{"gene":"MYO5A","run_date":"2026-06-10T05:19:52","timeline":{"discoveries":[{"year":2003,"finding":"Deletion of the MYO5A F-exon (a tissue-restricted exon) causes hypopigmentation restricted to the melanocyte lineage in Griscelli syndrome type 1, demonstrating that the F-exon is required for MYO5A function specifically in melanocytes. MYO5A operates in a RAB27A/melanophilin (MLPH)-dependent receptor complex to transport melanosomes to the periphery of melanocytes.","method":"Genetic analysis of GS patient mutations combined with functional analysis of exon-deleted MYO5A and epistasis with RAB27A and MLPH mutations","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis across three pathway components (MYO5A, RAB27A, MLPH) with functional consequence, replicated across multiple patient kindreds and mouse models","pmids":["12897212"],"is_preprint":false},{"year":2004,"finding":"MYO5A is required for peripheral accumulation of melanosomes in melanocytes but is nonessential for melanosome transfer to neighboring keratinocytes. The dilute suppressor (dsu) gene functions in an MYO5A-independent pathway to alter pigment incorporation into hair.","method":"Analysis of MYO5A-deficient mice (dilute mutants) combined with genetic epistasis using dsu suppressor mutants; direct observation of melanosome distribution","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — loss-of-function mouse model with defined cellular phenotype (melanosome distribution) plus genetic epistasis placing dsu in a parallel pathway","pmids":["15550542"],"is_preprint":false},{"year":2000,"finding":"The MYO5A globular tail domain binds organelle cargoes for intracellular transport. A dominant-negative flailer protein containing only the C-terminal 711 amino acids of MYO5A (including the globular tail domain) competes with wild-type MYO5A and prevents localization of smooth endoplasmic reticulum (SER) vesicles to dendritic spines of cerebellar Purkinje cells.","method":"Biochemical and genetic studies in flailer mice expressing a Gnb5-Myo5a hybrid protein; competition assay showing displacement of SER vesicles from dendritic spines","journal":"Human molecular genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — dominant-negative competition experiment in vivo with defined organelle cargo (SER vesicles) and cellular phenotype (Purkinje cell dendritic spine), supported by genetic analysis","pmids":["10749990"],"is_preprint":false},{"year":2021,"finding":"Loss-of-function mutations in Myo5a reduce full-length MYO5A protein and cause deficient melanosome transport, directly linking MYO5A motor function to melanosome distribution in melanocytes.","method":"Whole-genome sequencing, RNA-seq, RT-qPCR, western blot for MYO5A protein, and direct observation of melanosome transport in mutant C57BL/6 mice","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function mouse model with multiple methods (sequencing, protein quantification, melanosome transport assay), single lab","pmids":["33715225"],"is_preprint":false},{"year":2017,"finding":"In a rat model, Myo5a mutation abolishes MYO5A protein in the brain and impairs transport and distribution of subcellular organelles in somatodendritic processes of neurons, resulting in hyperphosphorylation of alpha-synuclein and tau, accumulation of the autotoxic dopamine metabolite DOPAL, and alpha-synuclein accumulation in mitochondria of dopaminergic neurons associated with impaired respiratory complex I and IV activity.","method":"Analysis of spontaneous autosomal recessive Myo5a mutant rats; biochemical assays for protein phosphorylation, aldehyde dehydrogenase activity, and mitochondrial respiratory complex activity","journal":"Brain research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function rat model with multiple biochemical readouts (phosphorylation, enzyme activity, mitochondrial function), single lab","pmids":["29217155"],"is_preprint":false},{"year":2025,"finding":"A splice variant in Myo5a exon 14 ablates MYO5A protein expression and causes cerebellar developmental defects with expansion of PAX6-positive cells in the external granule layer. Mass spectrometry of cerebellar extracts identified differentially abundant proteins involved in short-range organelle transport and early endosomes. MYO5A was found to interact with ANKFY1, a known effector of the endosomal protein RAB5A, linking MYO5A to early endosomal trafficking. Neurons from mutant mice had elongated mitochondria, linking MYO5A to mitochondrial homeostasis.","method":"Genome sequencing, genome-wide mapping, immunofluorescence (PAX6 staining), mass spectrometry of cerebellar extracts, co-immunoprecipitation/interaction assay (MYO5A–ANKFY1), primary neuron morphology analysis","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function mouse model combined with mass spectrometry and a direct interaction assay (MYO5A–ANKFY1), single lab, novel findings not yet replicated","pmids":["40022605"],"is_preprint":false},{"year":2013,"finding":"The globular tail domain of human MYO5A was successfully expressed, purified, and crystallized, diffracting to 2.5 Å resolution, establishing that the domain is amenable to structural analysis and confirming its folded, autonomous structure.","method":"Protein expression, purification, crystallization, and X-ray diffraction data collection","journal":"Acta crystallographica Section F","confidence":"Low","confidence_rationale":"Tier 1 / Weak — crystallization and preliminary diffraction reported, but no structure solved or functional validation presented in this abstract; single report","pmids":["24192353"],"is_preprint":false},{"year":2021,"finding":"A homozygous frameshift insertion in MYO5A predicted to truncate 269 amino acids of the myosin VA protein causes coat color dilution and neurological defects in a miniature Dachshund, phenocopying Griscelli syndrome type 1 in humans and demonstrating conservation of MYO5A function across mammals.","method":"Whole-genome sequencing of affected dog vs. 795 controls; co-segregation analysis in the index family; histopathological analysis of melanin distribution","journal":"Genes","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function variant identified by genome sequencing with co-segregation and histopathology, consistent with established MYO5A mechanism across species","pmids":["34680875"],"is_preprint":false}],"current_model":"MYO5A encodes an actin-based motor protein (myosin Va) that uses its C-terminal globular tail domain to bind organelle cargoes—including melanosomes (via a RAB27A/melanophilin receptor complex), smooth endoplasmic reticulum vesicles, and early endosomes (via ANKFY1/RAB5A)—and transport them to the cell periphery in melanocytes and along somatodendritic processes in neurons; loss of MYO5A causes melanosome clumping in melanocyte perinuclear regions, failure of SER delivery to dendritic spines, dysregulation of mitochondrial morphology, and secondary neurochemical perturbations including alpha-synuclein hyperphosphorylation and dopamine metabolite accumulation."},"narrative":{"mechanistic_narrative":"MYO5A encodes myosin Va, an actin-based motor protein that transports intracellular organelle cargoes to the cell periphery and into specialized cellular processes [PMID:12897212, PMID:10749990]. In melanocytes, MYO5A operates within a RAB27A/melanophilin (MLPH) receptor complex to drive peripheral accumulation of melanosomes; loss of function disrupts this distribution, and genetic epistasis across MYO5A, RAB27A, and MLPH places these three components in one transport pathway underlying Griscelli syndrome type 1, with a melanocyte-restricted F-exon required for pigment-cell function [PMID:12897212, PMID:15550542]. Cargo recognition is mediated by the autonomously folded C-terminal globular tail domain, which binds organelles for transport: a dominant-negative fragment comprising only this domain competitively displaces smooth endoplasmic reticulum vesicles from Purkinje cell dendritic spines [PMID:10749990, PMID:24192353]. In neurons, MYO5A is required for organelle transport and distribution within somatodendritic processes [PMID:29217155], and it links to early endosomal trafficking through a physical interaction with ANKFY1, an effector of RAB5A [PMID:40022605]. Loss of MYO5A in the nervous system produces cerebellar developmental defects with expansion of PAX6-positive external granule layer cells, elongated mitochondria indicating disrupted mitochondrial homeostasis, and secondary neurochemical perturbations including hyperphosphorylation of alpha-synuclein and tau, DOPAL accumulation, and mitochondrial alpha-synuclein deposition with impaired respiratory complex I and IV activity [PMID:29217155, PMID:40022605]. The motor's function is conserved across mammals, with loss-of-function truncating mutations phenocopying Griscelli syndrome type 1 [PMID:34680875].","teleology":[{"year":2000,"claim":"Established that the MYO5A C-terminal globular tail domain is the cargo-binding module by showing a fragment containing only this domain acts as a dominant negative against organelle delivery, defining how the motor engages cargo.","evidence":"Dominant-negative competition assay in flailer mice expressing a Gnb5-Myo5a hybrid, scoring SER vesicle localization to Purkinje cell dendritic spines","pmids":["10749990"],"confidence":"High","gaps":["Did not resolve the molecular receptor on SER vesicles","Tail-cargo interaction inferred from competition, not direct binding"]},{"year":2003,"claim":"Resolved how MYO5A recognizes melanosome cargo by placing it in a RAB27A/MLPH receptor complex and showing a melanocyte-restricted F-exon is required for pigment-cell function, explaining tissue specificity of Griscelli syndrome type 1.","evidence":"Genetic analysis of Griscelli patient mutations with epistasis across MYO5A, RAB27A, and MLPH","pmids":["12897212"],"confidence":"High","gaps":["Structural basis of the tail-MLPH-RAB27A interface not defined","Mechanism of F-exon regulation of cargo binding unresolved"]},{"year":2004,"claim":"Defined the cellular boundary of MYO5A function by showing it drives peripheral melanosome accumulation but is dispensable for melanosome transfer to keratinocytes, and placed the dsu suppressor in a parallel pathway.","evidence":"Dilute (Myo5a-deficient) mouse melanosome distribution analysis with dsu genetic epistasis","pmids":["15550542"],"confidence":"High","gaps":["Molecular identity and mechanism of the dsu pathway not established here","Does not address neuronal cargo"]},{"year":2013,"claim":"Showed the globular tail domain is an autonomously folded, structurally tractable module, enabling structural study of cargo recognition.","evidence":"Expression, purification, crystallization, and 2.5 A diffraction of the human MYO5A globular tail","pmids":["24192353"],"confidence":"Low","gaps":["No structure solved or deposited in this report","No functional or cargo-bound complex structure"]},{"year":2017,"claim":"Extended MYO5A function into neuronal organelle homeostasis by linking its loss to impaired somatodendritic organelle transport and downstream neurochemical pathology in dopaminergic neurons.","evidence":"Spontaneous recessive Myo5a mutant rats with biochemical assays for protein phosphorylation, aldehyde dehydrogenase activity, and mitochondrial respiratory complex activity","pmids":["29217155"],"confidence":"Medium","gaps":["Alpha-synuclein/tau and DOPAL changes are secondary consequences with undefined causal chain","Single lab, single model"]},{"year":2021,"claim":"Confirmed by independent loss-of-function models that reduced full-length MYO5A protein directly causes deficient melanosome transport, and that truncating MYO5A mutations phenocopy Griscelli syndrome type 1 across mammals.","evidence":"Loss-of-function mutant mice (genome/RNA sequencing, protein quantification, melanosome transport) and a Dachshund frameshift variant with co-segregation and histopathology","pmids":["33715225","34680875"],"confidence":"Medium","gaps":["Does not add new molecular mechanism beyond confirming motor requirement","Conservation inferred phenotypically, not biochemically"]},{"year":2025,"claim":"Connected MYO5A to early endosomal trafficking and mitochondrial homeostasis by identifying a direct MYO5A-ANKFY1 (RAB5A effector) interaction and showing cerebellar developmental and mitochondrial defects on MYO5A loss.","evidence":"Loss-of-function mutant mice with mass spectrometry of cerebellar extracts, PAX6 immunofluorescence, co-immunoprecipitation (MYO5A-ANKFY1), and primary neuron morphology","pmids":["40022605"],"confidence":"Medium","gaps":["MYO5A-ANKFY1 interaction from single Co-IP, not reciprocally validated or reconstituted","Causal link between endosomal trafficking and mitochondrial elongation not established","Single lab, not yet replicated"]},{"year":null,"claim":"How MYO5A motor activity is coordinated and regulated across its distinct cargo systems (melanosomes, SER vesicles, early endosomes) and how cargo loss propagates to mitochondrial and neurochemical pathology remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No cargo-bound structural model of the tail-receptor complexes","Mechanism linking organelle transport defects to alpha-synuclein/tau pathology undefined","Regulation of cargo selection between melanocyte and neuronal contexts unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003774","term_label":"cytoskeletal motor activity","supporting_discovery_ids":[0,2,3]},{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[0,2]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[2]}],"localization":[{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[0,2]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[5]}],"pathway":[{"term_id":"R-HSA-9609507","term_label":"Protein localization","supporting_discovery_ids":[0,2]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[2,5]}],"complexes":[],"partners":["RAB27A","MLPH","ANKFY1","RAB5A"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q9Y4I1","full_name":"Unconventional myosin-Va","aliases":["Dilute myosin heavy chain, non-muscle","Myosin heavy chain 12","Myosin-12","Myoxin"],"length_aa":1855,"mass_kda":215.4,"function":"Processive actin-based motor that can move in large steps approximating the 36-nm pseudo-repeat of the actin filament. Can hydrolyze ATP in the presence of actin, which is essential for its function as a motor protein (PubMed:10448864). Involved in melanosome transport. Also mediates the transport of vesicles to the plasma membrane (By similarity). May also be required for some polarization process involved in dendrite formation (By similarity)","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/Q9Y4I1/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/MYO5A","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CTTN","stoichiometry":0.2},{"gene":"DYNLL1","stoichiometry":0.2},{"gene":"DYNLL2","stoichiometry":0.2},{"gene":"NPM1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/MYO5A","total_profiled":1310},"omim":[{"mim_id":"617379","title":"MYOSIN XIX; MYO19","url":"https://www.omim.org/entry/617379"},{"mim_id":"614423","title":"TRANSMEMBRANE PROTEIN 237; TMEM237","url":"https://www.omim.org/entry/614423"},{"mim_id":"612880","title":"SYNAPTOTAGMIN-LIKE 2; SYTL2","url":"https://www.omim.org/entry/612880"},{"mim_id":"611790","title":"MYOSIN VIIA- AND RAB-INTERACTING PROTEIN; MYRIP","url":"https://www.omim.org/entry/611790"},{"mim_id":"611491","title":"RAS ASSOCIATION AND DILUTE DOMAINS PROTEIN; RADIL","url":"https://www.omim.org/entry/611491"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Focal adhesion sites","reliability":"Approved"},{"location":"Centriolar satellite","reliability":"Approved"},{"location":"Primary cilium","reliability":"Additional"},{"location":"Basal body","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"},{"location":"Calyx","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"brain","ntpm":31.4},{"tissue":"parathyroid gland","ntpm":36.7}],"url":"https://www.proteinatlas.org/search/MYO5A"},"hgnc":{"alias_symbol":["MYO5","GS1","MYR12"],"prev_symbol":["MYH12"]},"alphafold":{"accession":"Q9Y4I1","domains":[{"cath_id":"2.30.30,2.30.30","chopping":"2-64","consensus_level":"medium","plddt":85.3733,"start":2,"end":64},{"cath_id":"3.30.70.1590","chopping":"699-753","consensus_level":"medium","plddt":88.4255,"start":699,"end":753},{"cath_id":"-","chopping":"755-914","consensus_level":"medium","plddt":79.5587,"start":755,"end":914},{"cath_id":"-","chopping":"1478-1599","consensus_level":"high","plddt":85.8893,"start":1478,"end":1599}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y4I1","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y4I1-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9Y4I1-F1-predicted_aligned_error_v6.png","plddt_mean":76.69},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=MYO5A","jax_strain_url":"https://www.jax.org/strain/search?query=MYO5A"},"sequence":{"accession":"Q9Y4I1","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9Y4I1.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9Y4I1/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9Y4I1"}},"corpus_meta":[{"pmid":"12897212","id":"PMC_12897212","title":"Griscelli syndrome restricted to hypopigmentation results from a melanophilin defect (GS3) or a MYO5A F-exon deletion (GS1).","date":"2003","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/12897212","citation_count":218,"is_preprint":false},{"pmid":"8682864","id":"PMC_8682864","title":"Synthetic lethality screen identifies a novel yeast myosin I gene (MYO5): myosin I proteins are required for polarization of the actin cytoskeleton.","date":"1996","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/8682864","citation_count":196,"is_preprint":false},{"pmid":"12058346","id":"PMC_12058346","title":"Evidence that Griscelli syndrome with neurological involvement is caused by mutations in RAB27A, not MYO5A.","date":"2002","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/12058346","citation_count":60,"is_preprint":false},{"pmid":"15550542","id":"PMC_15550542","title":"dsu functions in a MYO5A-independent pathway to suppress the coat color of dilute mice.","date":"2004","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/15550542","citation_count":42,"is_preprint":false},{"pmid":"8188282","id":"PMC_8188282","title":"Cloning, analysis, and chromosomal localization of myoxin (MYH12), the human homologue to the mouse dilute gene.","date":"1994","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/8188282","citation_count":36,"is_preprint":false},{"pmid":"32325088","id":"PMC_32325088","title":"LINC01980 facilitates esophageal squamous cell carcinoma progression via regulation of miR-190a-5p/MYO5A pathway.","date":"2020","source":"Archives of biochemistry and biophysics","url":"https://pubmed.ncbi.nlm.nih.gov/32325088","citation_count":28,"is_preprint":false},{"pmid":"10749990","id":"PMC_10749990","title":"The mouse neurological mutant flailer expresses a novel hybrid gene derived by exon shuffling between Gnb5 and Myo5a.","date":"2000","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/10749990","citation_count":24,"is_preprint":false},{"pmid":"29950866","id":"PMC_29950866","title":"MYO5A inhibition by miR-145 acts as a predictive marker of occult neck lymph node metastasis in human laryngeal squamous cell carcinoma.","date":"2018","source":"OncoTargets and therapy","url":"https://pubmed.ncbi.nlm.nih.gov/29950866","citation_count":18,"is_preprint":false},{"pmid":"20656786","id":"PMC_20656786","title":"Candida albicans Vrp1 is required for polarized morphogenesis and interacts with Wal1 and Myo5.","date":"2010","source":"Microbiology (Reading, England)","url":"https://pubmed.ncbi.nlm.nih.gov/20656786","citation_count":14,"is_preprint":false},{"pmid":"29217155","id":"PMC_29217155","title":"Pleiotropic neuropathological and biochemical alterations associated with Myo5a mutation in a rat Model.","date":"2017","source":"Brain research","url":"https://pubmed.ncbi.nlm.nih.gov/29217155","citation_count":12,"is_preprint":false},{"pmid":"35596628","id":"PMC_35596628","title":"Fatal melanoma with a novel MYO5A-BRAF fusion and small associated conventional nevus: A case report and review of literature.","date":"2022","source":"Journal of cutaneous pathology","url":"https://pubmed.ncbi.nlm.nih.gov/35596628","citation_count":12,"is_preprint":false},{"pmid":"7835087","id":"PMC_7835087","title":"Cloning and regional assignment of the human myosin heavy chain 12 (MYH12) gene to chromosome band 15q21.","date":"1995","source":"Cytogenetics and cell genetics","url":"https://pubmed.ncbi.nlm.nih.gov/7835087","citation_count":11,"is_preprint":false},{"pmid":"33715225","id":"PMC_33715225","title":"Novel mutations in the Myo5a gene cause a dilute coat color phenotype in mice.","date":"2021","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/33715225","citation_count":10,"is_preprint":false},{"pmid":"32556925","id":"PMC_32556925","title":"Central nervous system ganglioneuroblastoma harboring MYO5A-NTRK3 fusion.","date":"2020","source":"Brain tumor pathology","url":"https://pubmed.ncbi.nlm.nih.gov/32556925","citation_count":9,"is_preprint":false},{"pmid":"34680875","id":"PMC_34680875","title":"MYO5A Frameshift Variant in a Miniature Dachshund with Coat Color Dilution and Neurological Defects Resembling Human Griscelli Syndrome Type 1.","date":"2021","source":"Genes","url":"https://pubmed.ncbi.nlm.nih.gov/34680875","citation_count":9,"is_preprint":false},{"pmid":"37667251","id":"PMC_37667251","title":"circFNDC3B promotes esophageal squamous cell carcinoma progression by targeting MYO5A via miR-370-3p/miR-136-5p.","date":"2023","source":"BMC cancer","url":"https://pubmed.ncbi.nlm.nih.gov/37667251","citation_count":7,"is_preprint":false},{"pmid":"38129784","id":"PMC_38129784","title":"MYO5A overexpression promotes invasion and correlates with low lymphocyte infiltration in head and neck squamous carcinoma.","date":"2023","source":"BMC cancer","url":"https://pubmed.ncbi.nlm.nih.gov/38129784","citation_count":5,"is_preprint":false},{"pmid":"36884165","id":"PMC_36884165","title":"Circ-FNDC3B Functions as an Oncogenic Factor in Esophageal Squamous Cell Carcinoma via Upregulating MYO5A by Absorbing miR-136-5p and miR-370-3p.","date":"2023","source":"Biochemical genetics","url":"https://pubmed.ncbi.nlm.nih.gov/36884165","citation_count":4,"is_preprint":false},{"pmid":"10036975","id":"PMC_10036975","title":"Loss of heterozygosity at the dilute-short ear (Myo5a-Bmp5) region of the mouse: mitotic recombination or double non-disjunction?","date":"1998","source":"Genetical research","url":"https://pubmed.ncbi.nlm.nih.gov/10036975","citation_count":2,"is_preprint":false},{"pmid":"40022605","id":"PMC_40022605","title":"A novel, rapidly progressive ataxia due to a spontaneous Myo5a mutation in mice impairs transport proteins and alters mitochondria.","date":"2025","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/40022605","citation_count":0,"is_preprint":false},{"pmid":"38437672","id":"PMC_38437672","title":"Rare variant of large pediatric glioneuronal tumor with novel MYO5A::NTRK3 fusion: illustrative case.","date":"2024","source":"Journal of neurosurgery. Case lessons","url":"https://pubmed.ncbi.nlm.nih.gov/38437672","citation_count":0,"is_preprint":false},{"pmid":"37694106","id":"PMC_37694106","title":"MYO5A Inhibition by miR-145 Acts as a Predictive Marker of Occult Neck Lymph Node Metastasis in Human Laryngeal Squamous Cell Carcinoma [Retraction].","date":"2023","source":"OncoTargets and therapy","url":"https://pubmed.ncbi.nlm.nih.gov/37694106","citation_count":0,"is_preprint":false},{"pmid":"24192353","id":"PMC_24192353","title":"Purification, crystallization and preliminary crystallographic analysis of the globular domain of the human type V myosin Myo5a.","date":"2013","source":"Acta crystallographica. Section F, Structural biology and crystallization communications","url":"https://pubmed.ncbi.nlm.nih.gov/24192353","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.03.21.25324422","title":"Radiolabeling Molecular Biomarkers of Invasive Pituitary Neuroendocrine Tumors: A Systematic Review","date":"2025-03-23","source":"bioRxiv","url":"https://doi.org/10.1101/2025.03.21.25324422","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.07.07.25331056","title":"Serum Exosomal Multi-Omic Signatures Stratify Glucose Tolerance in Cystic Fibrosis and Reveal Partial Therapeutic Reprogramming by CFTR Modulators","date":"2025-07-08","source":"bioRxiv","url":"https://doi.org/10.1101/2025.07.07.25331056","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":13525,"output_tokens":2207,"usd":0.03684,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9262,"output_tokens":2924,"usd":0.059705,"stage2_stop_reason":"end_turn"},"total_usd":0.096545,"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\": 2003,\n      \"finding\": \"Deletion of the MYO5A F-exon (a tissue-restricted exon) causes hypopigmentation restricted to the melanocyte lineage in Griscelli syndrome type 1, demonstrating that the F-exon is required for MYO5A function specifically in melanocytes. MYO5A operates in a RAB27A/melanophilin (MLPH)-dependent receptor complex to transport melanosomes to the periphery of melanocytes.\",\n      \"method\": \"Genetic analysis of GS patient mutations combined with functional analysis of exon-deleted MYO5A and epistasis with RAB27A and MLPH mutations\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis across three pathway components (MYO5A, RAB27A, MLPH) with functional consequence, replicated across multiple patient kindreds and mouse models\",\n      \"pmids\": [\"12897212\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"MYO5A is required for peripheral accumulation of melanosomes in melanocytes but is nonessential for melanosome transfer to neighboring keratinocytes. The dilute suppressor (dsu) gene functions in an MYO5A-independent pathway to alter pigment incorporation into hair.\",\n      \"method\": \"Analysis of MYO5A-deficient mice (dilute mutants) combined with genetic epistasis using dsu suppressor mutants; direct observation of melanosome distribution\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — loss-of-function mouse model with defined cellular phenotype (melanosome distribution) plus genetic epistasis placing dsu in a parallel pathway\",\n      \"pmids\": [\"15550542\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"The MYO5A globular tail domain binds organelle cargoes for intracellular transport. A dominant-negative flailer protein containing only the C-terminal 711 amino acids of MYO5A (including the globular tail domain) competes with wild-type MYO5A and prevents localization of smooth endoplasmic reticulum (SER) vesicles to dendritic spines of cerebellar Purkinje cells.\",\n      \"method\": \"Biochemical and genetic studies in flailer mice expressing a Gnb5-Myo5a hybrid protein; competition assay showing displacement of SER vesicles from dendritic spines\",\n      \"journal\": \"Human molecular genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — dominant-negative competition experiment in vivo with defined organelle cargo (SER vesicles) and cellular phenotype (Purkinje cell dendritic spine), supported by genetic analysis\",\n      \"pmids\": [\"10749990\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Loss-of-function mutations in Myo5a reduce full-length MYO5A protein and cause deficient melanosome transport, directly linking MYO5A motor function to melanosome distribution in melanocytes.\",\n      \"method\": \"Whole-genome sequencing, RNA-seq, RT-qPCR, western blot for MYO5A protein, and direct observation of melanosome transport in mutant C57BL/6 mice\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function mouse model with multiple methods (sequencing, protein quantification, melanosome transport assay), single lab\",\n      \"pmids\": [\"33715225\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"In a rat model, Myo5a mutation abolishes MYO5A protein in the brain and impairs transport and distribution of subcellular organelles in somatodendritic processes of neurons, resulting in hyperphosphorylation of alpha-synuclein and tau, accumulation of the autotoxic dopamine metabolite DOPAL, and alpha-synuclein accumulation in mitochondria of dopaminergic neurons associated with impaired respiratory complex I and IV activity.\",\n      \"method\": \"Analysis of spontaneous autosomal recessive Myo5a mutant rats; biochemical assays for protein phosphorylation, aldehyde dehydrogenase activity, and mitochondrial respiratory complex activity\",\n      \"journal\": \"Brain research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function rat model with multiple biochemical readouts (phosphorylation, enzyme activity, mitochondrial function), single lab\",\n      \"pmids\": [\"29217155\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"A splice variant in Myo5a exon 14 ablates MYO5A protein expression and causes cerebellar developmental defects with expansion of PAX6-positive cells in the external granule layer. Mass spectrometry of cerebellar extracts identified differentially abundant proteins involved in short-range organelle transport and early endosomes. MYO5A was found to interact with ANKFY1, a known effector of the endosomal protein RAB5A, linking MYO5A to early endosomal trafficking. Neurons from mutant mice had elongated mitochondria, linking MYO5A to mitochondrial homeostasis.\",\n      \"method\": \"Genome sequencing, genome-wide mapping, immunofluorescence (PAX6 staining), mass spectrometry of cerebellar extracts, co-immunoprecipitation/interaction assay (MYO5A–ANKFY1), primary neuron morphology analysis\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function mouse model combined with mass spectrometry and a direct interaction assay (MYO5A–ANKFY1), single lab, novel findings not yet replicated\",\n      \"pmids\": [\"40022605\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"The globular tail domain of human MYO5A was successfully expressed, purified, and crystallized, diffracting to 2.5 Å resolution, establishing that the domain is amenable to structural analysis and confirming its folded, autonomous structure.\",\n      \"method\": \"Protein expression, purification, crystallization, and X-ray diffraction data collection\",\n      \"journal\": \"Acta crystallographica Section F\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 1 / Weak — crystallization and preliminary diffraction reported, but no structure solved or functional validation presented in this abstract; single report\",\n      \"pmids\": [\"24192353\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"A homozygous frameshift insertion in MYO5A predicted to truncate 269 amino acids of the myosin VA protein causes coat color dilution and neurological defects in a miniature Dachshund, phenocopying Griscelli syndrome type 1 in humans and demonstrating conservation of MYO5A function across mammals.\",\n      \"method\": \"Whole-genome sequencing of affected dog vs. 795 controls; co-segregation analysis in the index family; histopathological analysis of melanin distribution\",\n      \"journal\": \"Genes\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function variant identified by genome sequencing with co-segregation and histopathology, consistent with established MYO5A mechanism across species\",\n      \"pmids\": [\"34680875\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"MYO5A encodes an actin-based motor protein (myosin Va) that uses its C-terminal globular tail domain to bind organelle cargoes—including melanosomes (via a RAB27A/melanophilin receptor complex), smooth endoplasmic reticulum vesicles, and early endosomes (via ANKFY1/RAB5A)—and transport them to the cell periphery in melanocytes and along somatodendritic processes in neurons; loss of MYO5A causes melanosome clumping in melanocyte perinuclear regions, failure of SER delivery to dendritic spines, dysregulation of mitochondrial morphology, and secondary neurochemical perturbations including alpha-synuclein hyperphosphorylation and dopamine metabolite accumulation.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"MYO5A encodes myosin Va, an actin-based motor protein that transports intracellular organelle cargoes to the cell periphery and into specialized cellular processes [#0, #2]. In melanocytes, MYO5A operates within a RAB27A/melanophilin (MLPH) receptor complex to drive peripheral accumulation of melanosomes; loss of function disrupts this distribution, and genetic epistasis across MYO5A, RAB27A, and MLPH places these three components in one transport pathway underlying Griscelli syndrome type 1, with a melanocyte-restricted F-exon required for pigment-cell function [#0, #1]. Cargo recognition is mediated by the autonomously folded C-terminal globular tail domain, which binds organelles for transport: a dominant-negative fragment comprising only this domain competitively displaces smooth endoplasmic reticulum vesicles from Purkinje cell dendritic spines [#2, #6]. In neurons, MYO5A is required for organelle transport and distribution within somatodendritic processes [#4], and it links to early endosomal trafficking through a physical interaction with ANKFY1, an effector of RAB5A [#5]. Loss of MYO5A in the nervous system produces cerebellar developmental defects with expansion of PAX6-positive external granule layer cells, elongated mitochondria indicating disrupted mitochondrial homeostasis, and secondary neurochemical perturbations including hyperphosphorylation of alpha-synuclein and tau, DOPAL accumulation, and mitochondrial alpha-synuclein deposition with impaired respiratory complex I and IV activity [#4, #5]. The motor's function is conserved across mammals, with loss-of-function truncating mutations phenocopying Griscelli syndrome type 1 [#7].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Established that the MYO5A C-terminal globular tail domain is the cargo-binding module by showing a fragment containing only this domain acts as a dominant negative against organelle delivery, defining how the motor engages cargo.\",\n      \"evidence\": \"Dominant-negative competition assay in flailer mice expressing a Gnb5-Myo5a hybrid, scoring SER vesicle localization to Purkinje cell dendritic spines\",\n      \"pmids\": [\"10749990\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve the molecular receptor on SER vesicles\", \"Tail-cargo interaction inferred from competition, not direct binding\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Resolved how MYO5A recognizes melanosome cargo by placing it in a RAB27A/MLPH receptor complex and showing a melanocyte-restricted F-exon is required for pigment-cell function, explaining tissue specificity of Griscelli syndrome type 1.\",\n      \"evidence\": \"Genetic analysis of Griscelli patient mutations with epistasis across MYO5A, RAB27A, and MLPH\",\n      \"pmids\": [\"12897212\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of the tail-MLPH-RAB27A interface not defined\", \"Mechanism of F-exon regulation of cargo binding unresolved\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Defined the cellular boundary of MYO5A function by showing it drives peripheral melanosome accumulation but is dispensable for melanosome transfer to keratinocytes, and placed the dsu suppressor in a parallel pathway.\",\n      \"evidence\": \"Dilute (Myo5a-deficient) mouse melanosome distribution analysis with dsu genetic epistasis\",\n      \"pmids\": [\"15550542\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular identity and mechanism of the dsu pathway not established here\", \"Does not address neuronal cargo\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Showed the globular tail domain is an autonomously folded, structurally tractable module, enabling structural study of cargo recognition.\",\n      \"evidence\": \"Expression, purification, crystallization, and 2.5 A diffraction of the human MYO5A globular tail\",\n      \"pmids\": [\"24192353\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structure solved or deposited in this report\", \"No functional or cargo-bound complex structure\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Extended MYO5A function into neuronal organelle homeostasis by linking its loss to impaired somatodendritic organelle transport and downstream neurochemical pathology in dopaminergic neurons.\",\n      \"evidence\": \"Spontaneous recessive Myo5a mutant rats with biochemical assays for protein phosphorylation, aldehyde dehydrogenase activity, and mitochondrial respiratory complex activity\",\n      \"pmids\": [\"29217155\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Alpha-synuclein/tau and DOPAL changes are secondary consequences with undefined causal chain\", \"Single lab, single model\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Confirmed by independent loss-of-function models that reduced full-length MYO5A protein directly causes deficient melanosome transport, and that truncating MYO5A mutations phenocopy Griscelli syndrome type 1 across mammals.\",\n      \"evidence\": \"Loss-of-function mutant mice (genome/RNA sequencing, protein quantification, melanosome transport) and a Dachshund frameshift variant with co-segregation and histopathology\",\n      \"pmids\": [\"33715225\", \"34680875\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Does not add new molecular mechanism beyond confirming motor requirement\", \"Conservation inferred phenotypically, not biochemically\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Connected MYO5A to early endosomal trafficking and mitochondrial homeostasis by identifying a direct MYO5A-ANKFY1 (RAB5A effector) interaction and showing cerebellar developmental and mitochondrial defects on MYO5A loss.\",\n      \"evidence\": \"Loss-of-function mutant mice with mass spectrometry of cerebellar extracts, PAX6 immunofluorescence, co-immunoprecipitation (MYO5A-ANKFY1), and primary neuron morphology\",\n      \"pmids\": [\"40022605\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"MYO5A-ANKFY1 interaction from single Co-IP, not reciprocally validated or reconstituted\", \"Causal link between endosomal trafficking and mitochondrial elongation not established\", \"Single lab, not yet replicated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How MYO5A motor activity is coordinated and regulated across its distinct cargo systems (melanosomes, SER vesicles, early endosomes) and how cargo loss propagates to mitochondrial and neurochemical pathology remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No cargo-bound structural model of the tail-receptor complexes\", \"Mechanism linking organelle transport defects to alpha-synuclein/tau pathology undefined\", \"Regulation of cargo selection between melanocyte and neuronal contexts unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003774\", \"supporting_discovery_ids\": [0, 2, 3]},\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [5]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9609507\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [2, 5]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"RAB27A\", \"MLPH\", \"ANKFY1\", \"RAB5A\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}