{"gene":"ZMYND10","run_date":"2026-06-11T09:02:06","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. Loss of ZMYND10 results in absence of axonemal dynein components DNAH5 and DNALI1 from respiratory cilia.","method":"Co-immunoprecipitation, immunofluorescence colocalization with centriole markers, whole-exome resequencing, zebrafish zmynd10 morpholino knockdown (ciliary paralysis, cystic kidneys, otolith defects), Xenopus knockdown (ciliogenesis defect)","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP defining interaction domains, multiple model organism knockdowns, replicated across two independent papers in the same issue","pmids":["23891469"],"is_preprint":false},{"year":2013,"finding":"ZMYND10 (BLU) is a cytoplasmic protein required for assembly of both inner dynein arms (IDAs) and outer dynein arms (ODAs) in motile cilia/flagella. Loss-of-function mutations cause complete cilia immotility and dual dynein arm loss at the ultrastructural level. The MYND-type zinc finger domain is important for function. Human ZMYND10 interacts with LRRC6 in the cytoplasm.","method":"Biallelic mutation identification in PCD families, immunofluorescence/electron microscopy of ciliary axonemes, Drosophila P-element gene silencing (IDA and ODA defects, proprioception deficit, male sterility), tagged protein localization, Co-IP with LRRC6, missense rescue experiments in Drosophila","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (EM ultrastructure, immunofluorescence, Drosophila genetic model, Co-IP, rescue experiments), replicated independently","pmids":["23891471"],"is_preprint":false},{"year":2018,"finding":"ZMYND10 acts as a novel co-chaperone that confers specificity of the FKBP8-HSP90 chaperone complex towards axonemal dynein heavy chain clients required for cilia motility. Loss of ZMYND10 perturbs chaperoning of axonemal dynein heavy chains, triggering broader degradation of dynein motor subunits. Pharmacological inhibition of FKBP8 phenocopies dynein motor instability associated with ZMYND10 loss. Human disease-causing ZMYND10 variants disrupt its ability to act as an FKBP8-HSP90 co-chaperone.","method":"Mouse genetics (Zmynd10 knockout), quantitative proteomics, imaging, pharmacological FKBP8 inhibition in airway cells, functional analysis of disease-causing variants","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — mouse KO with quantitative proteomics, pharmacological phenocopy, disease variant functional validation; multiple orthogonal methods in one rigorous study","pmids":["29916806"],"is_preprint":false},{"year":2018,"finding":"ZMYND10 stabilizes ODA intermediate chain protein DNAI1 during cytoplasmic pre-assembly of dynein arms; ZMYND10 interacts with ODA components and other dynein assembly factors (LRRC6, DYX1C1, C21ORF59). Stabilization of DNAI1 by ZMYND10 subsequently stabilizes DNAI2. Levels of these co-assembly proteins are significantly reduced in Zmynd10-/- mice. The 9+2 axoneme structure is normal in Zmynd10-/- mice, indicating a specific pre-assembly function rather than structural role.","method":"Zmynd10-/- mouse model, co-immunoprecipitation, co-expression stability assays, immunofluorescence, electron microscopy of cilia","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — KO mouse with defined molecular phenotype, Co-IP interaction mapping, co-expression stability assays with multiple subunits, mechanistic ordering of DNAI1/DNAI2 stabilization","pmids":["29601588"],"is_preprint":false},{"year":2017,"finding":"In medaka fish, zmynd10 is exclusively expressed in cells with motile cilia; morpholino knockdown causes loss of outer dynein arms and ciliary immotility affecting left-right axis determination. The C-terminal MYND-type zinc finger domain is important but not exclusively required for function, as a truncated protein lacking zf-MYND retained partial activity in rescue experiments. Zmynd10 knockout adult fish exhibit sperm dysmotility, scoliosis, and progressive polycystic kidney.","method":"Morpholino knockdown, TALEN knockout, transmission electron microscopy, rescue experiments with truncation mutants, high-speed video microscopy","journal":"Developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — zebrafish/medaka model with EM ultrastructure, domain truncation rescue, single lab","pmids":["28823919"],"is_preprint":false},{"year":2004,"finding":"The BLU (ZMYND10) promoter is activated by environmental stresses such as heat shock and is regulated by the transcription factor E2F. The promoter and first exon are located within a CpG island. Promoter hypermethylation causes silencing, which can be reversed by 5-aza-2'-deoxycytidine treatment. Ectopic BLU expression inhibits colony formation of cancer cells, consistent with tumor suppressor activity.","method":"Promoter reporter assays, methylation-specific PCR, 5-aza-2'-deoxycytidine demethylation, colony formation assay, E2F binding analysis","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — promoter reporter assay, E2F regulation, demethylation rescue, colony formation; single lab but multiple orthogonal methods","pmids":["15122337"],"is_preprint":false},{"year":2006,"finding":"BLU/ZMYND10 functionally suppresses tumor formation in vivo when expressed in NPC cells implanted in nude mice; doxycycline-mediated downregulation of BLU in these tumor-suppressive clones restores tumor formation ability, providing direct causal evidence for its tumor suppressor function.","method":"Gene inactivation test (GIT) with tetracycline-regulated expression system, nude mouse xenograft assay","journal":"International journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — inducible expression system with in vivo tumor suppression reversal, single lab","pmids":["16929489"],"is_preprint":false},{"year":2012,"finding":"BLU (ZMYND10) directly interacts with sMEK1 (a regulatory subunit of protein phosphatase 4) via its N-terminal domain binding to the C-terminal domain of sMEK1. This interaction increases sMEK1 expression and induces pro-apoptotic activity.","method":"Co-immunoprecipitation, domain mapping by deletion constructs, apoptosis assays","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP with domain mapping, functional apoptosis assay; single lab","pmids":["22349239"],"is_preprint":false},{"year":2012,"finding":"BLU/ZMYND10 re-expression in NPC cells inhibits clonogenic growth, arrests cell cycle at G1 phase, downregulates JNK activity, inhibits cyclin D1 promoter activity, and reduces phosphorylation of c-Jun.","method":"Adenoviral BLU re-expression, flow cytometry cell cycle analysis, reporter gene assay for JNK and cyclin D1 promoter activities, immunoblotting for c-Jun phosphorylation","journal":"BMC cancer","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — multiple readouts (cell cycle, JNK signaling, cyclin D1 promoter) in a single lab using re-expression approach","pmids":["22727408"],"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, and inhibits cellular invasion, migration, and tube formation in vitro. In vivo, BLU expression inhibits tumor growth and suppresses angiogenesis in matrigel plug assays.","method":"PCR array, stable transfection, ELISA for secreted VEGF, invasion/migration assay, tube formation assay, nude mouse xenograft and matrigel plug angiogenesis assay","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — multiple in vitro and in vivo assays in single lab; pathway connection to VEGF/angiogenesis established by multiple readouts","pmids":["25347745"],"is_preprint":false},{"year":2018,"finding":"BLU/ZMYND10 inhibits ERK signaling by reducing protein substrate phosphorylation, inhibiting Elk reporter activity, and blocking cyclin D1 (CCND1) promoter activity, thereby arresting cell cycle at G1. BLU antagonizes the effect of HRAS V12G on ERK activation and cyclin D1/B1 promoter activities.","method":"Xenograft tumor injection with BLU-expressing adenovirus, reporter gene co-transfection, phosphorylation immunoblotting, FACS cell cycle analysis","journal":"International journal of clinical and experimental pathology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, reporter gene and immunoblotting only, limited mechanistic depth","pmids":["31938097"],"is_preprint":false},{"year":2015,"finding":"BLU promoter activity is regulated by transcription factor Sp1; methylation of the -39 CpG site in the BLU proximal promoter directly prevents Sp1 binding and reduces transcriptional activity by ~70%. Knockdown of BLU promotes cellular proliferation and colony formation in gastric cancer cells.","method":"Bisulfite sequencing, ChIP, EMSA, luciferase reporter assay, siRNA knockdown, colony formation assay","journal":"International journal of oncology","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — EMSA and ChIP directly demonstrate Sp1 binding loss at methylated site, corroborated by reporter assay; single lab, multiple orthogonal methods","pmids":["26043875"],"is_preprint":false},{"year":2019,"finding":"ZMYND10 suppresses breast cancer tumorigenicity through a miR145-5p/NEDD9 signaling axis: ectopic ZMYND10 expression enhances miR145-5p expression, which suppresses NEDD9 protein by targeting its 3'-UTR, leading to reduced cell migration, invasion, and xenograft tumor growth.","method":"Ectopic expression in breast cancer cell lines, luciferase 3'-UTR reporter assay, migration/invasion assays, xenograft tumor growth in vivo","journal":"Clinical epigenetics","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — luciferase 3'-UTR validation of miR145-5p/NEDD9 link, in vivo xenograft confirmation; single lab","pmids":["31801619"],"is_preprint":false},{"year":2010,"finding":"A CTCF-binding insulator located between the tandem BLU and RASSF1A genes at 3p21.3 creates distinct epigenetic domains, providing a barrier between the two gene loci. In normal cells, distinct methylation and chromatin boundaries are separated by the CTCF binding domains; in cancer cells, these boundaries are lost. Treatment with demethylation reagent or HDAC inhibitor restores CTCF binding and barrier effect.","method":"Gel shift assay (EMSA), ChIP-PCR, methylation-specific oligonucleotide array, bisulfite sequencing, pharmacological treatments","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — EMSA and ChIP directly demonstrate CTCF binding at insulator, bisulfite sequencing defines epigenetic boundaries; single lab","pmids":["20877461"],"is_preprint":false},{"year":2020,"finding":"In zebrafish, CRISPR/Cas9 knockout of zmynd10 recapitulates scoliosis in viable adult fish, and coding variants in zmynd10 identified by whole-exome sequencing are associated with adolescent idiopathic scoliosis susceptibility, linking zmynd10 dynein assembly factor function to spinal curvature.","method":"CRISPR/Cas9 knockout in zebrafish, whole-exome sequencing of AIS patient cohort","journal":"Frontiers in cell and developmental biology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — zebrafish KO phenotype reported but limited mechanistic pathway detail; single lab","pmids":["33251213"],"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, suggesting ZMYND10 is involved in regulating IFT in addition to dynein arm assembly.","method":"RNAi knockdown in Paramecium, immunofluorescence localization of IFT43, swimming behavior assay","journal":"European journal of protistology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single-organism RNAi study, single lab, ciliary IFT localization without direct mechanistic pathway placement","pmids":["33279757"],"is_preprint":false},{"year":2017,"finding":"BLU/ZMYND10 re-expression promotes TRAIL-induced apoptosis in NPC cells by inhibiting the NF-κB pathway, as evidenced by reduced IKKα, p65 NF-κB, and NF-κB-induced anti-apoptotic factors cFLIPL and cIAP2, along with enhanced caspase-8 cleavage.","method":"Recombinant adenoviral BLU infection, NF-κB reporter assay, FACS-based TMRE/annexin V assays, immunoblotting for NF-κB pathway components","journal":"Oncotarget","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, NF-κB reporter and immunoblotting without direct mechanistic link between ZMYND10 and IKK complex","pmids":["28029652"],"is_preprint":false},{"year":2025,"finding":"Zmynd10 drives centriole amplification and multiciliogenesis through transcriptional activation of the E2f4 promoter, which in turn regulates Deup1 expression; knockdown of Zmynd10 in mouse ependymal cells reduces ciliary density and downregulates E2f4 and Deup1 at mRNA and protein levels.","method":"Zmynd10 siRNA knockdown in mouse ependymal cells (mEPCs), E2f4 promoter-luciferase reporter assay, E2f4 siRNA knockdown, RT-qPCR and immunoblotting","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — promoter reporter assay directly links ZMYND10 to E2f4 transcription, epistasis with E2f4 knockdown showing Deup1 dependence; single lab","pmids":["41413096"],"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, physically interacts with LRRC6 and other dynein assembly factors, and additionally drives multiciliogenesis through transcriptional activation of the E2f4-Deup1 pathway; loss-of-function mutations in ZMYND10 cause primary ciliary dyskinesia by preventing proper dynein arm assembly and axonemal targeting."},"narrative":{"mechanistic_narrative":"ZMYND10 is a cytoplasmic factor essential for the pre-assembly of axonemal dynein arms that power motile cilia and flagella, and its loss causes primary ciliary dyskinesia through complete loss of ciliary motility [PMID:23891471, PMID:29916806]. Mechanistically, ZMYND10 acts as a co-chaperone that confers specificity of the FKBP8–HSP90 chaperone complex toward axonemal dynein heavy chain clients; loss of ZMYND10 destabilizes these clients and triggers broader degradation of dynein motor subunits, and pharmacological FKBP8 inhibition phenocopies this instability [PMID:29916806]. During cytoplasmic pre-assembly, ZMYND10 stabilizes the outer dynein arm intermediate chain DNAI1, which in turn stabilizes DNAI2, and it physically associates with dynein assembly factors LRRC6, DYX1C1, and C21ORF59 [PMID:29601588]. The interaction with LRRC6 is mediated by the LRRC6 CS domain and the ZMYND10 C-terminal domain, and disease-causing mutations in either protein abrogate this binding; ZMYND10 colocalizes with centriolar markers and its loss eliminates axonemal DNAH5 and DNALI1 from cilia while leaving the 9+2 axoneme structurally intact, defining a pre-assembly rather than structural role [PMID:23891469, PMID:29601588]. Beyond dynein assembly, ZMYND10 promotes centriole amplification and multiciliogenesis through transcriptional activation of the E2f4 promoter, which regulates Deup1 expression [PMID:41413096]. A separate body of work characterizes ZMYND10/BLU as an epigenetically silenced 3p21.3 tumor suppressor whose re-expression arrests the cell cycle and suppresses tumorigenicity across nasopharyngeal, gastric, and breast cancer models [PMID:15122337, PMID:16929489, PMID:26043875].","teleology":[{"year":2013,"claim":"Established ZMYND10 as a PCD gene and defined its first molecular partnership, answering whether and how a previously uncharacterized protein contributes to cilia motility.","evidence":"Biallelic mutation identification in PCD families, EM ultrastructure showing dual dynein arm loss, reciprocal Co-IP mapping ZMYND10–LRRC6 interaction domains, and model-organism knockdowns (zebrafish, Xenopus, Drosophila)","pmids":["23891469","23891471"],"confidence":"High","gaps":["Did not resolve the biochemical activity of ZMYND10 (chaperone vs structural)","Mechanism by which LRRC6 binding supports dynein assembly unresolved","Did not identify the specific dynein clients stabilized"]},{"year":2018,"claim":"Resolved the biochemical function of ZMYND10 as a co-chaperone and ordered its action on specific dynein subunits, explaining why its loss causes broad dynein motor degradation.","evidence":"Zmynd10 knockout mice with quantitative proteomics, pharmacological FKBP8 inhibition phenocopy, Co-IP interaction mapping, and co-expression stability assays demonstrating DNAI1→DNAI2 stabilization hierarchy","pmids":["29916806","29601588"],"confidence":"High","gaps":["Structural basis of FKBP8–HSP90–ZMYND10–client assembly not determined","How ZMYND10 selects dynein heavy chain clients unknown","Order of recruitment relative to LRRC6/DYX1C1/C21ORF59 not fully resolved"]},{"year":2017,"claim":"Confirmed conserved dynein-assembly function across species and probed the contribution of the MYND zinc finger domain.","evidence":"Medaka morpholino knockdown and TALEN knockout with EM, high-speed video microscopy, and truncation-mutant rescue showing partial activity without zf-MYND","pmids":["28823919"],"confidence":"Medium","gaps":["Domain contributions only partially mapped","Did not define which dynein arms require which domains"]},{"year":2020,"claim":"Extended ZMYND10 ciliary roles beyond dynein assembly, raising the question of involvement in intraflagellar transport and spinal development.","evidence":"Paramecium RNAi with IFT43 localization analysis; zebrafish CRISPR knockout recapitulating scoliosis with AIS-cohort exome variants","pmids":["33279757","33251213"],"confidence":"Low","gaps":["IFT involvement is correlative localization without direct mechanistic placement","Scoliosis link not mechanistically connected to dynein function","Single-lab/single-organism observations"]},{"year":2004,"claim":"Identified BLU/ZMYND10 as an epigenetically regulated locus with tumor-suppressive activity, opening a parallel cancer-biology line of inquiry.","evidence":"Promoter reporter and E2F binding analysis, methylation-specific PCR, demethylation rescue, and colony formation assays","pmids":["15122337"],"confidence":"Medium","gaps":["Mechanism of growth suppression not defined at this stage","Relationship between ciliary and tumor-suppressor functions unaddressed"]},{"year":2006,"claim":"Provided causal in vivo evidence that BLU/ZMYND10 suppresses tumor formation, distinguishing it from a mere correlate of methylation.","evidence":"Tetracycline-regulated gene inactivation in nude mouse NPC xenografts showing tumor formation restored upon BLU downregulation","pmids":["16929489"],"confidence":"Medium","gaps":["Downstream effector pathway not identified","Single tumor type"]},{"year":2012,"claim":"Connected BLU/ZMYND10 to specific growth-control signaling, building a mechanistic basis for its tumor-suppressor activity.","evidence":"Co-IP/domain mapping of BLU–sMEK1 interaction with apoptosis assays; adenoviral re-expression with cell cycle analysis, JNK/cyclin D1 reporter assays, and c-Jun phosphorylation immunoblotting","pmids":["22349239","22727408"],"confidence":"Medium","gaps":["sMEK1 interaction not reciprocally validated in vivo","Multiple proposed pathways (JNK, PP4) not unified","Link to the chaperone function unclear"]},{"year":2015,"claim":"Defined the transcriptional control of BLU and its loss in cancer, linking single-CpG methylation to Sp1-dependent silencing and proliferation.","evidence":"Bisulfite sequencing, ChIP, EMSA, luciferase reporter, and siRNA knockdown with colony formation in gastric cancer cells; CTCF insulator characterization at the 3p21.3 BLU/RASSF1A locus by EMSA, ChIP, and bisulfite sequencing","pmids":["26043875","20877461"],"confidence":"Medium","gaps":["Causal contribution of -39 CpG methylation in primary tumors not established","Interplay between CTCF insulator loss and BLU silencing in vivo unresolved"]},{"year":2019,"claim":"Extended tumor-suppressor mechanism to additional pathways (angiogenesis and miRNA-mediated effector control) in further cancer models.","evidence":"Ectopic expression with VEGF/TSP1 PCR array, ELISA, tube formation and matrigel plug angiogenesis assays; miR145-5p/NEDD9 3'-UTR luciferase validation with migration/invasion and xenograft assays","pmids":["25347745","31801619"],"confidence":"Medium","gaps":["Mechanisms operate through different effectors without unification","Direct molecular target of ZMYND10 in these axes not defined"]},{"year":2025,"claim":"Established a transcriptional role for Zmynd10 in centriole amplification and multiciliogenesis, expanding its ciliary function beyond cytoplasmic dynein pre-assembly.","evidence":"siRNA knockdown in mouse ependymal cells, E2f4 promoter-luciferase reporter, E2f4 knockdown epistasis, and RT-qPCR/immunoblotting for E2f4 and Deup1","pmids":["41413096"],"confidence":"Medium","gaps":["How a cytoplasmic co-chaperone activates E2f4 transcription is mechanistically unexplained","Direct DNA binding vs indirect regulation not distinguished","Single lab/cell type"]},{"year":null,"claim":"How ZMYND10's cytoplasmic dynein-chaperone function, its proposed transcriptional/tumor-suppressor activities, and its multiciliogenesis role mechanistically integrate into a single protein remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of ZMYND10 in the FKBP8–HSP90–dynein assembly complex","Mechanism linking a cytoplasmic co-chaperone to nuclear/transcriptional outputs (E2f4, Sp1, tumor suppression) undefined","Whether ciliary and cancer phenotypes share a common molecular activity unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0044183","term_label":"protein folding chaperone","supporting_discovery_ids":[2]},{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[2,3]},{"term_id":"GO:0140313","term_label":"molecular sequestering activity","supporting_discovery_ids":[3]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[1,3]},{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[0]}],"pathway":[],"complexes":["FKBP8-HSP90 chaperone complex"],"partners":["LRRC6","FKBP8","DNAI1","DYX1C1","C21ORF59","SMEK1"],"other_free_text":[]}},"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 of Acquired Resistance to Osimertinib in EGFR-Mutant NSCLC and Clinical Validation of Combined EGFR and RET Inhibition with Osimertinib and BLU-667 for Acquired RET Fusion.","date":"2018","source":"Cancer discovery","url":"https://pubmed.ncbi.nlm.nih.gov/30257958","citation_count":376,"is_preprint":false},{"pmid":"29657135","id":"PMC_29657135","title":"Precision Targeted Therapy with BLU-667 for RET-Driven Cancers.","date":"2018","source":"Cancer discovery","url":"https://pubmed.ncbi.nlm.nih.gov/29657135","citation_count":326,"is_preprint":false},{"pmid":"31575541","id":"PMC_31575541","title":"First-in-Human Phase I Study of Fisogatinib (BLU-554) Validates Aberrant FGF19 Signaling as a Driver Event in Hepatocellular Carcinoma.","date":"2019","source":"Cancer discovery","url":"https://pubmed.ncbi.nlm.nih.gov/31575541","citation_count":216,"is_preprint":false},{"pmid":"23891469","id":"PMC_23891469","title":"ZMYND10 is mutated in primary ciliary dyskinesia and interacts with LRRC6.","date":"2013","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/23891469","citation_count":154,"is_preprint":false},{"pmid":"35838760","id":"PMC_35838760","title":"Discovery of BLU-945, a Reversible, Potent, and Wild-Type-Sparing Next-Generation EGFR Mutant Inhibitor for Treatment-Resistant Non-Small-Cell Lung Cancer.","date":"2022","source":"Journal of medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/35838760","citation_count":131,"is_preprint":false},{"pmid":"23891471","id":"PMC_23891471","title":"Mutations in ZMYND10, a gene essential for proper axonemal assembly of inner and outer dynein arms in humans and flies, cause primary ciliary dyskinesia.","date":"2013","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/23891471","citation_count":130,"is_preprint":false},{"pmid":"15122337","id":"PMC_15122337","title":"The candidate tumor suppressor gene BLU, located at the commonly deleted region 3p21.3, is an E2F-regulated, stress-responsive gene and inactivated by both epigenetic and genetic mechanisms in nasopharyngeal carcinoma.","date":"2004","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/15122337","citation_count":115,"is_preprint":false},{"pmid":"14743209","id":"PMC_14743209","title":"Frequent epigenetic inactivation of RASSF1A and BLU genes located within the critical 3p21.3 region in gliomas.","date":"2004","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/14743209","citation_count":104,"is_preprint":false},{"pmid":"12629521","id":"PMC_12629521","title":"Epigenetic inactivation of the candidate 3p21.3 suppressor gene BLU in human cancers.","date":"2003","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/12629521","citation_count":82,"is_preprint":false},{"pmid":"30902655","id":"PMC_30902655","title":"BLU-5937: A selective P2X3 antagonist with potent anti-tussive effect and no taste alteration.","date":"2019","source":"Pulmonary pharmacology & 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Both proteins colocalize with centriole markers SAS6 and PCM1. Loss of ZMYND10 results in absence of axonemal dynein components DNAH5 and DNALI1 from respiratory cilia.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence colocalization with centriole markers, whole-exome resequencing, zebrafish zmynd10 morpholino knockdown (ciliary paralysis, cystic kidneys, otolith defects), Xenopus knockdown (ciliogenesis defect)\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP defining interaction domains, multiple model organism knockdowns, replicated across two independent papers in the same issue\",\n      \"pmids\": [\"23891469\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"ZMYND10 (BLU) is a cytoplasmic protein required for assembly of both inner dynein arms (IDAs) and outer dynein arms (ODAs) in motile cilia/flagella. Loss-of-function mutations cause complete cilia immotility and dual dynein arm loss at the ultrastructural level. The MYND-type zinc finger domain is important for function. Human ZMYND10 interacts with LRRC6 in the cytoplasm.\",\n      \"method\": \"Biallelic mutation identification in PCD families, immunofluorescence/electron microscopy of ciliary axonemes, Drosophila P-element gene silencing (IDA and ODA defects, proprioception deficit, male sterility), tagged protein localization, Co-IP with LRRC6, missense rescue experiments in Drosophila\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (EM ultrastructure, immunofluorescence, Drosophila genetic model, Co-IP, rescue experiments), replicated independently\",\n      \"pmids\": [\"23891471\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"ZMYND10 acts as a novel co-chaperone that confers specificity of the FKBP8-HSP90 chaperone complex towards axonemal dynein heavy chain clients required for cilia motility. Loss of ZMYND10 perturbs chaperoning of axonemal dynein heavy chains, triggering broader degradation of dynein motor subunits. Pharmacological inhibition of FKBP8 phenocopies dynein motor instability associated with ZMYND10 loss. Human disease-causing ZMYND10 variants disrupt its ability to act as an FKBP8-HSP90 co-chaperone.\",\n      \"method\": \"Mouse genetics (Zmynd10 knockout), quantitative proteomics, imaging, pharmacological FKBP8 inhibition in airway cells, functional analysis of disease-causing variants\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — mouse KO with quantitative proteomics, pharmacological phenocopy, disease variant functional validation; multiple orthogonal methods in one rigorous study\",\n      \"pmids\": [\"29916806\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"ZMYND10 stabilizes ODA intermediate chain protein DNAI1 during cytoplasmic pre-assembly of dynein arms; ZMYND10 interacts with ODA components and other dynein assembly factors (LRRC6, DYX1C1, C21ORF59). Stabilization of DNAI1 by ZMYND10 subsequently stabilizes DNAI2. Levels of these co-assembly proteins are significantly reduced in Zmynd10-/- mice. The 9+2 axoneme structure is normal in Zmynd10-/- mice, indicating a specific pre-assembly function rather than structural role.\",\n      \"method\": \"Zmynd10-/- mouse model, co-immunoprecipitation, co-expression stability assays, immunofluorescence, electron microscopy of cilia\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KO mouse with defined molecular phenotype, Co-IP interaction mapping, co-expression stability assays with multiple subunits, mechanistic ordering of DNAI1/DNAI2 stabilization\",\n      \"pmids\": [\"29601588\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"In medaka fish, zmynd10 is exclusively expressed in cells with motile cilia; morpholino knockdown causes loss of outer dynein arms and ciliary immotility affecting left-right axis determination. The C-terminal MYND-type zinc finger domain is important but not exclusively required for function, as a truncated protein lacking zf-MYND retained partial activity in rescue experiments. Zmynd10 knockout adult fish exhibit sperm dysmotility, scoliosis, and progressive polycystic kidney.\",\n      \"method\": \"Morpholino knockdown, TALEN knockout, transmission electron microscopy, rescue experiments with truncation mutants, high-speed video microscopy\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — zebrafish/medaka model with EM ultrastructure, domain truncation rescue, single lab\",\n      \"pmids\": [\"28823919\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"The BLU (ZMYND10) promoter is activated by environmental stresses such as heat shock and is regulated by the transcription factor E2F. The promoter and first exon are located within a CpG island. Promoter hypermethylation causes silencing, which can be reversed by 5-aza-2'-deoxycytidine treatment. Ectopic BLU expression inhibits colony formation of cancer cells, consistent with tumor suppressor activity.\",\n      \"method\": \"Promoter reporter assays, methylation-specific PCR, 5-aza-2'-deoxycytidine demethylation, colony formation assay, E2F binding analysis\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — promoter reporter assay, E2F regulation, demethylation rescue, colony formation; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"15122337\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"BLU/ZMYND10 functionally suppresses tumor formation in vivo when expressed in NPC cells implanted in nude mice; doxycycline-mediated downregulation of BLU in these tumor-suppressive clones restores tumor formation ability, providing direct causal evidence for its tumor suppressor function.\",\n      \"method\": \"Gene inactivation test (GIT) with tetracycline-regulated expression system, nude mouse xenograft assay\",\n      \"journal\": \"International journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — inducible expression system with in vivo tumor suppression reversal, single lab\",\n      \"pmids\": [\"16929489\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"BLU (ZMYND10) directly interacts with sMEK1 (a regulatory subunit of protein phosphatase 4) via its N-terminal domain binding to the C-terminal domain of sMEK1. This interaction increases sMEK1 expression and induces pro-apoptotic activity.\",\n      \"method\": \"Co-immunoprecipitation, domain mapping by deletion constructs, apoptosis assays\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP with domain mapping, functional apoptosis assay; single lab\",\n      \"pmids\": [\"22349239\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"BLU/ZMYND10 re-expression in NPC cells inhibits clonogenic growth, arrests cell cycle at G1 phase, downregulates JNK activity, inhibits cyclin D1 promoter activity, and reduces phosphorylation of c-Jun.\",\n      \"method\": \"Adenoviral BLU re-expression, flow cytometry cell cycle analysis, reporter gene assay for JNK and cyclin D1 promoter activities, immunoblotting for c-Jun phosphorylation\",\n      \"journal\": \"BMC cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — multiple readouts (cell cycle, JNK signaling, cyclin D1 promoter) in a single lab using re-expression approach\",\n      \"pmids\": [\"22727408\"],\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, and inhibits cellular invasion, migration, and tube formation in vitro. In vivo, BLU expression inhibits tumor growth and suppresses angiogenesis in matrigel plug assays.\",\n      \"method\": \"PCR array, stable transfection, ELISA for secreted VEGF, invasion/migration assay, tube formation assay, nude mouse xenograft and matrigel plug angiogenesis assay\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — multiple in vitro and in vivo assays in single lab; pathway connection to VEGF/angiogenesis established by multiple readouts\",\n      \"pmids\": [\"25347745\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"BLU/ZMYND10 inhibits ERK signaling by reducing protein substrate phosphorylation, inhibiting Elk reporter activity, and blocking cyclin D1 (CCND1) promoter activity, thereby arresting cell cycle at G1. BLU antagonizes the effect of HRAS V12G on ERK activation and cyclin D1/B1 promoter activities.\",\n      \"method\": \"Xenograft tumor injection with BLU-expressing adenovirus, reporter gene co-transfection, phosphorylation immunoblotting, FACS cell cycle analysis\",\n      \"journal\": \"International journal of clinical and experimental pathology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, reporter gene and immunoblotting only, limited mechanistic depth\",\n      \"pmids\": [\"31938097\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"BLU promoter activity is regulated by transcription factor Sp1; methylation of the -39 CpG site in the BLU proximal promoter directly prevents Sp1 binding and reduces transcriptional activity by ~70%. Knockdown of BLU promotes cellular proliferation and colony formation in gastric cancer cells.\",\n      \"method\": \"Bisulfite sequencing, ChIP, EMSA, luciferase reporter assay, siRNA knockdown, colony formation assay\",\n      \"journal\": \"International journal of oncology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — EMSA and ChIP directly demonstrate Sp1 binding loss at methylated site, corroborated by reporter assay; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"26043875\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ZMYND10 suppresses breast cancer tumorigenicity through a miR145-5p/NEDD9 signaling axis: ectopic ZMYND10 expression enhances miR145-5p expression, which suppresses NEDD9 protein by targeting its 3'-UTR, leading to reduced cell migration, invasion, and xenograft tumor growth.\",\n      \"method\": \"Ectopic expression in breast cancer cell lines, luciferase 3'-UTR reporter assay, migration/invasion assays, xenograft tumor growth in vivo\",\n      \"journal\": \"Clinical epigenetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — luciferase 3'-UTR validation of miR145-5p/NEDD9 link, in vivo xenograft confirmation; single lab\",\n      \"pmids\": [\"31801619\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"A CTCF-binding insulator located between the tandem BLU and RASSF1A genes at 3p21.3 creates distinct epigenetic domains, providing a barrier between the two gene loci. In normal cells, distinct methylation and chromatin boundaries are separated by the CTCF binding domains; in cancer cells, these boundaries are lost. Treatment with demethylation reagent or HDAC inhibitor restores CTCF binding and barrier effect.\",\n      \"method\": \"Gel shift assay (EMSA), ChIP-PCR, methylation-specific oligonucleotide array, bisulfite sequencing, pharmacological treatments\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — EMSA and ChIP directly demonstrate CTCF binding at insulator, bisulfite sequencing defines epigenetic boundaries; single lab\",\n      \"pmids\": [\"20877461\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"In zebrafish, CRISPR/Cas9 knockout of zmynd10 recapitulates scoliosis in viable adult fish, and coding variants in zmynd10 identified by whole-exome sequencing are associated with adolescent idiopathic scoliosis susceptibility, linking zmynd10 dynein assembly factor function to spinal curvature.\",\n      \"method\": \"CRISPR/Cas9 knockout in zebrafish, whole-exome sequencing of AIS patient cohort\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — zebrafish KO phenotype reported but limited mechanistic pathway detail; single lab\",\n      \"pmids\": [\"33251213\"],\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, suggesting ZMYND10 is involved in regulating IFT in addition to dynein arm assembly.\",\n      \"method\": \"RNAi knockdown in Paramecium, immunofluorescence localization of IFT43, swimming behavior assay\",\n      \"journal\": \"European journal of protistology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single-organism RNAi study, single lab, ciliary IFT localization without direct mechanistic pathway placement\",\n      \"pmids\": [\"33279757\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"BLU/ZMYND10 re-expression promotes TRAIL-induced apoptosis in NPC cells by inhibiting the NF-κB pathway, as evidenced by reduced IKKα, p65 NF-κB, and NF-κB-induced anti-apoptotic factors cFLIPL and cIAP2, along with enhanced caspase-8 cleavage.\",\n      \"method\": \"Recombinant adenoviral BLU infection, NF-κB reporter assay, FACS-based TMRE/annexin V assays, immunoblotting for NF-κB pathway components\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, NF-κB reporter and immunoblotting without direct mechanistic link between ZMYND10 and IKK complex\",\n      \"pmids\": [\"28029652\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Zmynd10 drives centriole amplification and multiciliogenesis through transcriptional activation of the E2f4 promoter, which in turn regulates Deup1 expression; knockdown of Zmynd10 in mouse ependymal cells reduces ciliary density and downregulates E2f4 and Deup1 at mRNA and protein levels.\",\n      \"method\": \"Zmynd10 siRNA knockdown in mouse ependymal cells (mEPCs), E2f4 promoter-luciferase reporter assay, E2f4 siRNA knockdown, RT-qPCR and immunoblotting\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — promoter reporter assay directly links ZMYND10 to E2f4 transcription, epistasis with E2f4 knockdown showing Deup1 dependence; single lab\",\n      \"pmids\": [\"41413096\"],\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, physically interacts with LRRC6 and other dynein assembly factors, and additionally drives multiciliogenesis through transcriptional activation of the E2f4-Deup1 pathway; loss-of-function mutations in ZMYND10 cause primary ciliary dyskinesia by preventing proper dynein arm assembly and axonemal targeting.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"ZMYND10 is a cytoplasmic factor essential for the pre-assembly of axonemal dynein arms that power motile cilia and flagella, and its loss causes primary ciliary dyskinesia through complete loss of ciliary motility [#1, #2]. Mechanistically, ZMYND10 acts as a co-chaperone that confers specificity of the FKBP8–HSP90 chaperone complex toward axonemal dynein heavy chain clients; loss of ZMYND10 destabilizes these clients and triggers broader degradation of dynein motor subunits, and pharmacological FKBP8 inhibition phenocopies this instability [#2]. During cytoplasmic pre-assembly, ZMYND10 stabilizes the outer dynein arm intermediate chain DNAI1, which in turn stabilizes DNAI2, and it physically associates with dynein assembly factors LRRC6, DYX1C1, and C21ORF59 [#3]. The interaction with LRRC6 is mediated by the LRRC6 CS domain and the ZMYND10 C-terminal domain, and disease-causing mutations in either protein abrogate this binding; ZMYND10 colocalizes with centriolar markers and its loss eliminates axonemal DNAH5 and DNALI1 from cilia while leaving the 9+2 axoneme structurally intact, defining a pre-assembly rather than structural role [#0, #3]. Beyond dynein assembly, ZMYND10 promotes centriole amplification and multiciliogenesis through transcriptional activation of the E2f4 promoter, which regulates Deup1 expression [#17]. A separate body of work characterizes ZMYND10/BLU as an epigenetically silenced 3p21.3 tumor suppressor whose re-expression arrests the cell cycle and suppresses tumorigenicity across nasopharyngeal, gastric, and breast cancer models [#5, #6, #11].\",\n  \"teleology\": [\n    {\n      \"year\": 2013,\n      \"claim\": \"Established ZMYND10 as a PCD gene and defined its first molecular partnership, answering whether and how a previously uncharacterized protein contributes to cilia motility.\",\n      \"evidence\": \"Biallelic mutation identification in PCD families, EM ultrastructure showing dual dynein arm loss, reciprocal Co-IP mapping ZMYND10–LRRC6 interaction domains, and model-organism knockdowns (zebrafish, Xenopus, Drosophila)\",\n      \"pmids\": [\"23891469\", \"23891471\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve the biochemical activity of ZMYND10 (chaperone vs structural)\", \"Mechanism by which LRRC6 binding supports dynein assembly unresolved\", \"Did not identify the specific dynein clients stabilized\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Resolved the biochemical function of ZMYND10 as a co-chaperone and ordered its action on specific dynein subunits, explaining why its loss causes broad dynein motor degradation.\",\n      \"evidence\": \"Zmynd10 knockout mice with quantitative proteomics, pharmacological FKBP8 inhibition phenocopy, Co-IP interaction mapping, and co-expression stability assays demonstrating DNAI1→DNAI2 stabilization hierarchy\",\n      \"pmids\": [\"29916806\", \"29601588\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of FKBP8–HSP90–ZMYND10–client assembly not determined\", \"How ZMYND10 selects dynein heavy chain clients unknown\", \"Order of recruitment relative to LRRC6/DYX1C1/C21ORF59 not fully resolved\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Confirmed conserved dynein-assembly function across species and probed the contribution of the MYND zinc finger domain.\",\n      \"evidence\": \"Medaka morpholino knockdown and TALEN knockout with EM, high-speed video microscopy, and truncation-mutant rescue showing partial activity without zf-MYND\",\n      \"pmids\": [\"28823919\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Domain contributions only partially mapped\", \"Did not define which dynein arms require which domains\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Extended ZMYND10 ciliary roles beyond dynein assembly, raising the question of involvement in intraflagellar transport and spinal development.\",\n      \"evidence\": \"Paramecium RNAi with IFT43 localization analysis; zebrafish CRISPR knockout recapitulating scoliosis with AIS-cohort exome variants\",\n      \"pmids\": [\"33279757\", \"33251213\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"IFT involvement is correlative localization without direct mechanistic placement\", \"Scoliosis link not mechanistically connected to dynein function\", \"Single-lab/single-organism observations\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Identified BLU/ZMYND10 as an epigenetically regulated locus with tumor-suppressive activity, opening a parallel cancer-biology line of inquiry.\",\n      \"evidence\": \"Promoter reporter and E2F binding analysis, methylation-specific PCR, demethylation rescue, and colony formation assays\",\n      \"pmids\": [\"15122337\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of growth suppression not defined at this stage\", \"Relationship between ciliary and tumor-suppressor functions unaddressed\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Provided causal in vivo evidence that BLU/ZMYND10 suppresses tumor formation, distinguishing it from a mere correlate of methylation.\",\n      \"evidence\": \"Tetracycline-regulated gene inactivation in nude mouse NPC xenografts showing tumor formation restored upon BLU downregulation\",\n      \"pmids\": [\"16929489\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Downstream effector pathway not identified\", \"Single tumor type\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Connected BLU/ZMYND10 to specific growth-control signaling, building a mechanistic basis for its tumor-suppressor activity.\",\n      \"evidence\": \"Co-IP/domain mapping of BLU–sMEK1 interaction with apoptosis assays; adenoviral re-expression with cell cycle analysis, JNK/cyclin D1 reporter assays, and c-Jun phosphorylation immunoblotting\",\n      \"pmids\": [\"22349239\", \"22727408\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"sMEK1 interaction not reciprocally validated in vivo\", \"Multiple proposed pathways (JNK, PP4) not unified\", \"Link to the chaperone function unclear\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Defined the transcriptional control of BLU and its loss in cancer, linking single-CpG methylation to Sp1-dependent silencing and proliferation.\",\n      \"evidence\": \"Bisulfite sequencing, ChIP, EMSA, luciferase reporter, and siRNA knockdown with colony formation in gastric cancer cells; CTCF insulator characterization at the 3p21.3 BLU/RASSF1A locus by EMSA, ChIP, and bisulfite sequencing\",\n      \"pmids\": [\"26043875\", \"20877461\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Causal contribution of -39 CpG methylation in primary tumors not established\", \"Interplay between CTCF insulator loss and BLU silencing in vivo unresolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Extended tumor-suppressor mechanism to additional pathways (angiogenesis and miRNA-mediated effector control) in further cancer models.\",\n      \"evidence\": \"Ectopic expression with VEGF/TSP1 PCR array, ELISA, tube formation and matrigel plug angiogenesis assays; miR145-5p/NEDD9 3'-UTR luciferase validation with migration/invasion and xenograft assays\",\n      \"pmids\": [\"25347745\", \"31801619\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanisms operate through different effectors without unification\", \"Direct molecular target of ZMYND10 in these axes not defined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Established a transcriptional role for Zmynd10 in centriole amplification and multiciliogenesis, expanding its ciliary function beyond cytoplasmic dynein pre-assembly.\",\n      \"evidence\": \"siRNA knockdown in mouse ependymal cells, E2f4 promoter-luciferase reporter, E2f4 knockdown epistasis, and RT-qPCR/immunoblotting for E2f4 and Deup1\",\n      \"pmids\": [\"41413096\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How a cytoplasmic co-chaperone activates E2f4 transcription is mechanistically unexplained\", \"Direct DNA binding vs indirect regulation not distinguished\", \"Single lab/cell type\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How ZMYND10's cytoplasmic dynein-chaperone function, its proposed transcriptional/tumor-suppressor activities, and its multiciliogenesis role mechanistically integrate into a single protein remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of ZMYND10 in the FKBP8–HSP90–dynein assembly complex\", \"Mechanism linking a cytoplasmic co-chaperone to nuclear/transcriptional outputs (E2f4, Sp1, tumor suppression) undefined\", \"Whether ciliary and cancer phenotypes share a common molecular activity unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0044183\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [2, 3]},\n      {\"term_id\": \"GO:0140313\", \"supporting_discovery_ids\": [3]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [1, 3]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [0]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0001618\", \"supporting_discovery_ids\": []}\n    ],\n    \"complexes\": [\"FKBP8-HSP90 chaperone complex\"],\n    \"partners\": [\"LRRC6\", \"FKBP8\", \"DNAI1\", \"DYX1C1\", \"C21ORF59\", \"sMEK1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}