{"gene":"DNAH10","run_date":"2026-06-09T23:54:42","timeline":{"discoveries":[{"year":2023,"finding":"DNAH10 encodes an inner dynein arm (IDA) heavy chain subunit in motile cilia and sperm flagella; loss-of-function DNAH10 variants in a PCD patient caused absence of DNAH10 and DNALI1 in respiratory cilia, with disordered axoneme 9+2 architecture and IDA defects confirmed by transmission electron microscopy. Dnah10-knockin and Dnah10-knockout mice recapitulated PCD phenotypes including chronic respiratory infection, male infertility, and hydrocephalus.","method":"Exome sequencing, immunostaining, transmission electron microscopy, Dnah10 knockin/knockout mouse models","journal":"Frontiers of medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (TEM ultrastructure, immunostaining, in vivo mouse models) in a single study establishing IDA subunit function","pmids":["37314648"],"is_preprint":false},{"year":2021,"finding":"Bi-allelic DNAH10 variants (homozygous frameshift and compound heterozygous missense) cause MMAF with IDA deficiency in sperm flagella; immunofluorescence showed reduction of both DNAH10 and the IDA-related protein DNAH1 in patient sperm, indicating DNAH10 is required for IDA assembly in sperm.","method":"Whole-exome sequencing, H&E staining, scanning electron microscopy, transmission electron microscopy, immunofluorescence","journal":"Journal of assisted reproduction and genetics","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal structural and protein-localization methods in a single study confirming IDA role","pmids":["34657236"],"is_preprint":false},{"year":2021,"finding":"Disruption of dnah10 in zebrafish (CRISPR F0 screen and stable mutant) causes recessive adult-viable scoliosis; dnah10 mutant ependymal monocilia lining the hindbrain and spinal canal showed reduced beat frequency, correlating with disassembly of the Reissner fiber and onset of body curvature, placing DNAH10 function in monocilia motility required for Reissner fiber polymerization and spine alignment.","method":"CRISPR/Cas9 F0 screen, stable zebrafish mutant, high-speed cilia beat frequency imaging, Reissner fiber immunostaining","journal":"Developmental biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic loss-of-function with defined cellular phenotype (cilia beat frequency) and pathway placement (Reissner fiber), replicated in stable mutant after F0 screen","pmids":["34915022"],"is_preprint":false},{"year":2018,"finding":"Morpholino knockdown and CRISPR/Cas9 mutation of dnah10 in zebrafish disrupted cardiac looping and produced abnormal expression of the left-right patterning markers lefty2 and pitx2, establishing DNAH10 function upstream of laterality determination during embryogenesis.","method":"Morpholino knockdown, CRISPR/Cas9-mediated mutation, whole-mount in situ hybridization (lefty2, pitx2) in zebrafish","journal":"Genome medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — two independent loss-of-function approaches (morpholino and CRISPR) with molecular marker readout in the same study","pmids":["29843777"],"is_preprint":false},{"year":2025,"finding":"DNAH10 interacts with CFAP57, DYNLL1, and CCDC73 to form a double-headed inner dynein arm f (IDAf) complex in cilia; Co-IP confirmed these interactions, and loss of DNAH10 in patients and Dnah10-KO mice led to reduced expression of all three partners and defective IDAf assembly, resulting in ciliary dysfunction and pulmonary fibrosis.","method":"Co-immunoprecipitation, immunostaining, Dnah10 knockout mice, scanning electron microscopy, proteomic analysis","journal":"Orphanet journal of rare diseases","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP identifying specific complex partners, confirmed by in vivo KO mouse model with multiple orthogonal readouts","pmids":["40898283"],"is_preprint":false},{"year":2025,"finding":"DNAH10 exerts a bridging function between UCHL3 and PACRG in the manchette during spermiogenesis; UCHL3 binds PACRG and stabilizes it via deubiquitination, and DNAH10 enhances this UCHL3-PACRG interaction. DNAH10 deficiency leads to impaired manchette function, aberrant localization of axonemal proteins, and abnormal sperm head and flagella morphology.","method":"Co-immunoprecipitation, immunofluorescence, genetic loss-of-function analysis in patient and mouse models","journal":"Development (Cambridge, England)","confidence":"High","confidence_rationale":"Tier 2 / Moderate — Co-IP establishing ternary complex, mechanistic deubiquitination pathway placement, confirmed with cellular localization phenotype","pmids":["41058558"],"is_preprint":false},{"year":2026,"finding":"Biallelic DNAH10 variants in humans with skeletal developmental abnormalities are associated with reduced DNAH10 protein; Dnah10-knockout mice showed polydactyly, impaired cartilage development, and abnormal ossification. Mechanistically, Dnah10 loss caused abnormal primary cilia morphology, attenuated Hedgehog signaling, impaired osteoblast differentiation, and defective chondrocyte maturation, revealing a role for DNAH10 in primary cilia-mediated skeletal development.","method":"Whole-exome sequencing, in vitro missense variant protein abundance assay, Dnah10-KO mouse model, primary cilia morphology analysis, Hedgehog signaling pathway assay","journal":"Journal of medical genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo KO model with pathway placement (Hedgehog), but primary cilia role is a new and single-study finding","pmids":["42086325"],"is_preprint":false},{"year":2023,"finding":"DNALI1 loss in patient sperm and Dnali1-KO mice caused loss of DNAH1 and DNAH7 but NOT DNAH10, demonstrating that DNAH10 belongs to a distinct partial IDA subspecies that is independent of DNALI1.","method":"Immunofluorescence in patient sperm and Dnali1-KO mouse sperm (negative result for DNAH10 loss)","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — rigorous negative result (DNAH10 unaffected) in parallel with positive controls for other dynein subunits, establishing IDA subspecies distinction","pmids":["36792588"],"is_preprint":false},{"year":2024,"finding":"DNAH9 variants in asthenospermia patients led to dysfunction of flagellar ultrastructure-related proteins including DNAH10, as shown by immunofluorescence, indicating DNAH10 protein localization in sperm flagella is dependent on intact DNAH9.","method":"Immunofluorescence in patient sperm carrying biallelic DNAH9 variants","journal":"Journal of human genetics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single-method (immunofluorescence), single lab, DNAH10 as secondary finding in a DNAH9 paper","pmids":["39523437"],"is_preprint":false},{"year":2024,"finding":"Repeated freeze-thaw cycles of bovine sperm significantly decreased DNAH10 protein levels and disrupted the 9+2 axonemal structure, as shown by transmission electron microscopy and protein quantification, correlating with reduced sperm motility.","method":"Transmission electron microscopy, western blot/protein level quantification after repeated freeze-thaw treatment","journal":"Cryobiology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — observational protein-level measurement in a stress model, single lab, no direct functional manipulation of DNAH10","pmids":["38593909"],"is_preprint":false},{"year":2026,"finding":"DNAI4 deficiency in mice caused a remarkable reduction in DNAH10 in testes and sperm tails, and immunoprecipitation demonstrated that DNAI4 interacts with intraflagellar transport protein IFT144; these data place DNAH10 as a downstream IDA component regulated by DNAI4-dependent intraflagellar transport.","method":"Immunoprecipitation, western blot, electron microscopy, Dnai4-KO mouse model","journal":"Development (Cambridge, England)","confidence":"Low","confidence_rationale":"Tier 3 / Weak — DNAH10 is a secondary finding; direct interaction of DNAH10 with DNAI4 not demonstrated, reduction is inferred from KO phenotype","pmids":["42083518"],"is_preprint":false}],"current_model":"DNAH10 encodes an inner dynein arm (IDA) heavy chain that is essential for the motility of sperm flagella, respiratory cilia, and ependymal monocilia: it assembles into the double-headed IDAf complex by interacting with CFAP57, DYNLL1, and CCDC73, and during spermiogenesis bridges the UCHL3-PACRG complex at the manchette to facilitate intra-manchette transport and proper sperm head/flagella morphogenesis; loss-of-function causes primary ciliary dyskinesia, male infertility (MMAF), scoliosis via Reissner fiber disassembly in zebrafish, and left-right laterality defects, while a newly identified role in primary cilia links DNAH10 to Hedgehog signaling-dependent skeletal development."},"narrative":{"mechanistic_narrative":"DNAH10 encodes an inner dynein arm (IDA) heavy chain required for the motility of motile cilia and sperm flagella, where its loss disrupts the 9+2 axonemal architecture and IDA assembly, causing primary ciliary dyskinesia and multiple morphological abnormalities of the sperm flagella (MMAF) [PMID:37314648, PMID:34657236]. It assembles into a double-headed inner dynein arm f (IDAf) complex with CFAP57, DYNLL1, and CCDC73, and its loss destabilizes all three partners and abolishes IDAf assembly [PMID:40898283]; DNAH10 defines an IDA subspecies distinct from the DNALI1-dependent arms, since DNALI1 loss does not affect DNAH10 [PMID:36792588]. Beyond the axoneme, DNAH10 bridges the UCHL3–PACRG complex within the manchette during spermiogenesis to support intra-manchette transport and proper sperm head and flagellar morphogenesis [PMID:41058558]. In vivo loss-of-function across zebrafish and mice links DNAH10 to ciliary motility-dependent processes including left-right laterality determination [PMID:29843777], Reissner fiber polymerization and spine alignment via ependymal monocilia beating [PMID:34915022], and primary cilia-mediated Hedgehog signaling in skeletal development [PMID:42086325]. Biallelic DNAH10 variants cause this spectrum of human disease, encompassing PCD with respiratory and laterality defects [PMID:37314648], male infertility with MMAF [PMID:34657236], and skeletal developmental abnormalities [PMID:42086325].","teleology":[{"year":2018,"claim":"Placed DNAH10 upstream of vertebrate left-right axis determination, the first functional readout connecting it to ciliary patterning before its dynein role was molecularly defined.","evidence":"Morpholino knockdown and CRISPR/Cas9 mutation of dnah10 in zebrafish with lefty2/pitx2 in situ hybridization","pmids":["29843777"],"confidence":"High","gaps":["Did not define DNAH10's molecular activity or its position within the dynein arm","Cardiac looping phenotype not connected to a specific ciliary subcompartment"]},{"year":2021,"claim":"Established DNAH10 as required for IDA assembly in sperm, defining its first human disease association (MMAF) and showing co-dependence with other IDA components.","evidence":"Whole-exome sequencing of MMAF patients with SEM/TEM and immunofluorescence showing reduced DNAH10 and DNAH1 in sperm","pmids":["34657236"],"confidence":"High","gaps":["Did not resolve direct binding partners within the IDA complex","Mechanism of co-loss of DNAH1 not established"]},{"year":2021,"claim":"Extended DNAH10 function to ependymal monocilia, linking its motility role to Reissner fiber polymerization and spine alignment.","evidence":"CRISPR F0 screen and stable zebrafish mutant with cilia beat-frequency imaging and Reissner fiber immunostaining","pmids":["34915022"],"confidence":"High","gaps":["Did not establish how reduced beat frequency mechanistically drives Reissner fiber disassembly","DNAH10's molecular interactions in monocilia not defined"]},{"year":2023,"claim":"Confirmed DNAH10 as an IDA heavy chain subunit in respiratory cilia and showed loss causes PCD ultrastructural defects, unifying the cilia and sperm phenotypes in mammalian models.","evidence":"Exome sequencing of a PCD patient, TEM, immunostaining, and Dnah10 knockin/knockout mice","pmids":["37314648"],"confidence":"High","gaps":["Specific IDA complex composition not yet defined","Co-loss of DNALI1 mechanism not resolved"]},{"year":2023,"claim":"Distinguished DNAH10 as belonging to a DNALI1-independent IDA subspecies, refining the architecture of inner dynein arm heterogeneity.","evidence":"Immunofluorescence in DNALI1-deficient patient and Dnali1-KO mouse sperm showing DNAH10 unaffected while DNAH1/DNAH7 lost","pmids":["36792588"],"confidence":"Medium","gaps":["Negative result defines independence but not the positive assembly pathway for DNAH10","Which adaptor stabilizes the DNAH10 subspecies not identified"]},{"year":2025,"claim":"Defined the molecular complex DNAH10 assembles into, identifying its direct partners and the IDAf complex it builds.","evidence":"Reciprocal Co-IP for CFAP57, DYNLL1, CCDC73, with Dnah10-KO mice and proteomics showing reduced partner expression and defective IDAf assembly","pmids":["40898283"],"confidence":"High","gaps":["Stoichiometry and structural arrangement of the double-headed IDAf complex not resolved","Order of complex assembly not established"]},{"year":2025,"claim":"Revealed a non-axonemal role: DNAH10 bridges the UCHL3-PACRG deubiquitination module at the manchette to support sperm head and flagellar morphogenesis.","evidence":"Co-IP establishing the ternary complex plus immunofluorescence and loss-of-function in patient and mouse models","pmids":["41058558"],"confidence":"High","gaps":["How DNAH10 enhances the UCHL3-PACRG interaction biochemically not defined","Connection between manchette bridging and axonemal IDA role not integrated"]},{"year":2026,"claim":"Implicated DNAH10 in primary (non-motile) cilia and Hedgehog signaling, expanding its role beyond motile ciliogenesis to skeletal development.","evidence":"Whole-exome sequencing, in vitro variant abundance assay, Dnah10-KO mice with primary cilia morphology and Hedgehog pathway assays","pmids":["42086325"],"confidence":"Medium","gaps":["Primary cilia role is a single-study finding","How an inner dynein arm heavy chain functions in non-motile primary cilia not mechanistically explained"]},{"year":null,"claim":"How DNAH10's distinct activities — axonemal IDAf motor, manchette bridging factor, and primary cilia/Hedgehog regulator — are mechanistically reconciled within one protein remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of DNAH10 or the IDAf complex","Direct interaction partners of DNAH10 in primary cilia not identified","Regulation of DNAH10 by intraflagellar transport (DNAI4/IFT144) only inferred indirectly"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003774","term_label":"cytoskeletal motor activity","supporting_discovery_ids":[0,1,4]},{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[0,4]}],"localization":[{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[0,2,4,6]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[0,1]}],"pathway":[{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[3,6]},{"term_id":"R-HSA-1474165","term_label":"Reproduction","supporting_discovery_ids":[1,5]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[6]}],"complexes":["inner dynein arm f (IDAf) complex"],"partners":["CFAP57","DYNLL1","CCDC73","UCHL3","PACRG"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8IVF4","full_name":"Dynein axonemal heavy chain 10","aliases":["Axonemal beta dynein heavy chain 10","Ciliary dynein heavy chain 10"],"length_aa":4471,"mass_kda":514.8,"function":"Force generating protein of respiratory cilia. Produces force towards the minus ends of microtubules. Dynein has ATPase activity; the force-producing power stroke is thought to occur on release of ADP. Involved in sperm motility; implicated in sperm flagellar assembly (PubMed:34237282). Probable inner arm dynein heavy chain","subcellular_location":"Cytoplasm, cytoskeleton, cilium axoneme","url":"https://www.uniprot.org/uniprotkb/Q8IVF4/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/DNAH10","classification":"Not Classified","n_dependent_lines":5,"n_total_lines":1208,"dependency_fraction":0.0041390728476821195},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/DNAH10","total_profiled":1310},"omim":[{"mim_id":"619515","title":"SPERMATOGENIC FAILURE 56; SPGF56","url":"https://www.omim.org/entry/619515"},{"mim_id":"605884","title":"DYNEIN, AXONEMAL, HEAVY CHAIN 10; DNAH10","url":"https://www.omim.org/entry/605884"},{"mim_id":"258150","title":"SPERMATOGENIC FAILURE 1; SPGF1","url":"https://www.omim.org/entry/258150"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Principal piece","reliability":"Supported"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"fallopian 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Dnah10-knockin and Dnah10-knockout mice recapitulated PCD phenotypes including chronic respiratory infection, male infertility, and hydrocephalus.\",\n      \"method\": \"Exome sequencing, immunostaining, transmission electron microscopy, Dnah10 knockin/knockout mouse models\",\n      \"journal\": \"Frontiers of medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (TEM ultrastructure, immunostaining, in vivo mouse models) in a single study establishing IDA subunit function\",\n      \"pmids\": [\"37314648\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Bi-allelic DNAH10 variants (homozygous frameshift and compound heterozygous missense) cause MMAF with IDA deficiency in sperm flagella; immunofluorescence showed reduction of both DNAH10 and the IDA-related protein DNAH1 in patient sperm, indicating DNAH10 is required for IDA assembly in sperm.\",\n      \"method\": \"Whole-exome sequencing, H&E staining, scanning electron microscopy, transmission electron microscopy, immunofluorescence\",\n      \"journal\": \"Journal of assisted reproduction and genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal structural and protein-localization methods in a single study confirming IDA role\",\n      \"pmids\": [\"34657236\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Disruption of dnah10 in zebrafish (CRISPR F0 screen and stable mutant) causes recessive adult-viable scoliosis; dnah10 mutant ependymal monocilia lining the hindbrain and spinal canal showed reduced beat frequency, correlating with disassembly of the Reissner fiber and onset of body curvature, placing DNAH10 function in monocilia motility required for Reissner fiber polymerization and spine alignment.\",\n      \"method\": \"CRISPR/Cas9 F0 screen, stable zebrafish mutant, high-speed cilia beat frequency imaging, Reissner fiber immunostaining\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic loss-of-function with defined cellular phenotype (cilia beat frequency) and pathway placement (Reissner fiber), replicated in stable mutant after F0 screen\",\n      \"pmids\": [\"34915022\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Morpholino knockdown and CRISPR/Cas9 mutation of dnah10 in zebrafish disrupted cardiac looping and produced abnormal expression of the left-right patterning markers lefty2 and pitx2, establishing DNAH10 function upstream of laterality determination during embryogenesis.\",\n      \"method\": \"Morpholino knockdown, CRISPR/Cas9-mediated mutation, whole-mount in situ hybridization (lefty2, pitx2) in zebrafish\",\n      \"journal\": \"Genome medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — two independent loss-of-function approaches (morpholino and CRISPR) with molecular marker readout in the same study\",\n      \"pmids\": [\"29843777\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"DNAH10 interacts with CFAP57, DYNLL1, and CCDC73 to form a double-headed inner dynein arm f (IDAf) complex in cilia; Co-IP confirmed these interactions, and loss of DNAH10 in patients and Dnah10-KO mice led to reduced expression of all three partners and defective IDAf assembly, resulting in ciliary dysfunction and pulmonary fibrosis.\",\n      \"method\": \"Co-immunoprecipitation, immunostaining, Dnah10 knockout mice, scanning electron microscopy, proteomic analysis\",\n      \"journal\": \"Orphanet journal of rare diseases\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP identifying specific complex partners, confirmed by in vivo KO mouse model with multiple orthogonal readouts\",\n      \"pmids\": [\"40898283\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"DNAH10 exerts a bridging function between UCHL3 and PACRG in the manchette during spermiogenesis; UCHL3 binds PACRG and stabilizes it via deubiquitination, and DNAH10 enhances this UCHL3-PACRG interaction. DNAH10 deficiency leads to impaired manchette function, aberrant localization of axonemal proteins, and abnormal sperm head and flagella morphology.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence, genetic loss-of-function analysis in patient and mouse models\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP establishing ternary complex, mechanistic deubiquitination pathway placement, confirmed with cellular localization phenotype\",\n      \"pmids\": [\"41058558\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Biallelic DNAH10 variants in humans with skeletal developmental abnormalities are associated with reduced DNAH10 protein; Dnah10-knockout mice showed polydactyly, impaired cartilage development, and abnormal ossification. Mechanistically, Dnah10 loss caused abnormal primary cilia morphology, attenuated Hedgehog signaling, impaired osteoblast differentiation, and defective chondrocyte maturation, revealing a role for DNAH10 in primary cilia-mediated skeletal development.\",\n      \"method\": \"Whole-exome sequencing, in vitro missense variant protein abundance assay, Dnah10-KO mouse model, primary cilia morphology analysis, Hedgehog signaling pathway assay\",\n      \"journal\": \"Journal of medical genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo KO model with pathway placement (Hedgehog), but primary cilia role is a new and single-study finding\",\n      \"pmids\": [\"42086325\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"DNALI1 loss in patient sperm and Dnali1-KO mice caused loss of DNAH1 and DNAH7 but NOT DNAH10, demonstrating that DNAH10 belongs to a distinct partial IDA subspecies that is independent of DNALI1.\",\n      \"method\": \"Immunofluorescence in patient sperm and Dnali1-KO mouse sperm (negative result for DNAH10 loss)\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — rigorous negative result (DNAH10 unaffected) in parallel with positive controls for other dynein subunits, establishing IDA subspecies distinction\",\n      \"pmids\": [\"36792588\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"DNAH9 variants in asthenospermia patients led to dysfunction of flagellar ultrastructure-related proteins including DNAH10, as shown by immunofluorescence, indicating DNAH10 protein localization in sperm flagella is dependent on intact DNAH9.\",\n      \"method\": \"Immunofluorescence in patient sperm carrying biallelic DNAH9 variants\",\n      \"journal\": \"Journal of human genetics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single-method (immunofluorescence), single lab, DNAH10 as secondary finding in a DNAH9 paper\",\n      \"pmids\": [\"39523437\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Repeated freeze-thaw cycles of bovine sperm significantly decreased DNAH10 protein levels and disrupted the 9+2 axonemal structure, as shown by transmission electron microscopy and protein quantification, correlating with reduced sperm motility.\",\n      \"method\": \"Transmission electron microscopy, western blot/protein level quantification after repeated freeze-thaw treatment\",\n      \"journal\": \"Cryobiology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — observational protein-level measurement in a stress model, single lab, no direct functional manipulation of DNAH10\",\n      \"pmids\": [\"38593909\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"DNAI4 deficiency in mice caused a remarkable reduction in DNAH10 in testes and sperm tails, and immunoprecipitation demonstrated that DNAI4 interacts with intraflagellar transport protein IFT144; these data place DNAH10 as a downstream IDA component regulated by DNAI4-dependent intraflagellar transport.\",\n      \"method\": \"Immunoprecipitation, western blot, electron microscopy, Dnai4-KO mouse model\",\n      \"journal\": \"Development (Cambridge, England)\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — DNAH10 is a secondary finding; direct interaction of DNAH10 with DNAI4 not demonstrated, reduction is inferred from KO phenotype\",\n      \"pmids\": [\"42083518\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"DNAH10 encodes an inner dynein arm (IDA) heavy chain that is essential for the motility of sperm flagella, respiratory cilia, and ependymal monocilia: it assembles into the double-headed IDAf complex by interacting with CFAP57, DYNLL1, and CCDC73, and during spermiogenesis bridges the UCHL3-PACRG complex at the manchette to facilitate intra-manchette transport and proper sperm head/flagella morphogenesis; loss-of-function causes primary ciliary dyskinesia, male infertility (MMAF), scoliosis via Reissner fiber disassembly in zebrafish, and left-right laterality defects, while a newly identified role in primary cilia links DNAH10 to Hedgehog signaling-dependent skeletal development.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"DNAH10 encodes an inner dynein arm (IDA) heavy chain required for the motility of motile cilia and sperm flagella, where its loss disrupts the 9+2 axonemal architecture and IDA assembly, causing primary ciliary dyskinesia and multiple morphological abnormalities of the sperm flagella (MMAF) [#0, #1]. It assembles into a double-headed inner dynein arm f (IDAf) complex with CFAP57, DYNLL1, and CCDC73, and its loss destabilizes all three partners and abolishes IDAf assembly [#4]; DNAH10 defines an IDA subspecies distinct from the DNALI1-dependent arms, since DNALI1 loss does not affect DNAH10 [#7]. Beyond the axoneme, DNAH10 bridges the UCHL3–PACRG complex within the manchette during spermiogenesis to support intra-manchette transport and proper sperm head and flagellar morphogenesis [#5]. In vivo loss-of-function across zebrafish and mice links DNAH10 to ciliary motility-dependent processes including left-right laterality determination [#3], Reissner fiber polymerization and spine alignment via ependymal monocilia beating [#2], and primary cilia-mediated Hedgehog signaling in skeletal development [#6]. Biallelic DNAH10 variants cause this spectrum of human disease, encompassing PCD with respiratory and laterality defects [#0], male infertility with MMAF [#1], and skeletal developmental abnormalities [#6].\",\n  \"teleology\": [\n    {\n      \"year\": 2018,\n      \"claim\": \"Placed DNAH10 upstream of vertebrate left-right axis determination, the first functional readout connecting it to ciliary patterning before its dynein role was molecularly defined.\",\n      \"evidence\": \"Morpholino knockdown and CRISPR/Cas9 mutation of dnah10 in zebrafish with lefty2/pitx2 in situ hybridization\",\n      \"pmids\": [\"29843777\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define DNAH10's molecular activity or its position within the dynein arm\", \"Cardiac looping phenotype not connected to a specific ciliary subcompartment\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Established DNAH10 as required for IDA assembly in sperm, defining its first human disease association (MMAF) and showing co-dependence with other IDA components.\",\n      \"evidence\": \"Whole-exome sequencing of MMAF patients with SEM/TEM and immunofluorescence showing reduced DNAH10 and DNAH1 in sperm\",\n      \"pmids\": [\"34657236\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve direct binding partners within the IDA complex\", \"Mechanism of co-loss of DNAH1 not established\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Extended DNAH10 function to ependymal monocilia, linking its motility role to Reissner fiber polymerization and spine alignment.\",\n      \"evidence\": \"CRISPR F0 screen and stable zebrafish mutant with cilia beat-frequency imaging and Reissner fiber immunostaining\",\n      \"pmids\": [\"34915022\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish how reduced beat frequency mechanistically drives Reissner fiber disassembly\", \"DNAH10's molecular interactions in monocilia not defined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Confirmed DNAH10 as an IDA heavy chain subunit in respiratory cilia and showed loss causes PCD ultrastructural defects, unifying the cilia and sperm phenotypes in mammalian models.\",\n      \"evidence\": \"Exome sequencing of a PCD patient, TEM, immunostaining, and Dnah10 knockin/knockout mice\",\n      \"pmids\": [\"37314648\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific IDA complex composition not yet defined\", \"Co-loss of DNALI1 mechanism not resolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Distinguished DNAH10 as belonging to a DNALI1-independent IDA subspecies, refining the architecture of inner dynein arm heterogeneity.\",\n      \"evidence\": \"Immunofluorescence in DNALI1-deficient patient and Dnali1-KO mouse sperm showing DNAH10 unaffected while DNAH1/DNAH7 lost\",\n      \"pmids\": [\"36792588\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Negative result defines independence but not the positive assembly pathway for DNAH10\", \"Which adaptor stabilizes the DNAH10 subspecies not identified\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Defined the molecular complex DNAH10 assembles into, identifying its direct partners and the IDAf complex it builds.\",\n      \"evidence\": \"Reciprocal Co-IP for CFAP57, DYNLL1, CCDC73, with Dnah10-KO mice and proteomics showing reduced partner expression and defective IDAf assembly\",\n      \"pmids\": [\"40898283\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and structural arrangement of the double-headed IDAf complex not resolved\", \"Order of complex assembly not established\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Revealed a non-axonemal role: DNAH10 bridges the UCHL3-PACRG deubiquitination module at the manchette to support sperm head and flagellar morphogenesis.\",\n      \"evidence\": \"Co-IP establishing the ternary complex plus immunofluorescence and loss-of-function in patient and mouse models\",\n      \"pmids\": [\"41058558\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How DNAH10 enhances the UCHL3-PACRG interaction biochemically not defined\", \"Connection between manchette bridging and axonemal IDA role not integrated\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Implicated DNAH10 in primary (non-motile) cilia and Hedgehog signaling, expanding its role beyond motile ciliogenesis to skeletal development.\",\n      \"evidence\": \"Whole-exome sequencing, in vitro variant abundance assay, Dnah10-KO mice with primary cilia morphology and Hedgehog pathway assays\",\n      \"pmids\": [\"42086325\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Primary cilia role is a single-study finding\", \"How an inner dynein arm heavy chain functions in non-motile primary cilia not mechanistically explained\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How DNAH10's distinct activities — axonemal IDAf motor, manchette bridging factor, and primary cilia/Hedgehog regulator — are mechanistically reconciled within one protein remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of DNAH10 or the IDAf complex\", \"Direct interaction partners of DNAH10 in primary cilia not identified\", \"Regulation of DNAH10 by intraflagellar transport (DNAI4/IFT144) only inferred indirectly\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003774\", \"supporting_discovery_ids\": [0, 1, 4]},\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [0, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [0, 2, 4, 6]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [3, 6]},\n      {\"term_id\": \"R-HSA-1474165\", \"supporting_discovery_ids\": [1, 5]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [6]}\n    ],\n    \"complexes\": [\"inner dynein arm f (IDAf) complex\"],\n    \"partners\": [\"CFAP57\", \"DYNLL1\", \"CCDC73\", \"UCHL3\", \"PACRG\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":5,"faith_total":5,"faith_pct":100.0}}