Double-mutant mouse epistasis with hearing and cochlear morphology readouts\",\n      \"pmids\": [\"12966030\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not identify the molecular cargo of the independent pathway\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Demonstrated Myo15a is necessary and sufficient for normal stereocilia and hearing by rescuing the mutant phenotype, establishing direct causality.\",\n      \"evidence\": \"BAC transgene rescue in shaker2 mice with ABR and morphology\",\n      \"pmids\": [\"16580798\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of structural maintenance not resolved\", \"Isoform-specific contributions not distinguished\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Mapped functional requirements to specific regions—the N-terminal extension and the motor domain—linking domain integrity to hearing.\",\n      \"evidence\": \"Mutation/linkage analysis of consanguineous families plus molecular modeling of a motor-domain missense variant\",\n      \"pmids\": [\"17546645\", \"17853461\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Motor-domain powerstroke effect is computational only\", \"No biochemical validation of the predicted defect\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Extended Myo15 function beyond the cochlea by tying a MyTH4-domain mutation to retinal degeneration and detecting retinal expression.\",\n      \"evidence\": \"Mutation identification, retinal in situ/RT-PCR, ERG, and histology in a mutant rat\",\n      \"pmids\": [\"21479269\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Retinal molecular role undefined\", \"No partner or cargo identified in retina\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Resolved that distinct isoform classes drive two separable processes—stereocilia development versus long-term maintenance—reconciling variable patient phenotypes with genotype.\",\n      \"evidence\": \"Synthesis of domain-specific mouse models and human genotype-phenotype correlations; CRISPR-corrected patient iPSC hair cell-like cells\",\n      \"pmids\": [\"27375115\", \"26915297\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular trigger for the developmental-to-maintenance switch not defined\", \"iPSC model is not native cochlear tissue\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Provided the biochemical basis of motor function and cargo organization: characterized the ATPase cycle as suited to processive oligomeric motility, and showed the Whirlin–Myo15–Eps8 complex phase-separates to bundle actin.\",\n      \"evidence\": \"Recombinant motor-domain transient kinetics; in vitro ternary-complex reconstitution, phase-separation and actin-bundling assays with deafness-variant mutagenesis\",\n      \"pmids\": [\"33372036\", \"33626355\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Oligomerization state in vivo not directly shown\", \"Link between motor kinetics and condensate delivery not directly tested in cells\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Showed a synonymous splice-altering variant produces a milder progressive phenotype, distinguishing splicing defects from biallelic loss-of-function in pathogenesis.\",\n      \"evidence\": \"Mini-gene splicing assay and co-segregation across 10 families\",\n      \"pmids\": [\"33398081\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Residual protein function from aberrant splicing not quantified\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Identified an isoform handoff in which a postnatal isoform sustains elongation-complex delivery and adult stereocilia maintenance, and tied MYO15A isoforms to mechanotransduction-dependent cytoskeletal remodeling.\",\n      \"evidence\": \"Isoform cloning/expression profiling, conditional mutant mice with stereocilia morphology and EC localization; EM with MET blockade in isoform-specific mutants (both preprint)\",\n      \"pmids\": [\"40027801\", \"bio_10.1101_2024.09.04.611210\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Preprint, single-lab data\", \"Mechanism coordinating MET signaling with isoform activity unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How motor kinetics, isoform switching, and phase-separated complex delivery are integrated in vivo to specify stereocilia length and maintenance remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No in vivo demonstration of motor oligomerization driving condensate transport\", \"Retinal mechanism uncharacterized\", \"WHRN–MYO15A interface disruption tested only computationally\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [9]},\n      {\"term_id\": \"GO:0003774\", \"supporting_discovery_ids\": [9, 1]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [8, 9]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [9]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [1, 8, 12]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9709957\", \"supporting_discovery_ids\": [0, 3]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [7, 11]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [0, 10]}\n    ],\n    \"complexes\": [\"Whirlin–Myosin 15–Eps8 tip complex (elongation-promoting complex)\"],\n    \"partners\": [\"WHRN\", \"EPS8\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}