{"gene":"ZMYND10","run_date":"2026-04-28T23:00:24","timeline":{"discoveries":[{"year":2013,"finding":"ZMYND10 protein physically interacts with LRRC6 via the LRRC6 CS domain and the ZMYND10 C-terminal domain; certain disease-causing mutations in either protein abrogate this interaction. Both proteins colocalize with centriole markers SAS6 and PCM1 in the cytoplasm.","method":"Co-immunoprecipitation, domain mapping with mutants, immunofluorescence colocalization with centriole markers SAS6/PCM1","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP with domain-level mutagenesis, replicated across two independent papers in same year","pmids":["23891469","23891471"],"is_preprint":false},{"year":2013,"finding":"Loss of ZMYND10 function (mutations in PCD patients, knockdown in zebrafish and Xenopus, Drosophila P-element silencing) causes absence of both inner dynein arms (IDA) and outer dynein arms (ODA) from cilia/flagella, leading to complete ciliary immotility, laterality defects, and male sterility. ZMYND10 is localized primarily to the cytoplasm.","method":"Patient mutation analysis, zebrafish morpholino knockdown (ciliary paralysis, cystic kidneys, otolith defects), Xenopus knockdown, Drosophila P-element gene silencing (IDA/ODA loss by EM, proprioception deficits, sterility), immunofluorescence","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal model organisms, ultrastructural (EM) validation, replicated in two independent papers","pmids":["23891469","23891471"],"is_preprint":false},{"year":2018,"finding":"ZMYND10 acts as a co-chaperone that confers specificity of the FKBP8-HSP90 chaperone complex toward axonemal dynein heavy chain clients. Loss of ZMYND10 perturbs chaperoning of axonemal dynein heavy chains and triggers broader degradation of dynein motor subunits. Pharmacological inhibition of FKBP8 phenocopies the dynein motor instability seen in ZMYND10-deficient airway cells. Human disease-causing ZMYND10 variants disrupt its ability to act as an FKBP8-HSP90 co-chaperone.","method":"Mouse knockout genetics, quantitative proteomics, pharmacological FKBP8 inhibition, imaging, co-chaperone functional assays with disease variants","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1-2 — mouse KO combined with quantitative proteomics, pharmacological phenocopy, and functional validation of disease variants in one study","pmids":["29916806"],"is_preprint":false},{"year":2018,"finding":"ZMYND10 interacts with ODA intermediate chain components and cytoplasmic pre-assembly factors including LRRC6, DYX1C1, and C21ORF59. ZMYND10 stabilizes DNAI1 (ODA intermediate chain 1), which in turn stabilizes DNAI2. Loss of ZMYND10 in Zmynd10-/- mice causes absence of IDA and ODA despite normal 9+2 axoneme structure and normal cilia number.","method":"Co-immunoprecipitation, Zmynd10-/- mouse knockout, Western blot stability assays with co-expression experiments, transmission electron microscopy","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, KO mouse with EM ultrastructural phenotype, co-expression protein stability hierarchy established with multiple subunits","pmids":["29601588"],"is_preprint":false},{"year":2017,"finding":"In medaka fish, zmynd10 knockdown causes loss of outer dynein arms (ODA) and ciliary immotility; the C-terminal MYND-type zinc finger domain is important for function but an additional functional domain also exists, as a C-terminal truncation retaining no zf-MYND is still partially functional. Adult zmynd10 TALEN knockout mutants display sperm dysmotility, scoliosis, and progressive polycystic kidney.","method":"Morpholino knockdown, TALEN knockout in medaka, transmission electron microscopy (ODA loss), rescue experiments with truncation mutants","journal":"Developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 — EM ultrastructural validation and domain rescue in a single lab","pmids":["28823919"],"is_preprint":false},{"year":2020,"finding":"In Paramecium tetraurelia, RNAi depletion of ZMYND10 causes severe ciliary defects and abnormal localization of the intraflagellar transport protein IFT43 along cilia, indicating a role in regulating IFT in addition to dynein arm assembly.","method":"RNAi knockdown, immunofluorescence localization of IFT43","journal":"European journal of protistology","confidence":"Low","confidence_rationale":"Tier 3 — single model organism (Paramecium), single lab, ortholog relevance uncertain","pmids":["33279757"],"is_preprint":false},{"year":2020,"finding":"CRISPR/Cas9 knockout of zmynd10 in zebrafish recapitulates scoliosis in viable adult fish, linking ZMYND10 function to spinal curvature consistent with ciliary dysmotility causing cerebrospinal fluid flow defects.","method":"CRISPR/Cas9 targeted knockout in zebrafish, morphological phenotype scoring in adults","journal":"Frontiers in cell and developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 — CRISPR KO in vivo with clear phenotype, but single lab and limited mechanistic follow-up","pmids":["33251213"],"is_preprint":false},{"year":2019,"finding":"ZMYND10 enhances expression of miR145-5p in breast cancer cells, which suppresses NEDD9 protein by targeting the 3'-UTR of NEDD9 mRNA. Ectopic ZMYND10 expression induces apoptosis and suppresses cell growth, migration, invasion, and xenograft tumor growth.","method":"Ectopic expression in breast cancer cell lines, luciferase 3'-UTR reporter assay, in vivo xenograft assay","journal":"Clinical epigenetics","confidence":"Medium","confidence_rationale":"Tier 3 — functional assays with luciferase reporter validation, single lab","pmids":["31801619"],"is_preprint":false},{"year":2012,"finding":"BLU/ZMYND10 directly interacts with sMEK1 (regulatory subunit of protein phosphatase 4) via its N-terminal domain binding to the C-terminal domain of sMEK1, and this interaction induces pro-apoptotic activity and increases sMEK1 expression.","method":"Co-immunoprecipitation, domain-mapping experiments, apoptosis assays","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 3 — Co-IP with domain mapping, single lab, functional apoptosis readout","pmids":["22349239"],"is_preprint":false},{"year":2012,"finding":"Re-expression of BLU/ZMYND10 in nasopharyngeal carcinoma cells arrests cell cycle at G1 phase, downregulates JNK and cyclin D1 promoter activities, and inhibits c-Jun phosphorylation, inhibiting clonogenic growth.","method":"Adenoviral re-expression, flow cytometry cell cycle analysis, reporter gene assay for JNK/cyclin D1, immunoblotting for phospho-c-Jun","journal":"BMC cancer","confidence":"Medium","confidence_rationale":"Tier 3 — multiple functional readouts in a single lab, no direct protein-protein interaction validation","pmids":["22727408"],"is_preprint":false},{"year":2006,"finding":"Re-expression of BLU/ZMYND10 in NPC cells suppresses tumor formation in nude mice in vivo, and doxycycline-mediated downregulation of ZMYND10 in tumor-suppressive clones restores tumor formation, providing functional evidence for ZMYND10 as a tumor suppressor.","method":"Tetracycline-regulated gene inactivation test (GIT), nude mouse xenograft assay","journal":"International journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 — inducible in vivo loss-of-function rescue experiment, but single lab","pmids":["16929489"],"is_preprint":false},{"year":2014,"finding":"BLU/ZMYND10 overexpression in NPC cells suppresses VEGF165, VEGF189, and TSP1 expression at RNA and protein levels, reduces secreted VEGF, inhibits cellular invasion, migration, and tube formation, and exerts anti-angiogenic activity in vivo in matrigel plug assays.","method":"Stable transfection, PCR array, VEGF ELISA, tube formation assay, matrigel plug in vivo angiogenesis assay, nude mouse xenograft","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 3 — multiple functional assays in vitro and in vivo, single lab, mechanistic link between ZMYND10 and VEGF regulation not molecularly resolved","pmids":["25347745"],"is_preprint":false},{"year":2025,"finding":"Zmynd10 knockdown in mouse ependymal cells (mEPCs) reduces ciliary density and downregulates E2f4 and Deup1 expression; Zmynd10 activates the E2f4 promoter transcriptionally, driving the E2f4-Deup1 axis required for centriole amplification and multiciliogenesis.","method":"shRNA knockdown in mEPCs, RT-qPCR, Western blot, luciferase promoter assay for E2f4","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 3 — promoter reporter assay plus KD phenotype, single lab, novel finding","pmids":["41413096"],"is_preprint":false},{"year":2018,"finding":"BLU/ZMYND10 inhibits ERK signaling by reducing ERK substrate phosphorylation, inhibiting Elk reporter activity, and blocking cyclin D1 (CCND1) promoter activity; HRAS V12G-activated ERK and cyclin D1/B1 promoter activities are antagonized by BLU, arresting cells in G1 and reducing G2/M population.","method":"Adenoviral re-expression in NPC cells and xenografts, phosphorylation assays, Elk reporter assay, CCND1/CCNB1 promoter reporter with co-transfection of RAS V12G, FACS cell cycle analysis","journal":"International journal of clinical and experimental pathology","confidence":"Low","confidence_rationale":"Tier 3 — reporter assays with single lab, no direct protein interaction validated","pmids":["31938097"],"is_preprint":false}],"current_model":"ZMYND10 is a cytoplasmic co-chaperone that confers specificity of the FKBP8-HSP90 chaperone complex toward axonemal dynein heavy chain clients, stabilizes intermediate chain proteins (particularly DNAI1) during cytoplasmic pre-assembly of inner and outer dynein arms, and physically interacts with LRRC6 and other dynein assembly factors; loss of ZMYND10 causes failure of dynein arm assembly onto the axoneme, resulting in primary ciliary dyskinesia with complete ciliary immotility, laterality defects, and male infertility, while in cancer contexts ZMYND10 also functions as a tumor suppressor by modulating JNK/ERK-cyclin D1 signaling, the miR145-5p/NEDD9 axis, and anti-angiogenic pathways."},"narrative":{"teleology":[{"year":2006,"claim":"ZMYND10 was first functionally validated as a bona fide tumor suppressor: inducible silencing of ZMYND10 in tumor-suppressive NPC clones restored tumorigenicity in nude mice, establishing that ZMYND10 expression is both necessary and sufficient for tumor suppression in this context.","evidence":"Tetracycline-regulated gene inactivation test with nude mouse xenografts of NPC cells","pmids":["16929489"],"confidence":"Medium","gaps":["Molecular target or signaling pathway mediating tumor suppression not identified","Single cancer type tested"]},{"year":2012,"claim":"The tumor-suppressive mechanism was linked to specific signaling pathways: ZMYND10 re-expression arrested NPC cells in G1 by downregulating JNK activity and cyclin D1 promoter activity, and separately interacted with sMEK1 (PP4 regulatory subunit) to promote apoptosis, defining candidate effector pathways.","evidence":"Reporter assays for JNK/cyclin D1, Co-IP with domain mapping for sMEK1, flow cytometry in NPC cells","pmids":["22727408","22349239"],"confidence":"Medium","gaps":["Whether JNK inhibition and sMEK1 interaction operate in the same or parallel pathways is unclear","No direct enzymatic mechanism linking ZMYND10 to phosphatase activity"]},{"year":2013,"claim":"ZMYND10 was identified as a ciliary disease gene: patient mutations, combined with loss-of-function in zebrafish, Xenopus, and Drosophila, established that ZMYND10 is required for assembly of both IDA and ODA onto motile cilia, and that it physically interacts with the dynein assembly factor LRRC6 at cytoplasmic centriolar satellites.","evidence":"Human PCD patient genetics, morpholino knockdown in zebrafish/Xenopus, Drosophila P-element silencing with EM ultrastructure, reciprocal Co-IP with domain mutagenesis, colocalization with SAS6/PCM1","pmids":["23891469","23891471"],"confidence":"High","gaps":["Biochemical mechanism of ZMYND10 in dynein arm pre-assembly not resolved","Whether ZMYND10 acts catalytically or as a scaffold unknown"]},{"year":2014,"claim":"ZMYND10 tumor-suppressive activity was extended to include anti-angiogenic function: ZMYND10 overexpression suppressed VEGF isoforms and inhibited endothelial tube formation both in vitro and in vivo, revealing a non-ciliary effector axis.","evidence":"PCR array, VEGF ELISA, tube formation assay, matrigel plug angiogenesis assay in NPC models","pmids":["25347745"],"confidence":"Medium","gaps":["Direct molecular mechanism connecting ZMYND10 to VEGF transcriptional regulation not identified","Whether anti-angiogenic and cell-cycle arrest functions are coupled is unknown"]},{"year":2017,"claim":"Domain analysis in medaka revealed that the C-terminal MYND zinc finger domain is important but not solely sufficient for ciliary function, as a truncation lacking the MYND domain retained partial activity, indicating an additional functional region.","evidence":"Morpholino knockdown and TALEN knockout in medaka with EM and rescue by truncation mutants","pmids":["28823919"],"confidence":"Medium","gaps":["Identity of the second functional domain not determined","Structure–function relationship for human ZMYND10 not directly tested"]},{"year":2018,"claim":"The core biochemical mechanism was resolved: ZMYND10 acts as a co-chaperone that directs the FKBP8–HSP90 complex toward axonemal dynein heavy chain clients, stabilizes DNAI1 which in turn stabilizes DNAI2, and interacts with a network of cytoplasmic dynein pre-assembly factors (LRRC6, DYX1C1, C21ORF59). Pharmacological FKBP8 inhibition phenocopied ZMYND10 loss.","evidence":"Zmynd10 knockout mouse, quantitative proteomics, FKBP8 pharmacological inhibition, Co-IP, Western blot stability assays, EM","pmids":["29916806","29601588"],"confidence":"High","gaps":["Structural basis for ZMYND10–FKBP8 interaction not determined","Whether ZMYND10 also functions in IDA-specific chaperone complexes not resolved","Stoichiometry and assembly order of the ZMYND10-containing pre-assembly complex unknown"]},{"year":2019,"claim":"A distinct tumor-suppressive mechanism was uncovered in breast cancer: ZMYND10 upregulates miR-145-5p, which directly targets the NEDD9 3′-UTR to suppress invasion and tumor growth, expanding the oncology-relevant effector repertoire beyond JNK/ERK signaling.","evidence":"Ectopic expression in breast cancer lines, luciferase 3′-UTR reporter, xenograft assay","pmids":["31801619"],"confidence":"Medium","gaps":["Mechanism by which ZMYND10 induces miR-145-5p expression unknown","Relevance of miR-145-5p/NEDD9 axis to ciliated cell biology not addressed"]},{"year":2025,"claim":"ZMYND10 was found to transcriptionally activate the E2f4 promoter, driving the E2f4–Deup1 axis required for centriole amplification during multiciliogenesis, revealing a role upstream of centriole biogenesis distinct from its dynein chaperoning function.","evidence":"shRNA knockdown in mouse ependymal cells, luciferase E2f4 promoter assay, RT-qPCR, Western blot","pmids":["41413096"],"confidence":"Medium","gaps":["Whether ZMYND10 binds the E2f4 promoter directly or via a cofactor is not resolved","Relationship between E2f4 transcriptional activation and dynein co-chaperone function unclear","Not yet replicated in other multiciliated cell types"]},{"year":null,"claim":"Key unresolved questions include the structural basis for ZMYND10's interaction with FKBP8 and dynein heavy chains, whether its transcriptional regulatory activities (E2f4, miR-145-5p) require the MYND zinc finger domain, and how its ciliary and tumor-suppressive functions are mechanistically related or independent.","evidence":"","pmids":[],"confidence":"High","gaps":["No crystal or cryo-EM structure of ZMYND10 or its complexes","Whether ciliary and tumor-suppressive functions share common interactors is untested","No reconstituted in vitro chaperone assay with purified components"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0044183","term_label":"protein folding chaperone","supporting_discovery_ids":[2]},{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[9,12]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,1]},{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[0]}],"pathway":[{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[1,2,3,4]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[9,13]}],"complexes":["FKBP8-HSP90 co-chaperone complex"],"partners":["LRRC6","FKBP8","DNAI1","DYX1C1","C21ORF59","SMEK1"],"other_free_text":[]},"mechanistic_narrative":"ZMYND10 is a cytoplasmic co-chaperone essential for the pre-assembly of inner and outer dynein arms (IDA/ODA) in motile cilia, with an additional role as a tumor suppressor in epithelial cancers. ZMYND10 confers substrate specificity to the FKBP8–HSP90 chaperone complex toward axonemal dynein heavy chain clients, stabilizes the ODA intermediate chain DNAI1, and physically interacts with dynein assembly factors LRRC6, DYX1C1, and C21ORF59 at cytoplasmic centriolar satellites [PMID:29916806, PMID:29601588, PMID:23891469]. Loss-of-function mutations in ZMYND10 cause primary ciliary dyskinesia characterized by complete ciliary immotility, situs inversus, and male infertility, as demonstrated in human patients and validated across zebrafish, Xenopus, Drosophila, medaka, and mouse models [PMID:23891471, PMID:28823919]. In cancer cells, ZMYND10 re-expression suppresses tumor growth by inhibiting JNK/ERK–cyclin D1 signaling and VEGF-mediated angiogenesis, and by upregulating miR-145-5p to target NEDD9 [PMID:22727408, PMID:25347745, PMID:31801619, PMID:16929489]."},"prefetch_data":{"uniprot":{"accession":"O75800","full_name":"Zinc finger MYND domain-containing protein 10","aliases":["Protein BLu"],"length_aa":440,"mass_kda":50.3,"function":"Plays a role in axonemal structure organization and motility (PubMed:23891469, PubMed:23891471). Involved in axonemal pre-assembly of inner and outer dynein arms (IDA and ODA, respectively) for proper axoneme building for cilia motility (By similarity). May act by indirectly regulating transcription of dynein proteins (By similarity)","subcellular_location":"Cytoplasm; Cytoplasm, cytoskeleton, microtubule organizing center, centrosome, centriolar satellite; Apical cell membrane; Dynein axonemal particle","url":"https://www.uniprot.org/uniprotkb/O75800/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/ZMYND10","classification":"Not Classified","n_dependent_lines":7,"n_total_lines":1208,"dependency_fraction":0.005794701986754967},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/ZMYND10","total_profiled":1310},"omim":[{"mim_id":"615444","title":"CILIARY DYSKINESIA, PRIMARY, 22; CILD22","url":"https://www.omim.org/entry/615444"},{"mim_id":"614935","title":"CILIARY DYSKINESIA, PRIMARY, 19; CILD19","url":"https://www.omim.org/entry/614935"},{"mim_id":"614930","title":"DYNEIN, AXONEMAL, ASSEMBLY FACTOR 11; DNAAF11","url":"https://www.omim.org/entry/614930"},{"mim_id":"607070","title":"ZINC FINGER MYND DOMAIN-CONTAINING PROTEIN 10; ZMYND10","url":"https://www.omim.org/entry/607070"},{"mim_id":"244400","title":"CILIARY DYSKINESIA, PRIMARY, 1; CILD1","url":"https://www.omim.org/entry/244400"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Plasma membrane","reliability":"Approved"},{"location":"Basal body","reliability":"Approved"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"choroid plexus","ntpm":80.2},{"tissue":"fallopian tube","ntpm":113.1},{"tissue":"testis","ntpm":226.5}],"url":"https://www.proteinatlas.org/search/ZMYND10"},"hgnc":{"alias_symbol":["BLU","CILD22","DNAAF7"],"prev_symbol":[]},"alphafold":{"accession":"O75800","domains":[{"cath_id":"-","chopping":"2-155_168-200_334-390","consensus_level":"medium","plddt":90.0257,"start":2,"end":390},{"cath_id":"1.20.1050","chopping":"204-331","consensus_level":"medium","plddt":91.8342,"start":204,"end":331}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O75800","model_url":"https://alphafold.ebi.ac.uk/files/AF-O75800-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O75800-F1-predicted_aligned_error_v6.png","plddt_mean":88.75},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=ZMYND10","jax_strain_url":"https://www.jax.org/strain/search?query=ZMYND10"},"sequence":{"accession":"O75800","fasta_url":"https://rest.uniprot.org/uniprotkb/O75800.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O75800/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O75800"}},"corpus_meta":[{"pmid":"30257958","id":"PMC_30257958","title":"Landscape 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Both proteins colocalize with centriole markers SAS6 and PCM1 in the cytoplasm.\",\n      \"method\": \"Co-immunoprecipitation, domain mapping with mutants, immunofluorescence colocalization with centriole markers SAS6/PCM1\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP with domain-level mutagenesis, replicated across two independent papers in same year\",\n      \"pmids\": [\"23891469\", \"23891471\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Loss of ZMYND10 function (mutations in PCD patients, knockdown in zebrafish and Xenopus, Drosophila P-element silencing) causes absence of both inner dynein arms (IDA) and outer dynein arms (ODA) from cilia/flagella, leading to complete ciliary immotility, laterality defects, and male sterility. ZMYND10 is localized primarily to the cytoplasm.\",\n      \"method\": \"Patient mutation analysis, zebrafish morpholino knockdown (ciliary paralysis, cystic kidneys, otolith defects), Xenopus knockdown, Drosophila P-element gene silencing (IDA/ODA loss by EM, proprioception deficits, sterility), immunofluorescence\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal model organisms, ultrastructural (EM) validation, replicated in two independent papers\",\n      \"pmids\": [\"23891469\", \"23891471\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"ZMYND10 acts as a co-chaperone that confers specificity of the FKBP8-HSP90 chaperone complex toward axonemal dynein heavy chain clients. Loss of ZMYND10 perturbs chaperoning of axonemal dynein heavy chains and triggers broader degradation of dynein motor subunits. Pharmacological inhibition of FKBP8 phenocopies the dynein motor instability seen in ZMYND10-deficient airway cells. Human disease-causing ZMYND10 variants disrupt its ability to act as an FKBP8-HSP90 co-chaperone.\",\n      \"method\": \"Mouse knockout genetics, quantitative proteomics, pharmacological FKBP8 inhibition, imaging, co-chaperone functional assays with disease variants\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — mouse KO combined with quantitative proteomics, pharmacological phenocopy, and functional validation of disease variants in one study\",\n      \"pmids\": [\"29916806\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"ZMYND10 interacts with ODA intermediate chain components and cytoplasmic pre-assembly factors including LRRC6, DYX1C1, and C21ORF59. ZMYND10 stabilizes DNAI1 (ODA intermediate chain 1), which in turn stabilizes DNAI2. Loss of ZMYND10 in Zmynd10-/- mice causes absence of IDA and ODA despite normal 9+2 axoneme structure and normal cilia number.\",\n      \"method\": \"Co-immunoprecipitation, Zmynd10-/- mouse knockout, Western blot stability assays with co-expression experiments, transmission electron microscopy\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, KO mouse with EM ultrastructural phenotype, co-expression protein stability hierarchy established with multiple subunits\",\n      \"pmids\": [\"29601588\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"In medaka fish, zmynd10 knockdown causes loss of outer dynein arms (ODA) and ciliary immotility; the C-terminal MYND-type zinc finger domain is important for function but an additional functional domain also exists, as a C-terminal truncation retaining no zf-MYND is still partially functional. Adult zmynd10 TALEN knockout mutants display sperm dysmotility, scoliosis, and progressive polycystic kidney.\",\n      \"method\": \"Morpholino knockdown, TALEN knockout in medaka, transmission electron microscopy (ODA loss), rescue experiments with truncation mutants\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — EM ultrastructural validation and domain rescue in a single lab\",\n      \"pmids\": [\"28823919\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"In Paramecium tetraurelia, RNAi depletion of ZMYND10 causes severe ciliary defects and abnormal localization of the intraflagellar transport protein IFT43 along cilia, indicating a role in regulating IFT in addition to dynein arm assembly.\",\n      \"method\": \"RNAi knockdown, immunofluorescence localization of IFT43\",\n      \"journal\": \"European journal of protistology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single model organism (Paramecium), single lab, ortholog relevance uncertain\",\n      \"pmids\": [\"33279757\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"CRISPR/Cas9 knockout of zmynd10 in zebrafish recapitulates scoliosis in viable adult fish, linking ZMYND10 function to spinal curvature consistent with ciliary dysmotility causing cerebrospinal fluid flow defects.\",\n      \"method\": \"CRISPR/Cas9 targeted knockout in zebrafish, morphological phenotype scoring in adults\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — CRISPR KO in vivo with clear phenotype, but single lab and limited mechanistic follow-up\",\n      \"pmids\": [\"33251213\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ZMYND10 enhances expression of miR145-5p in breast cancer cells, which suppresses NEDD9 protein by targeting the 3'-UTR of NEDD9 mRNA. Ectopic ZMYND10 expression induces apoptosis and suppresses cell growth, migration, invasion, and xenograft tumor growth.\",\n      \"method\": \"Ectopic expression in breast cancer cell lines, luciferase 3'-UTR reporter assay, in vivo xenograft assay\",\n      \"journal\": \"Clinical epigenetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — functional assays with luciferase reporter validation, single lab\",\n      \"pmids\": [\"31801619\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"BLU/ZMYND10 directly interacts with sMEK1 (regulatory subunit of protein phosphatase 4) via its N-terminal domain binding to the C-terminal domain of sMEK1, and this interaction induces pro-apoptotic activity and increases sMEK1 expression.\",\n      \"method\": \"Co-immunoprecipitation, domain-mapping experiments, apoptosis assays\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — Co-IP with domain mapping, single lab, functional apoptosis readout\",\n      \"pmids\": [\"22349239\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Re-expression of BLU/ZMYND10 in nasopharyngeal carcinoma cells arrests cell cycle at G1 phase, downregulates JNK and cyclin D1 promoter activities, and inhibits c-Jun phosphorylation, inhibiting clonogenic growth.\",\n      \"method\": \"Adenoviral re-expression, flow cytometry cell cycle analysis, reporter gene assay for JNK/cyclin D1, immunoblotting for phospho-c-Jun\",\n      \"journal\": \"BMC cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — multiple functional readouts in a single lab, no direct protein-protein interaction validation\",\n      \"pmids\": [\"22727408\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Re-expression of BLU/ZMYND10 in NPC cells suppresses tumor formation in nude mice in vivo, and doxycycline-mediated downregulation of ZMYND10 in tumor-suppressive clones restores tumor formation, providing functional evidence for ZMYND10 as a tumor suppressor.\",\n      \"method\": \"Tetracycline-regulated gene inactivation test (GIT), nude mouse xenograft assay\",\n      \"journal\": \"International journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — inducible in vivo loss-of-function rescue experiment, but single lab\",\n      \"pmids\": [\"16929489\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"BLU/ZMYND10 overexpression in NPC cells suppresses VEGF165, VEGF189, and TSP1 expression at RNA and protein levels, reduces secreted VEGF, inhibits cellular invasion, migration, and tube formation, and exerts anti-angiogenic activity in vivo in matrigel plug assays.\",\n      \"method\": \"Stable transfection, PCR array, VEGF ELISA, tube formation assay, matrigel plug in vivo angiogenesis assay, nude mouse xenograft\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — multiple functional assays in vitro and in vivo, single lab, mechanistic link between ZMYND10 and VEGF regulation not molecularly resolved\",\n      \"pmids\": [\"25347745\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Zmynd10 knockdown in mouse ependymal cells (mEPCs) reduces ciliary density and downregulates E2f4 and Deup1 expression; Zmynd10 activates the E2f4 promoter transcriptionally, driving the E2f4-Deup1 axis required for centriole amplification and multiciliogenesis.\",\n      \"method\": \"shRNA knockdown in mEPCs, RT-qPCR, Western blot, luciferase promoter assay for E2f4\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — promoter reporter assay plus KD phenotype, single lab, novel finding\",\n      \"pmids\": [\"41413096\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"BLU/ZMYND10 inhibits ERK signaling by reducing ERK substrate phosphorylation, inhibiting Elk reporter activity, and blocking cyclin D1 (CCND1) promoter activity; HRAS V12G-activated ERK and cyclin D1/B1 promoter activities are antagonized by BLU, arresting cells in G1 and reducing G2/M population.\",\n      \"method\": \"Adenoviral re-expression in NPC cells and xenografts, phosphorylation assays, Elk reporter assay, CCND1/CCNB1 promoter reporter with co-transfection of RAS V12G, FACS cell cycle analysis\",\n      \"journal\": \"International journal of clinical and experimental pathology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — reporter assays with single lab, no direct protein interaction validated\",\n      \"pmids\": [\"31938097\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"ZMYND10 is a cytoplasmic co-chaperone that confers specificity of the FKBP8-HSP90 chaperone complex toward axonemal dynein heavy chain clients, stabilizes intermediate chain proteins (particularly DNAI1) during cytoplasmic pre-assembly of inner and outer dynein arms, and physically interacts with LRRC6 and other dynein assembly factors; loss of ZMYND10 causes failure of dynein arm assembly onto the axoneme, resulting in primary ciliary dyskinesia with complete ciliary immotility, laterality defects, and male infertility, while in cancer contexts ZMYND10 also functions as a tumor suppressor by modulating JNK/ERK-cyclin D1 signaling, the miR145-5p/NEDD9 axis, and anti-angiogenic pathways.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"ZMYND10 is a cytoplasmic co-chaperone essential for the pre-assembly of inner and outer dynein arms (IDA/ODA) in motile cilia, with an additional role as a tumor suppressor in epithelial cancers. ZMYND10 confers substrate specificity to the FKBP8–HSP90 chaperone complex toward axonemal dynein heavy chain clients, stabilizes the ODA intermediate chain DNAI1, and physically interacts with dynein assembly factors LRRC6, DYX1C1, and C21ORF59 at cytoplasmic centriolar satellites [PMID:29916806, PMID:29601588, PMID:23891469]. Loss-of-function mutations in ZMYND10 cause primary ciliary dyskinesia characterized by complete ciliary immotility, situs inversus, and male infertility, as demonstrated in human patients and validated across zebrafish, Xenopus, Drosophila, medaka, and mouse models [PMID:23891471, PMID:28823919]. In cancer cells, ZMYND10 re-expression suppresses tumor growth by inhibiting JNK/ERK–cyclin D1 signaling and VEGF-mediated angiogenesis, and by upregulating miR-145-5p to target NEDD9 [PMID:22727408, PMID:25347745, PMID:31801619, PMID:16929489].\",\n  \"teleology\": [\n    {\n      \"year\": 2006,\n      \"claim\": \"ZMYND10 was first functionally validated as a bona fide tumor suppressor: inducible silencing of ZMYND10 in tumor-suppressive NPC clones restored tumorigenicity in nude mice, establishing that ZMYND10 expression is both necessary and sufficient for tumor suppression in this context.\",\n      \"evidence\": \"Tetracycline-regulated gene inactivation test with nude mouse xenografts of NPC cells\",\n      \"pmids\": [\"16929489\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular target or signaling pathway mediating tumor suppression not identified\", \"Single cancer type tested\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"The tumor-suppressive mechanism was linked to specific signaling pathways: ZMYND10 re-expression arrested NPC cells in G1 by downregulating JNK activity and cyclin D1 promoter activity, and separately interacted with sMEK1 (PP4 regulatory subunit) to promote apoptosis, defining candidate effector pathways.\",\n      \"evidence\": \"Reporter assays for JNK/cyclin D1, Co-IP with domain mapping for sMEK1, flow cytometry in NPC cells\",\n      \"pmids\": [\"22727408\", \"22349239\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether JNK inhibition and sMEK1 interaction operate in the same or parallel pathways is unclear\", \"No direct enzymatic mechanism linking ZMYND10 to phosphatase activity\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"ZMYND10 was identified as a ciliary disease gene: patient mutations, combined with loss-of-function in zebrafish, Xenopus, and Drosophila, established that ZMYND10 is required for assembly of both IDA and ODA onto motile cilia, and that it physically interacts with the dynein assembly factor LRRC6 at cytoplasmic centriolar satellites.\",\n      \"evidence\": \"Human PCD patient genetics, morpholino knockdown in zebrafish/Xenopus, Drosophila P-element silencing with EM ultrastructure, reciprocal Co-IP with domain mutagenesis, colocalization with SAS6/PCM1\",\n      \"pmids\": [\"23891469\", \"23891471\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Biochemical mechanism of ZMYND10 in dynein arm pre-assembly not resolved\", \"Whether ZMYND10 acts catalytically or as a scaffold unknown\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"ZMYND10 tumor-suppressive activity was extended to include anti-angiogenic function: ZMYND10 overexpression suppressed VEGF isoforms and inhibited endothelial tube formation both in vitro and in vivo, revealing a non-ciliary effector axis.\",\n      \"evidence\": \"PCR array, VEGF ELISA, tube formation assay, matrigel plug angiogenesis assay in NPC models\",\n      \"pmids\": [\"25347745\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular mechanism connecting ZMYND10 to VEGF transcriptional regulation not identified\", \"Whether anti-angiogenic and cell-cycle arrest functions are coupled is unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Domain analysis in medaka revealed that the C-terminal MYND zinc finger domain is important but not solely sufficient for ciliary function, as a truncation lacking the MYND domain retained partial activity, indicating an additional functional region.\",\n      \"evidence\": \"Morpholino knockdown and TALEN knockout in medaka with EM and rescue by truncation mutants\",\n      \"pmids\": [\"28823919\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Identity of the second functional domain not determined\", \"Structure–function relationship for human ZMYND10 not directly tested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"The core biochemical mechanism was resolved: ZMYND10 acts as a co-chaperone that directs the FKBP8–HSP90 complex toward axonemal dynein heavy chain clients, stabilizes DNAI1 which in turn stabilizes DNAI2, and interacts with a network of cytoplasmic dynein pre-assembly factors (LRRC6, DYX1C1, C21ORF59). Pharmacological FKBP8 inhibition phenocopied ZMYND10 loss.\",\n      \"evidence\": \"Zmynd10 knockout mouse, quantitative proteomics, FKBP8 pharmacological inhibition, Co-IP, Western blot stability assays, EM\",\n      \"pmids\": [\"29916806\", \"29601588\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for ZMYND10–FKBP8 interaction not determined\", \"Whether ZMYND10 also functions in IDA-specific chaperone complexes not resolved\", \"Stoichiometry and assembly order of the ZMYND10-containing pre-assembly complex unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"A distinct tumor-suppressive mechanism was uncovered in breast cancer: ZMYND10 upregulates miR-145-5p, which directly targets the NEDD9 3′-UTR to suppress invasion and tumor growth, expanding the oncology-relevant effector repertoire beyond JNK/ERK signaling.\",\n      \"evidence\": \"Ectopic expression in breast cancer lines, luciferase 3′-UTR reporter, xenograft assay\",\n      \"pmids\": [\"31801619\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which ZMYND10 induces miR-145-5p expression unknown\", \"Relevance of miR-145-5p/NEDD9 axis to ciliated cell biology not addressed\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"ZMYND10 was found to transcriptionally activate the E2f4 promoter, driving the E2f4–Deup1 axis required for centriole amplification during multiciliogenesis, revealing a role upstream of centriole biogenesis distinct from its dynein chaperoning function.\",\n      \"evidence\": \"shRNA knockdown in mouse ependymal cells, luciferase E2f4 promoter assay, RT-qPCR, Western blot\",\n      \"pmids\": [\"41413096\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether ZMYND10 binds the E2f4 promoter directly or via a cofactor is not resolved\", \"Relationship between E2f4 transcriptional activation and dynein co-chaperone function unclear\", \"Not yet replicated in other multiciliated cell types\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the structural basis for ZMYND10's interaction with FKBP8 and dynein heavy chains, whether its transcriptional regulatory activities (E2f4, miR-145-5p) require the MYND zinc finger domain, and how its ciliary and tumor-suppressive functions are mechanistically related or independent.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No crystal or cryo-EM structure of ZMYND10 or its complexes\", \"Whether ciliary and tumor-suppressive functions share common interactors is untested\", \"No reconstituted in vitro chaperone assay with purified components\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0044183\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [9, 12]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [1, 2, 3, 4]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [9, 13]}\n    ],\n    \"complexes\": [\n      \"FKBP8-HSP90 co-chaperone complex\"\n    ],\n    \"partners\": [\n      \"LRRC6\",\n      \"FKBP8\",\n      \"DNAI1\",\n      \"DYX1C1\",\n      \"C21ORF59\",\n      \"SMEK1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}