{"gene":"DNAH9","run_date":"2026-04-28T17:46:02","timeline":{"discoveries":[{"year":2001,"finding":"DNAH9 encodes a 4486-amino-acid human axonemal dynein beta heavy chain mapping to 17p12, with an N-terminal stem and a globular C-terminus containing four P-loops constituting the motor domain, showing 67% identity to sea urchin axonemal beta heavy chain dyneins; the gene spans 390 kb across 69 exons and produces alternatively spliced transcripts in nasal epithelium and testis.","method":"cDNA cloning (5' RACE, RT-PCR, cDNA library screening), genomic sequencing of BAC clones, in silico domain analysis","journal":"Genomics","confidence":"High","confidence_rationale":"Tier 1 — complete cDNA/genomic structure determination with domain characterization; foundational paper","pmids":["11247663"],"is_preprint":false},{"year":2005,"finding":"In normal human ciliated airway epithelium, DNAH5 localizes pan-axonemally while DNAH9 shows a distinct regional distribution along the ciliary axoneme, indicating the existence of at least two distinct outer dynein arm (ODA) types; in patients with DNAH5 or DNAI1 mutations, DNAH5 is absent from the ciliary axoneme and accumulates at microtubule-organizing centers, whereas sperm tails from DNAH5-mutant patients retain normal ODA heavy chain distribution.","method":"High-resolution immunofluorescence imaging with specific antibodies, high-speed video microscopy","journal":"American journal of respiratory and critical care medicine","confidence":"High","confidence_rationale":"Tier 2 — direct subcellular localization with functional consequence (motility phenotype), large cohort, blinded analysis","pmids":["15750039"],"is_preprint":false},{"year":2000,"finding":"An axonemal dynein heavy chain (corresponding to DNAH9) is expressed early during airway epithelial ciliogenesis, with transcript expression preceding visible ciliation and the protein detectable in the cytoplasm and at the apical border of non-ciliated cells before cilia appear, suggesting a role in early ciliogenesis.","method":"Northern blot, immunohistochemistry, in vitro ciliogenesis model","journal":"American journal of respiratory cell and molecular biology","confidence":"Medium","confidence_rationale":"Tier 2 — direct localization during ciliogenesis with temporal functional inference, single lab","pmids":["11104725"],"is_preprint":false},{"year":2018,"finding":"DNAH9 is the beta heavy chain defining type 2 ODAs localised to the distal ciliary axoneme; DNAH9-deficient respiratory cilia lack DNAH5, DNAI1, and DNAI2 from the distal axonemal compartment, demonstrating that DNAH9 is essential for distal axonemal assembly of ODA type 2. Yeast two-hybrid and co-immunoprecipitation analyses demonstrated direct interaction of DNAH9 with DNAH5, DNAI2, and the ODA-docking complex component CCDC114. During ciliogenesis, proximally located DNAH11 (ODA type 1) is assembled first, followed by distally located DNAH9 (ODA type 2).","method":"High-resolution immunofluorescence, high-speed video microscopy, yeast two-hybrid, co-immunoprecipitation, next-generation sequencing","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 1–2 — reciprocal Co-IP plus yeast two-hybrid, functional localization by IFM, multiple independent families, orthogonal methods","pmids":["30471718"],"is_preprint":false},{"year":2018,"finding":"DNAH9 mutations in PCD patients cause loss of DNAH9/DNAH5-containing type 2 ODAs restricted to the distal cilia region, resulting in reduced beating frequency with subtle distal beating pattern defects; 3D electron tomography confirmed regional loss of ODAs from the distal cilium as either whole ODA loss or partial ODA volume loss. Paramecium DNAH9 knockdown confirmed an evolutionarily conserved function for DNAH9 in cilia motility and ODA stability.","method":"Next-generation sequencing, immunofluorescence, high-speed video microscopy, 3D electron tomography, Paramecium RNAi knockdown","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 1–2 — multiple orthogonal structural and functional methods, evolutionary conservation confirmed by model organism knockdown","pmids":["30471717"],"is_preprint":false},{"year":2008,"finding":"In patients with DNAI2 mutations, both DNAH5 and DNAH9 are completely absent from all ciliary axonemes, demonstrating that DNAI2 (an ODA intermediate chain) is required for assembly of both proximal and distal ODA complexes containing DNAH9. Conversely, in DNAH5-mutant cilia, DNAI2 shows complete absence, establishing interdependence among ODA components for axonemal incorporation.","method":"High-resolution immunofluorescence imaging, electron microscopy, protein expression analysis","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 2 — direct IFM localization across multiple patient genotypes establishing epistatic assembly relationships","pmids":["18950741"],"is_preprint":false},{"year":2016,"finding":"DNAH9 localizes to the distal region of respiratory ciliary axonemes (defining ODA type 2), while DNAH11 localizes only to the proximal region (defining ODA type 1); these two beta heavy chain paralogs define structurally and functionally distinct ODA complexes along the axoneme. In DNAH11-mutant cilia, DNAH9 retains distal localization, confirming independent assembly of these two ODA subtypes.","method":"High-resolution immunofluorescence with validated monoclonal antibody, TEM tomography, GFP-LRD mouse model","journal":"American journal of respiratory cell and molecular biology","confidence":"High","confidence_rationale":"Tier 2 — direct localization with validated antibody, confirmed in mouse model, multiple independent PCD families","pmids":["26909801"],"is_preprint":false},{"year":2019,"finding":"DNAH9 (a beta-type HC) is absent from sperm axonemes in control individuals, whereas DNAH17 and DNAH8 (but not DNAH5, DNAH9, or DNAH11) colocalize with alpha-tubulin along sperm axonemes; conversely, DNAH9 is present in respiratory cilia but not sperm, demonstrating cell-type-specific ODA heavy chain composition between respiratory cilia and sperm flagella.","method":"Immunofluorescence, immunoblot on sperm and respiratory cells from control individuals and DNAH17-mutant patients","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 2 — direct comparative localization in two cell types, multiple orthogonal methods establishing cell-type-specific ODA composition","pmids":["31178125"],"is_preprint":false},{"year":2021,"finding":"DNAH9 variants cause nonsyndromic severe asthenozoospermia without respiratory phenotype or situs inversus; immunofluorescence showed reduced DNAH9 protein in sperm tails, and electron microscopy revealed outer dynein arm ultrastructural defects in sperm axonemes of affected individuals.","method":"Whole exome sequencing, Sanger sequencing, transmission electron microscopy, immunofluorescence, qRT-PCR","journal":"Reproductive biology and endocrinology","confidence":"Medium","confidence_rationale":"Tier 2–3 — direct ultrastructural and protein localization evidence in human patients; single lab","pmids":["33610189"],"is_preprint":false},{"year":2022,"finding":"DNAH9 interacts with CCDC114 and GAS8 (as shown by co-immunoprecipitation), and DNAH9 knockdown in mice diminishes protein levels of both CCDC114 and GAS8; Dnah9 KD mice exhibit low lung function, mucin accumulation, and increased immune cell infiltration, recapitulating PCD phenotypes.","method":"Co-immunoprecipitation, immunostaining, western blot, Dnah9 knockdown mouse model, lung function testing","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP interaction validated in mouse model with defined phenotypic readouts; single lab","pmids":["35729109"],"is_preprint":false},{"year":2022,"finding":"dnah9 knockdown in zebrafish disturbs cardiac left-right patterning without affecting ciliogenesis in Kupffer's vesicle; Dnah9 knockout mice show compromised cardiac function, demonstrating a role for DNAH9 in left-right body asymmetry determination and cardiac development.","method":"Zebrafish morpholino knockdown, Dnah9 KO mouse model (C57BL/6n), cardiac function assessment, transmission electron microscopy","journal":"Human genetics","confidence":"Medium","confidence_rationale":"Tier 2 — loss-of-function in two model organisms with defined phenotypic readout; single lab","pmids":["35050399"],"is_preprint":false},{"year":2024,"finding":"Biallelic DNAH9 variants in asthenospermic patients cause significant reduction of outer dynein arms in sperm axoneme cross-sections and lead to decreased expression of flagellar ultrastructure-related proteins DNAI1, DNAH1, and DNAH10, indicating that DNAH9 is required for stability and axonemal incorporation of multiple ODA and associated proteins in sperm flagella.","method":"Transmission electron microscopy, immunofluorescence, Sanger sequencing, whole exome sequencing","journal":"Journal of human genetics","confidence":"Medium","confidence_rationale":"Tier 2–3 — direct ultrastructural evidence with protein co-dependency shown; single lab, small cohort","pmids":["39523437"],"is_preprint":false}],"current_model":"DNAH9 is an axonemal dynein beta heavy chain that defines type 2 outer dynein arms (ODAs) specifically in the distal compartment of respiratory cilia (while the paralog DNAH11 occupies the proximal ODA type 1 compartment); it physically interacts with DNAH5, DNAI2, and the ODA-docking component CCDC114, and is required for distal axonemal assembly of ODA type 2—its loss causes distal ODA deficiency, impaired ciliary beating, laterality defects, and chronic airway disease, while in sperm flagella DNAH9 is absent (replaced by DNAH17/DNAH8), though biallelic DNAH9 mutations can still disrupt sperm ODA integrity and cause asthenozoospermia."},"narrative":{"teleology":[{"year":2000,"claim":"Early ciliogenesis studies revealed that DNAH9 transcripts and protein appear in airway epithelial cells before visible ciliation, establishing that this dynein heavy chain is among the first axonemal components synthesized during differentiation.","evidence":"Northern blot, immunohistochemistry, and in vitro ciliogenesis model in human airway epithelium","pmids":["11104725"],"confidence":"Medium","gaps":["Single-lab observation without genetic perturbation","Temporal data do not establish whether DNAH9 is functionally required at the earliest ciliogenesis steps"]},{"year":2001,"claim":"Cloning of the full-length DNAH9 cDNA defined its domain architecture—an N-terminal stem and a C-terminal motor domain with four P-loops—placing it as a bona fide axonemal beta dynein heavy chain ortholog.","evidence":"5′ RACE, RT-PCR, BAC genomic sequencing, domain prediction","pmids":["11247663"],"confidence":"High","gaps":["No functional assays performed","ATPase activity not directly measured"]},{"year":2005,"claim":"High-resolution immunofluorescence demonstrated that DNAH9 occupies a restricted axonemal region distinct from pan-axonemal DNAH5, providing the first evidence that human respiratory cilia contain at least two molecularly distinct ODA types.","evidence":"Immunofluorescence with specific antibodies on human ciliated airway epithelium and PCD patient samples","pmids":["15750039"],"confidence":"High","gaps":["Proximal vs. distal boundary not precisely defined","Interaction partners not identified"]},{"year":2008,"claim":"Analysis of DNAI2- and DNAH5-mutant cilia showed that DNAH9 axonemal assembly depends on the intermediate chain DNAI2 and the alpha heavy chain DNAH5, establishing an epistatic assembly hierarchy among ODA subunits.","evidence":"Immunofluorescence and electron microscopy across multiple PCD genotypes","pmids":["18950741"],"confidence":"High","gaps":["Direct physical interactions not tested in this study","Whether DNAH9 reciprocally stabilizes DNAI2 was not addressed"]},{"year":2016,"claim":"Identification of DNAH11 as the proximal ODA beta heavy chain, together with demonstration that DNAH9 retains distal localization in DNAH11-mutant cilia, established that the two ODA subtypes assemble independently along the proximo-distal axis.","evidence":"Immunofluorescence with validated monoclonal antibodies, TEM tomography, GFP-LRD mouse model","pmids":["26909801"],"confidence":"High","gaps":["Signals determining positional identity of each ODA subtype remain unknown","No structural model of the two ODA subtypes"]},{"year":2018,"claim":"Two concurrent studies established DNAH9 as the disease gene for a PCD subtype characterized by distal-only ODA loss: direct interactions with DNAH5, DNAI2, and the docking component CCDC114 were confirmed by co-immunoprecipitation and yeast two-hybrid, and 3D electron tomography resolved regional ODA volume loss, while Paramecium RNAi validated evolutionary conservation.","evidence":"Patient genetics (multiple families), immunofluorescence, Co-IP, Y2H, 3D electron tomography, Paramecium RNAi","pmids":["30471718","30471717"],"confidence":"High","gaps":["Structural basis of DNAH9-CCDC114 docking interaction unresolved","How distal positional cues target DNAH9 versus DNAH11 remains unknown"]},{"year":2019,"claim":"Comparative localization showed that DNAH9 is absent from human sperm axonemes (replaced by DNAH17/DNAH8), revealing cell-type-specific ODA heavy chain composition and explaining why DNAH9-PCD patients can retain normal sperm motility.","evidence":"Immunofluorescence and immunoblot on respiratory cilia and sperm from controls and DNAH17-mutant patients","pmids":["31178125"],"confidence":"High","gaps":["Mechanism by which different beta HCs are selected in sperm versus respiratory cilia is unknown"]},{"year":2021,"claim":"Identification of biallelic DNAH9 variants causing nonsyndromic asthenozoospermia without respiratory disease indicated that DNAH9 contributes to sperm ODA integrity in some individuals despite its apparent absence from normal sperm axonemes, suggesting context- or allele-dependent effects.","evidence":"Whole exome sequencing, TEM, immunofluorescence, qRT-PCR on patient sperm","pmids":["33610189"],"confidence":"Medium","gaps":["Apparent contradiction with absence of DNAH9 in normal sperm not resolved","Small cohort, single lab","Functional rescue not performed"]},{"year":2022,"claim":"Mouse and zebrafish loss-of-function models demonstrated that DNAH9 is required for left-right asymmetry determination and cardiac function, broadening its role beyond airway cilia to nodal cilia-dependent laterality signaling, and Dnah9 knockdown mice recapitulated PCD-like lung pathology including mucin accumulation.","evidence":"Zebrafish morpholino knockdown, Dnah9 KO and KD mouse models, Co-IP, lung function testing","pmids":["35050399","35729109"],"confidence":"Medium","gaps":["Cardiac phenotype mechanism (direct versus secondary to laterality defect) not distinguished","Single-lab studies for each model organism"]},{"year":2024,"claim":"Further characterization of DNAH9-mutant sperm showed reduced axonemal incorporation of DNAI1, DNAH1, and DNAH10, indicating DNAH9 stabilizes additional ODA and inner dynein arm components in the flagellar context.","evidence":"TEM, immunofluorescence, whole exome and Sanger sequencing on asthenospermic patients","pmids":["39523437"],"confidence":"Medium","gaps":["Small cohort","Whether DNAH9 directly binds DNAH1/DNAH10 or acts indirectly is untested","Functional rescue not performed"]},{"year":null,"claim":"The positional cues that target DNAH9 to the distal axoneme while restricting DNAH11 to the proximal compartment remain unknown, and no high-resolution structural model of the human type 2 ODA complex exists.","evidence":"","pmids":[],"confidence":"High","gaps":["No cryo-EM or X-ray structure of human DNAH9-containing ODA","Distal targeting signal or adaptor not identified","Reconciliation of DNAH9 absence in normal sperm with sperm phenotype in DNAH9-mutant patients unresolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140657","term_label":"ATP-dependent activity","supporting_discovery_ids":[0]},{"term_id":"GO:0003774","term_label":"cytoskeletal motor activity","supporting_discovery_ids":[0,3,4]}],"localization":[{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[1,3,4,6,7]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[1,3,6]}],"pathway":[{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[2,3,4,6]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[10]}],"complexes":["Outer dynein arm type 2 (distal ODA)"],"partners":["DNAH5","DNAI2","CCDC114","GAS8","DNAI1"],"other_free_text":[]},"mechanistic_narrative":"DNAH9 is an axonemal dynein beta heavy chain that defines type 2 outer dynein arms (ODAs) in the distal compartment of motile respiratory cilia, functioning as an ATP-dependent minus-end-directed microtubule motor essential for ciliary beating. DNAH9 physically interacts with the ODA components DNAH5, DNAI2, and the docking complex subunit CCDC114, and its loss causes selective failure of distal ODA assembly, resulting in reduced ciliary beat frequency and subtle distal waveform defects that underlie primary ciliary dyskinesia with laterality defects and chronic airway disease [PMID:30471718, PMID:30471717]. Although DNAH9 is normally absent from sperm flagella—where DNAH17 and DNAH8 serve as the beta heavy chains [PMID:31178125]—biallelic DNAH9 variants can nonetheless disrupt sperm ODA integrity and cause severe asthenozoospermia [PMID:33610189, PMID:39523437]. Loss of DNAH9 function in zebrafish and mouse models disturbs left-right body axis determination and cardiac development, confirming an evolutionarily conserved role in nodal cilia-dependent laterality signaling [PMID:35050399]."},"prefetch_data":{"uniprot":{"accession":"Q9NYC9","full_name":"Dynein axonemal heavy chain 9","aliases":["Axonemal beta dynein heavy chain 9","Ciliary dynein heavy chain 9"],"length_aa":4486,"mass_kda":511.9,"function":"Force generating protein required for cilia beating in respiratory epithelia (PubMed:30471717, PubMed:30471718). Produces force towards the minus ends of microtubules (PubMed:30471717, PubMed:30471718). Key component of dynein, a family of motor proteins essential for movement along microtubules (By similarity). Dynein has ATPase activity; the force-producing power stroke is thought to occur on release of ADP (PubMed:30471717, PubMed:30471718). Required for structural and functional integrity of cilia (PubMed:30471717, PubMed:30471718)","subcellular_location":"Cytoplasm, cytoskeleton, cilium axoneme; Cell projection, cilium, flagellum","url":"https://www.uniprot.org/uniprotkb/Q9NYC9/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/DNAH9","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/DNAH9","total_profiled":1310},"omim":[{"mim_id":"618300","title":"CILIARY DYSKINESIA, PRIMARY, 40; CILD40","url":"https://www.omim.org/entry/618300"},{"mim_id":"618063","title":"CILIARY DYSKINESIA, PRIMARY, 38; CILD38","url":"https://www.omim.org/entry/618063"},{"mim_id":"618058","title":"CILIA- AND FLAGELLA-ASSOCIATED PROTEIN 300; CFAP300","url":"https://www.omim.org/entry/618058"},{"mim_id":"615408","title":"OUTER DYNEIN ARM DOCKING COMPLEX SUBUNIT 2; ODAD2","url":"https://www.omim.org/entry/615408"},{"mim_id":"614566","title":"DYNEIN, AXONEMAL, ASSEMBLY FACTOR 3; DNAAF3","url":"https://www.omim.org/entry/614566"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Flagellar centriole","reliability":"Supported"},{"location":"End piece","reliability":"Supported"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"brain","ntpm":13.5},{"tissue":"choroid plexus","ntpm":11.9},{"tissue":"fallopian tube","ntpm":33.1}],"url":"https://www.proteinatlas.org/search/DNAH9"},"hgnc":{"alias_symbol":["Dnahc9","KIAA0357","HL20","HL-20","DNAL1","DYH9"],"prev_symbol":["DNAH17L"]},"alphafold":{"accession":"Q9NYC9","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NYC9","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NYC9-3-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9NYC9-3-F1-predicted_aligned_error_v6.png","plddt_mean":92.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=DNAH9","jax_strain_url":"https://www.jax.org/strain/search?query=DNAH9"},"sequence":{"accession":"Q9NYC9","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9NYC9.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9NYC9/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9NYC9"}},"corpus_meta":[{"pmid":"15750039","id":"PMC_15750039","title":"Mislocalization of DNAH5 and DNAH9 in respiratory cells from patients with primary ciliary dyskinesia.","date":"2005","source":"American journal of respiratory and critical care medicine","url":"https://pubmed.ncbi.nlm.nih.gov/15750039","citation_count":229,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"30471717","id":"PMC_30471717","title":"Mutations in Outer Dynein Arm Heavy Chain DNAH9 Cause Motile Cilia Defects and Situs Inversus.","date":"2018","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/30471717","citation_count":100,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"21496787","id":"PMC_21496787","title":"Primary ciliary dyskinesia caused by homozygous mutation in DNAL1, encoding dynein light chain 1.","date":"2011","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/21496787","citation_count":98,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"11247663","id":"PMC_11247663","title":"Axonemal beta heavy chain dynein DNAH9: cDNA sequence, genomic structure, and investigation of its role in primary ciliary dyskinesia.","date":"2001","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/11247663","citation_count":38,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"33610189","id":"PMC_33610189","title":"Novel variants in DNAH9 lead to nonsyndromic severe asthenozoospermia.","date":"2021","source":"Reproductive biology and endocrinology : RB&E","url":"https://pubmed.ncbi.nlm.nih.gov/33610189","citation_count":28,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"35729109","id":"PMC_35729109","title":"Dnah9 mutant mice and organoid models recapitulate the clinical features of patients with PCD and provide an excellent platform for drug screening.","date":"2022","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/35729109","citation_count":19,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"26797031","id":"PMC_26797031","title":"Interaction between the DNAH9 gene and early smoke exposure in bronchial hyperresponsiveness.","date":"2016","source":"The European respiratory journal","url":"https://pubmed.ncbi.nlm.nih.gov/26797031","citation_count":18,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"35050399","id":"PMC_35050399","title":"Biallelic DNAH9 mutations are identified in Chinese patients with defective left-right patterning and cilia-related complex congenital heart disease.","date":"2022","source":"Human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/35050399","citation_count":14,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"36841509","id":"PMC_36841509","title":"Deletions in DNAL1 Cause Primary Ciliary Dyskinesia Across North American Indigenous Populations.","date":"2023","source":"The Journal of pediatrics","url":"https://pubmed.ncbi.nlm.nih.gov/36841509","citation_count":5,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"39523437","id":"PMC_39523437","title":"Novel variants in DNAH9 are present in two infertile patients with severe asthenospermia.","date":"2024","source":"Journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/39523437","citation_count":3,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"36712782","id":"PMC_36712782","title":"A Novel DNAH9 Gene Mutation Causing Primary Ciliary Dyskinesia With an Unusual Association of Jejunal Atresia in a Bahraini Child.","date":"2022","source":"Cureus","url":"https://pubmed.ncbi.nlm.nih.gov/36712782","citation_count":3,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"34008076","id":"PMC_34008076","title":"Whole-exome sequencing reveals a combination of extremely rare single-nucleotide polymorphism of DNAH9 and RSPH1 genes in a Japanese fetus with situs viscerum inversus.","date":"2021","source":"Medical molecular morphology","url":"https://pubmed.ncbi.nlm.nih.gov/34008076","citation_count":3,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"40376972","id":"PMC_40376972","title":"Novel compound heterozygous mutation in DNAH9 causes complex congenital heart disease.","date":"2025","source":"Molecular medicine reports","url":"https://pubmed.ncbi.nlm.nih.gov/40376972","citation_count":1,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"35116053","id":"PMC_35116053","title":"Fetal Congenital Heart Disease Caused by Compound Heterozygous Mutations in the DNAH9 Gene: A Case Report.","date":"2022","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/35116053","citation_count":1,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"26377939","id":"PMC_26377939","title":"Characterization and genomic structure of Dnah9, and its roles in nodal signaling pathways in the Japanese flounder (Paralichthys olivaceus).","date":"2015","source":"Fish physiology and biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/26377939","citation_count":0,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":"40065384","id":"PMC_40065384","title":"DNAH9 variants in children with post-infectious bronchiolitis/bronchitis obliterans.","date":"2025","source":"Orphanet journal of rare diseases","url":"https://pubmed.ncbi.nlm.nih.gov/40065384","citation_count":0,"is_preprint":false,"source_track":"pubmed_title"},{"pmid":null,"id":"bio_10.1101_2025.07.06.25330330","title":"Spatial and single-cell transcriptomics landscape of adenomyosis","date":"2025-07-07","source":"bioRxiv","url":"https://doi.org/10.1101/2025.07.06.25330330","citation_count":0,"is_preprint":true,"source_track":"pubmed_title"},{"pmid":"12477932","id":"PMC_12477932","title":"Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences.","date":"2002","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/12477932","citation_count":1479,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"14702039","id":"PMC_14702039","title":"Complete sequencing and characterization of 21,243 full-length human cDNAs.","date":"2003","source":"Nature genetics","url":"https://pubmed.ncbi.nlm.nih.gov/14702039","citation_count":754,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"26912792","id":"PMC_26912792","title":"An improved smaller biotin ligase for BioID proximity labeling.","date":"2016","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/26912792","citation_count":665,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"21873635","id":"PMC_21873635","title":"Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium.","date":"2011","source":"Briefings in bioinformatics","url":"https://pubmed.ncbi.nlm.nih.gov/21873635","citation_count":656,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"26344197","id":"PMC_26344197","title":"Panorama of ancient metazoan macromolecular complexes.","date":"2015","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/26344197","citation_count":407,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"25593309","id":"PMC_25593309","title":"Screen identifies bromodomain protein ZMYND8 in chromatin recognition of transcription-associated DNA damage that promotes homologous recombination.","date":"2015","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/25593309","citation_count":203,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"18950741","id":"PMC_18950741","title":"DNAI2 mutations cause primary ciliary dyskinesia with defects in the outer dynein arm.","date":"2008","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/18950741","citation_count":192,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"9205841","id":"PMC_9205841","title":"Prediction of the coding sequences of unidentified human genes. VII. The complete sequences of 100 new cDNA clones from brain which can code for large proteins in vitro.","date":"1997","source":"DNA research : an international journal for rapid publication of reports on genes and genomes","url":"https://pubmed.ncbi.nlm.nih.gov/9205841","citation_count":187,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"31178125","id":"PMC_31178125","title":"Mutations in DNAH17, Encoding a Sperm-Specific Axonemal Outer Dynein Arm Heavy Chain, Cause Isolated Male Infertility Due to Asthenozoospermia.","date":"2019","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/31178125","citation_count":145,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"23849778","id":"PMC_23849778","title":"ARMC4 mutations cause primary ciliary dyskinesia with randomization of left/right body asymmetry.","date":"2013","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/23849778","citation_count":123,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"34349018","id":"PMC_34349018","title":"Protein interaction landscapes revealed by advanced in vivo cross-linking-mass spectrometry.","date":"2021","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/34349018","citation_count":113,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"30471718","id":"PMC_30471718","title":"Recessive DNAH9 Loss-of-Function Mutations Cause Laterality Defects and Subtle Respiratory Ciliary-Beating Defects.","date":"2018","source":"American journal of human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/30471718","citation_count":109,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"20379614","id":"PMC_20379614","title":"Personalized smoking cessation: interactions between nicotine dose, dependence and quit-success genotype score.","date":"2010","source":"Molecular medicine (Cambridge, Mass.)","url":"https://pubmed.ncbi.nlm.nih.gov/20379614","citation_count":108,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"26909801","id":"PMC_26909801","title":"DNAH11 Localization in the Proximal Region of Respiratory Cilia Defines Distinct Outer Dynein Arm Complexes.","date":"2016","source":"American journal of respiratory cell and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/26909801","citation_count":101,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"31452512","id":"PMC_31452512","title":"Systematic identification of cancer cell vulnerabilities to natural killer cell-mediated immune surveillance.","date":"2019","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/31452512","citation_count":77,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"31586073","id":"PMC_31586073","title":"The midbody interactome reveals unexpected roles for PP1 phosphatases in cytokinesis.","date":"2019","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/31586073","citation_count":74,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"8812413","id":"PMC_8812413","title":"Multiple mouse chromosomal loci for dynein-based motility.","date":"1996","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/8812413","citation_count":71,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"35256949","id":"PMC_35256949","title":"Histone deacetylase inhibitors inhibit cervical cancer growth through Parkin acetylation-mediated mitophagy.","date":"2021","source":"Acta pharmaceutica Sinica. B","url":"https://pubmed.ncbi.nlm.nih.gov/35256949","citation_count":66,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"16147992","id":"PMC_16147992","title":"Analysis of BCL6-interacting proteins by tandem mass spectrometry.","date":"2005","source":"Molecular & cellular proteomics : MCP","url":"https://pubmed.ncbi.nlm.nih.gov/16147992","citation_count":45,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"11175280","id":"PMC_11175280","title":"Identification, tissue specific expression, and chromosomal localisation of several human dynein heavy chain genes.","date":"2000","source":"European journal of human genetics : EJHG","url":"https://pubmed.ncbi.nlm.nih.gov/11175280","citation_count":44,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"23049088","id":"PMC_23049088","title":"A genome-wide association study provides evidence for association of chromosome 8p23 (MYP10) and 10q21.1 (MYP15) with high myopia in the French Population.","date":"2012","source":"Investigative ophthalmology & visual science","url":"https://pubmed.ncbi.nlm.nih.gov/23049088","citation_count":44,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"24811271","id":"PMC_24811271","title":"Genome-wide SNP associations with rubella-specific cytokine responses in measles-mumps-rubella vaccine recipients.","date":"2014","source":"Immunogenetics","url":"https://pubmed.ncbi.nlm.nih.gov/24811271","citation_count":37,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"26167880","id":"PMC_26167880","title":"SR protein kinases promote splicing of nonconsensus introns.","date":"2015","source":"Nature structural & molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/26167880","citation_count":37,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"15845866","id":"PMC_15845866","title":"Identification and analysis of axonemal dynein light chain 1 in primary ciliary dyskinesia patients.","date":"2005","source":"American journal of respiratory cell and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/15845866","citation_count":34,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"40140646","id":"PMC_40140646","title":"Combined targeting of glioblastoma stem cells of different cellular states disrupts malignant progression.","date":"2025","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/40140646","citation_count":21,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"11104725","id":"PMC_11104725","title":"Characterization of an axonemal dynein heavy chain expressed early in airway epithelial ciliogenesis.","date":"2000","source":"American journal of respiratory cell and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/11104725","citation_count":17,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"27433848","id":"PMC_27433848","title":"BRCA2 mediates centrosome cohesion via an interaction with cytoplasmic dynein.","date":"2016","source":"Cell cycle (Georgetown, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/27433848","citation_count":17,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"32665550","id":"PMC_32665550","title":"NudCL2 regulates cell migration by stabilizing both myosin-9 and LIS1 with Hsp90.","date":"2020","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/32665550","citation_count":17,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"8703119","id":"PMC_8703119","title":"Characterization of a novel human dynein-related gene that is specifically expressed in testis.","date":"1996","source":"Mammalian genome : official journal of the International Mammalian Genome Society","url":"https://pubmed.ncbi.nlm.nih.gov/8703119","citation_count":17,"is_preprint":false,"source_track":"gene2pubmed"},{"pmid":"39503742","id":"PMC_39503742","title":"DNAH3 deficiency causes flagellar inner dynein arm loss and male infertility in humans and mice.","date":"2024","source":"eLife","url":"https://pubmed.ncbi.nlm.nih.gov/39503742","citation_count":12,"is_preprint":false,"source_track":"gene2pubmed"}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":9844,"output_tokens":2249,"usd":0.031634},"stage2":{"model":"claude-opus-4-6","input_tokens":5580,"output_tokens":2256,"usd":0.12645},"total_usd":0.362126,"stage1_batch_id":"msgbatch_0118RScg3WGaGkaZRtWZbtce","stage2_batch_id":"msgbatch_01Cpfzvtbj42aqp5oYZ5Te2s","note":"batch pricing = 50% of standard","round2_stage1":{"model":"claude-sonnet-4-6","input_tokens":23428,"output_tokens":3062,"usd":0.058107},"round2_rules_fired":"R2","round2_stage2":{"model":"claude-opus-4-6","input_tokens":6658,"output_tokens":2560,"usd":0.145935}},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2001,\n      \"finding\": \"DNAH9 encodes a human axonemal beta heavy chain dynein of 4486 amino acids, consisting of an N-terminal stem and a globular C-terminus containing four P-loops that constitute the motor domain, coupling ATPase activity with conformational changes to drive ciliary and flagellar bending.\",\n      \"method\": \"cDNA cloning, RT-PCR, genomic sequencing, sequence homology analysis\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 structural/biochemical characterization — single lab, sequence-based domain identification with functional inference from homology\",\n      \"pmids\": [\"11247663\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"In normal human respiratory ciliary axonemes, DNAH5 and DNAH9 show distinct regional distributions, indicating the existence of at least two distinct outer dynein arm (ODA) types along the axoneme; DNAH9 localizes to the distal portion of the ciliary axoneme.\",\n      \"method\": \"High-resolution immunofluorescence imaging of respiratory epithelial cells with specific antibodies\",\n      \"journal\": \"American journal of respiratory and critical care medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct localization experiment in human tissue, replicated across control and patient cohorts, widely cited\",\n      \"pmids\": [\"15750039\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"In sperm tails from patients with DNAH5 mutations, ODA heavy chain distribution including DNAH9 was normal, suggesting different modes of ODA assembly or incorporation in respiratory cilia versus sperm flagella.\",\n      \"method\": \"High-resolution immunofluorescence imaging of sperm cells\",\n      \"journal\": \"American journal of respiratory and critical care medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct localization comparison between two cell types in human samples, single lab\",\n      \"pmids\": [\"15750039\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"DNAH9 and its partner heavy chain DNAH5 co-localize to type 2 ODAs of the distal cilium; loss-of-function DNAH9 mutations cause selective loss of DNAH9/DNAH5-containing type 2 ODAs restricted to the distal cilia region, reducing beating frequency with a subtle beating pattern defect affecting distal cilia motility.\",\n      \"method\": \"Immunofluorescence localization, 3D electron tomography, high-speed video microscopy, Paramecium DNAH9 knockdown\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal methods (IF, 3D-ET, functional video microscopy, invertebrate knockdown), widely cited, consistent findings across labs\",\n      \"pmids\": [\"30471717\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Paramecium DNAH9 knockdown confirms an evolutionarily conserved function for DNAH9 in cilia motility and ODA stability.\",\n      \"method\": \"Paramecium knockdown (RNAi-equivalent), cilia motility assay\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic loss-of-function with defined cellular phenotype in a model organism, consistent with human data in same study\",\n      \"pmids\": [\"30471717\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"DNAH9 physically interacts with CCDC114 and GAS8, and loss of DNAH9 (knockdown in mice) diminishes protein levels of both CCDC114 and GAS8, placing DNAH9 within a protein complex required for ODA integrity.\",\n      \"method\": \"Co-immunoprecipitation, immunostaining, western blot in Dnah9 knockdown mouse model\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — co-IP interaction identified with functional consequence (reduced partner levels), single lab\",\n      \"pmids\": [\"35729109\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Dnah9 knockdown mice exhibit reduced lung function, mucin accumulation, and increased immune cell infiltration, demonstrating DNAH9 is required for normal mucociliary clearance in vivo.\",\n      \"method\": \"Dnah9 knockdown mouse model with lung function measurement, histology, immunostaining\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — clean knockdown with defined multi-parameter phenotypic readout, single lab\",\n      \"pmids\": [\"35729109\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"dnah9 knockdown in zebrafish disrupts cardiac left-right patterning without affecting ciliogenesis in Kupffer's vesicle, and Dnah9 knockout mice show compromised cardiac function, establishing a role for DNAH9 in left-right axis determination through ODA-dependent ciliary motility.\",\n      \"method\": \"Zebrafish dnah9 morpholino knockdown with cardiac laterality assessment; Dnah9 knockout C57BL/6n mouse model with cardiac function measurement\",\n      \"journal\": \"Human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic loss-of-function in two vertebrate model organisms with defined phenotypic readouts, single lab\",\n      \"pmids\": [\"35050399\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Loss-of-function DNAH9 variants in humans cause nonsyndromic severe asthenozoospermia with ultrastructural ODA defects in sperm flagella and reduced DNAH9 expression in sperm tails, without respiratory or situs inversus phenotypes, demonstrating a sperm-specific functional role.\",\n      \"method\": \"Whole exome sequencing, Sanger sequencing, transmission electron microscopy of sperm axoneme, immunofluorescence, qRT-PCR\",\n      \"journal\": \"Reproductive biology and endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — multiple orthogonal methods in human patients, single lab\",\n      \"pmids\": [\"33610189\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"DNAH9 variants causing loss of outer dynein arms in sperm axonemes also lead to secondary reduction of ODA-associated proteins DNAI1, DNAH1, and DNAH10, indicating DNAH9 is required for the structural integrity of the entire ODA complex in flagella.\",\n      \"method\": \"Transmission electron microscopy, immunofluorescence in patient sperm\",\n      \"journal\": \"Journal of human genetics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single lab, patient-based observation without reconstitution or direct interaction assay\",\n      \"pmids\": [\"39523437\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"A DNAH9 splicing mutation (c.3743+1G>T) leads to abnormal mRNA splicing as confirmed by minigene analysis, demonstrating a molecular mechanism by which intronic DNAH9 variants disrupt protein production.\",\n      \"method\": \"Minigene splicing assay, bioinformatics splice prediction\",\n      \"journal\": \"Molecular medicine reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — direct minigene functional assay of splicing, single lab but orthogonal to in silico prediction\",\n      \"pmids\": [\"40376972\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"DNAH9 is an axonemal beta heavy chain dynein that localizes specifically to type 2 outer dynein arms (ODAs) of the distal ciliary axoneme, where it partners with DNAH5 and interacts with CCDC114 and GAS8 to provide mechanical force for cilia and sperm flagella beating; loss of DNAH9 selectively disrupts distal ODA integrity, reducing ciliary beat frequency and mucociliary clearance, causing left-right axis defects, and impairing sperm motility without affecting ciliogenesis itself.\"\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2001,\n      \"finding\": \"DNAH9 encodes a 4486-amino-acid human axonemal dynein beta heavy chain mapping to 17p12, with an N-terminal stem and a globular C-terminus containing four P-loops constituting the motor domain, showing 67% identity to sea urchin axonemal beta heavy chain dyneins; the gene spans 390 kb across 69 exons and produces alternatively spliced transcripts in nasal epithelium and testis.\",\n      \"method\": \"cDNA cloning (5' RACE, RT-PCR, cDNA library screening), genomic sequencing of BAC clones, in silico domain analysis\",\n      \"journal\": \"Genomics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — complete cDNA/genomic structure determination with domain characterization; foundational paper\",\n      \"pmids\": [\"11247663\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"In normal human ciliated airway epithelium, DNAH5 localizes pan-axonemally while DNAH9 shows a distinct regional distribution along the ciliary axoneme, indicating the existence of at least two distinct outer dynein arm (ODA) types; in patients with DNAH5 or DNAI1 mutations, DNAH5 is absent from the ciliary axoneme and accumulates at microtubule-organizing centers, whereas sperm tails from DNAH5-mutant patients retain normal ODA heavy chain distribution.\",\n      \"method\": \"High-resolution immunofluorescence imaging with specific antibodies, high-speed video microscopy\",\n      \"journal\": \"American journal of respiratory and critical care medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct subcellular localization with functional consequence (motility phenotype), large cohort, blinded analysis\",\n      \"pmids\": [\"15750039\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"An axonemal dynein heavy chain (corresponding to DNAH9) is expressed early during airway epithelial ciliogenesis, with transcript expression preceding visible ciliation and the protein detectable in the cytoplasm and at the apical border of non-ciliated cells before cilia appear, suggesting a role in early ciliogenesis.\",\n      \"method\": \"Northern blot, immunohistochemistry, in vitro ciliogenesis model\",\n      \"journal\": \"American journal of respiratory cell and molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct localization during ciliogenesis with temporal functional inference, single lab\",\n      \"pmids\": [\"11104725\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"DNAH9 is the beta heavy chain defining type 2 ODAs localised to the distal ciliary axoneme; DNAH9-deficient respiratory cilia lack DNAH5, DNAI1, and DNAI2 from the distal axonemal compartment, demonstrating that DNAH9 is essential for distal axonemal assembly of ODA type 2. Yeast two-hybrid and co-immunoprecipitation analyses demonstrated direct interaction of DNAH9 with DNAH5, DNAI2, and the ODA-docking complex component CCDC114. During ciliogenesis, proximally located DNAH11 (ODA type 1) is assembled first, followed by distally located DNAH9 (ODA type 2).\",\n      \"method\": \"High-resolution immunofluorescence, high-speed video microscopy, yeast two-hybrid, co-immunoprecipitation, next-generation sequencing\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — reciprocal Co-IP plus yeast two-hybrid, functional localization by IFM, multiple independent families, orthogonal methods\",\n      \"pmids\": [\"30471718\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"DNAH9 mutations in PCD patients cause loss of DNAH9/DNAH5-containing type 2 ODAs restricted to the distal cilia region, resulting in reduced beating frequency with subtle distal beating pattern defects; 3D electron tomography confirmed regional loss of ODAs from the distal cilium as either whole ODA loss or partial ODA volume loss. Paramecium DNAH9 knockdown confirmed an evolutionarily conserved function for DNAH9 in cilia motility and ODA stability.\",\n      \"method\": \"Next-generation sequencing, immunofluorescence, high-speed video microscopy, 3D electron tomography, Paramecium RNAi knockdown\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 — multiple orthogonal structural and functional methods, evolutionary conservation confirmed by model organism knockdown\",\n      \"pmids\": [\"30471717\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"In patients with DNAI2 mutations, both DNAH5 and DNAH9 are completely absent from all ciliary axonemes, demonstrating that DNAI2 (an ODA intermediate chain) is required for assembly of both proximal and distal ODA complexes containing DNAH9. Conversely, in DNAH5-mutant cilia, DNAI2 shows complete absence, establishing interdependence among ODA components for axonemal incorporation.\",\n      \"method\": \"High-resolution immunofluorescence imaging, electron microscopy, protein expression analysis\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct IFM localization across multiple patient genotypes establishing epistatic assembly relationships\",\n      \"pmids\": [\"18950741\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"DNAH9 localizes to the distal region of respiratory ciliary axonemes (defining ODA type 2), while DNAH11 localizes only to the proximal region (defining ODA type 1); these two beta heavy chain paralogs define structurally and functionally distinct ODA complexes along the axoneme. In DNAH11-mutant cilia, DNAH9 retains distal localization, confirming independent assembly of these two ODA subtypes.\",\n      \"method\": \"High-resolution immunofluorescence with validated monoclonal antibody, TEM tomography, GFP-LRD mouse model\",\n      \"journal\": \"American journal of respiratory cell and molecular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct localization with validated antibody, confirmed in mouse model, multiple independent PCD families\",\n      \"pmids\": [\"26909801\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"DNAH9 (a beta-type HC) is absent from sperm axonemes in control individuals, whereas DNAH17 and DNAH8 (but not DNAH5, DNAH9, or DNAH11) colocalize with alpha-tubulin along sperm axonemes; conversely, DNAH9 is present in respiratory cilia but not sperm, demonstrating cell-type-specific ODA heavy chain composition between respiratory cilia and sperm flagella.\",\n      \"method\": \"Immunofluorescence, immunoblot on sperm and respiratory cells from control individuals and DNAH17-mutant patients\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct comparative localization in two cell types, multiple orthogonal methods establishing cell-type-specific ODA composition\",\n      \"pmids\": [\"31178125\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"DNAH9 variants cause nonsyndromic severe asthenozoospermia without respiratory phenotype or situs inversus; immunofluorescence showed reduced DNAH9 protein in sperm tails, and electron microscopy revealed outer dynein arm ultrastructural defects in sperm axonemes of affected individuals.\",\n      \"method\": \"Whole exome sequencing, Sanger sequencing, transmission electron microscopy, immunofluorescence, qRT-PCR\",\n      \"journal\": \"Reproductive biology and endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — direct ultrastructural and protein localization evidence in human patients; single lab\",\n      \"pmids\": [\"33610189\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"DNAH9 interacts with CCDC114 and GAS8 (as shown by co-immunoprecipitation), and DNAH9 knockdown in mice diminishes protein levels of both CCDC114 and GAS8; Dnah9 KD mice exhibit low lung function, mucin accumulation, and increased immune cell infiltration, recapitulating PCD phenotypes.\",\n      \"method\": \"Co-immunoprecipitation, immunostaining, western blot, Dnah9 knockdown mouse model, lung function testing\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP interaction validated in mouse model with defined phenotypic readouts; single lab\",\n      \"pmids\": [\"35729109\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"dnah9 knockdown in zebrafish disturbs cardiac left-right patterning without affecting ciliogenesis in Kupffer's vesicle; Dnah9 knockout mice show compromised cardiac function, demonstrating a role for DNAH9 in left-right body asymmetry determination and cardiac development.\",\n      \"method\": \"Zebrafish morpholino knockdown, Dnah9 KO mouse model (C57BL/6n), cardiac function assessment, transmission electron microscopy\",\n      \"journal\": \"Human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function in two model organisms with defined phenotypic readout; single lab\",\n      \"pmids\": [\"35050399\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Biallelic DNAH9 variants in asthenospermic patients cause significant reduction of outer dynein arms in sperm axoneme cross-sections and lead to decreased expression of flagellar ultrastructure-related proteins DNAI1, DNAH1, and DNAH10, indicating that DNAH9 is required for stability and axonemal incorporation of multiple ODA and associated proteins in sperm flagella.\",\n      \"method\": \"Transmission electron microscopy, immunofluorescence, Sanger sequencing, whole exome sequencing\",\n      \"journal\": \"Journal of human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 — direct ultrastructural evidence with protein co-dependency shown; single lab, small cohort\",\n      \"pmids\": [\"39523437\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"DNAH9 is an axonemal dynein beta heavy chain that defines type 2 outer dynein arms (ODAs) specifically in the distal compartment of respiratory cilia (while the paralog DNAH11 occupies the proximal ODA type 1 compartment); it physically interacts with DNAH5, DNAI2, and the ODA-docking component CCDC114, and is required for distal axonemal assembly of ODA type 2—its loss causes distal ODA deficiency, impaired ciliary beating, laterality defects, and chronic airway disease, while in sperm flagella DNAH9 is absent (replaced by DNAH17/DNAH8), though biallelic DNAH9 mutations can still disrupt sperm ODA integrity and cause asthenozoospermia.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"DNAH9 is an axonemal beta heavy chain dynein that provides ATP-dependent mechanical force for ciliary and flagellar beating, with a specific role in the distal region of the ciliary axoneme where it is incorporated into type 2 outer dynein arms (ODAs) together with DNAH5 [PMID:15750039, PMID:30471717]. DNAH9 physically interacts with CCDC114 and GAS8, and its loss destabilizes these partners and the entire ODA complex, leading to reduced ciliary beat frequency, impaired mucociliary clearance, mucin accumulation, and immune cell infiltration in the lung [PMID:35729109, PMID:30471717]. DNAH9 is also required for ODA-dependent motility in Kupffer's vesicle cilia that establishes left–right body axis asymmetry, and its disruption in zebrafish and mice causes cardiac laterality defects without affecting ciliogenesis itself [PMID:35050399]. Loss-of-function DNAH9 variants cause primary ciliary dyskinesia with situs defects and nonsyndromic severe asthenozoospermia through ultrastructural ODA loss in sperm flagella [PMID:30471717, PMID:33610189].\",\n  \"teleology\": [\n    {\n      \"year\": 2001,\n      \"claim\": \"Cloning of DNAH9 established its identity as a 4486-amino-acid axonemal beta heavy chain dynein with a four-P-loop motor domain, linking it to the ATP-driven force generation machinery of cilia and flagella.\",\n      \"evidence\": \"cDNA cloning, RT-PCR, and sequence homology analysis in human tissues\",\n      \"pmids\": [\"11247663\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No direct demonstration of ATPase or motor activity for the recombinant protein\",\n        \"No localization data within the axoneme\",\n        \"Functional inference relied entirely on sequence homology to Chlamydomonas dyneins\"\n      ]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"High-resolution imaging revealed that DNAH9 localizes specifically to the distal portion of the ciliary axoneme, distinct from DNAH5, establishing that human respiratory cilia contain at least two regional ODA subtypes and that DNAH9 defines the distal ODA.\",\n      \"evidence\": \"Immunofluorescence of human respiratory epithelial cells and sperm with specific antibodies\",\n      \"pmids\": [\"15750039\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"The mechanism determining region-specific ODA incorporation was unknown\",\n        \"Functional consequence of distal-restricted localization for beat pattern was not tested\",\n        \"Sperm flagella showed different ODA assembly rules, unexplained\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Loss-of-function DNAH9 mutations in humans and Paramecium knockdown demonstrated that DNAH9 is required for distal type 2 ODA assembly and normal ciliary beat frequency, causally linking the distal ODA subtype to motility and establishing DNAH9 as a primary ciliary dyskinesia gene.\",\n      \"evidence\": \"Patient genotyping, immunofluorescence, 3D electron tomography, high-speed video microscopy in human respiratory cells; RNAi knockdown with motility assay in Paramecium\",\n      \"pmids\": [\"30471717\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"The structural basis for selective distal ODA loss was not resolved at the molecular level\",\n        \"Contribution of DNAH9 versus DNAH5 to force generation within the type 2 ODA heterodimer was not dissected\"\n      ]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identification of DNAH9 loss-of-function variants causing isolated severe asthenozoospermia without respiratory symptoms demonstrated a tissue-specific threshold effect, where sperm flagella are more vulnerable to DNAH9 deficiency than respiratory cilia.\",\n      \"evidence\": \"Whole exome sequencing, TEM of sperm axoneme, immunofluorescence and qRT-PCR in patient sperm\",\n      \"pmids\": [\"33610189\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Why some DNAH9 mutations produce isolated male infertility while others cause full PCD with situs defects remains unresolved\",\n        \"Genotype–phenotype correlation across different DNAH9 domains was not established\"\n      ]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"DNAH9 was shown to physically interact with CCDC114 and GAS8, and its loss destabilizes both partners, placing DNAH9 within a defined protein complex required for ODA docking and integrity, and extending the phenotype to impaired mucociliary clearance and left–right axis determination.\",\n      \"evidence\": \"Co-IP, western blot, and immunostaining in Dnah9 knockdown mice; zebrafish morpholino knockdown with cardiac laterality assessment; Dnah9 knockout mouse cardiac function measurement\",\n      \"pmids\": [\"35729109\", \"35050399\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Direct versus indirect nature of the CCDC114 and GAS8 interactions (co-IP only, no reciprocal pulldown reported)\",\n        \"Whether DNAH9 loss affects ODA docking or only ODA heavy chain stability is unclear\",\n        \"The zebrafish result relied on morpholino knockdown without genetic mutant confirmation\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Patient sperm analysis showed that DNAH9 loss secondarily reduces ODA-associated proteins DNAI1, DNAH1, and DNAH10, indicating DNAH9 is a scaffold required for global ODA structural integrity in flagella, not just the type 2 subtype.\",\n      \"evidence\": \"TEM and immunofluorescence in patient sperm flagella\",\n      \"pmids\": [\"39523437\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"Observation from patient samples without reconstitution or direct interaction assays\",\n        \"Whether the reduction of DNAI1/DNAH1/DNAH10 reflects assembly failure or post-assembly degradation is unknown\",\n        \"Not independently confirmed by a second lab\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"A minigene assay confirmed that the intronic DNAH9 variant c.3743+1G>T causes aberrant mRNA splicing, establishing a molecular mechanism by which non-coding DNAH9 mutations disrupt protein production.\",\n      \"evidence\": \"Minigene splicing assay with bioinformatics splice site prediction\",\n      \"pmids\": [\"40376972\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Functional impact of the aberrant transcript on protein levels and ciliary phenotype was not directly measured in patient cells\",\n        \"Only one variant was functionally tested\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The structural basis for region-specific (distal vs. proximal) ODA subtype incorporation along the axoneme, the precise stoichiometry and architecture of the DNAH9-DNAH5-CCDC114-GAS8 complex, and the genotype–phenotype rules governing PCD-with-situs-defects versus isolated asthenozoospermia remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"No cryo-EM or crystal structure of DNAH9 or the type 2 ODA complex\",\n        \"Mechanism of distal-specific ODA targeting is unknown\",\n        \"Systematic genotype–phenotype study across DNAH9 domain mutations is lacking\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [0, 3]},\n      {\"term_id\": \"GO:0003774\", \"supporting_discovery_ids\": [0, 3, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [1, 3, 4, 7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [3, 5, 9]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"complexes\": [\n      \"Type 2 outer dynein arm (distal ODA)\"\n    ],\n    \"partners\": [\n      \"DNAH5\",\n      \"CCDC114\",\n      \"GAS8\",\n      \"DNAI1\",\n      \"DNAH1\",\n      \"DNAH10\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```\n\n--- ROUND 2 (R2/R3, augmented corpus) ---\n\n```json\n{\n  \"mechanistic_narrative\": \"DNAH9 is an axonemal dynein beta heavy chain that defines type 2 outer dynein arms (ODAs) in the distal compartment of motile respiratory cilia, functioning as an ATP-dependent minus-end-directed microtubule motor essential for ciliary beating. DNAH9 physically interacts with the ODA components DNAH5, DNAI2, and the docking complex subunit CCDC114, and its loss causes selective failure of distal ODA assembly, resulting in reduced ciliary beat frequency and subtle distal waveform defects that underlie primary ciliary dyskinesia with laterality defects and chronic airway disease [PMID:30471718, PMID:30471717]. Although DNAH9 is normally absent from sperm flagella—where DNAH17 and DNAH8 serve as the beta heavy chains [PMID:31178125]—biallelic DNAH9 variants can nonetheless disrupt sperm ODA integrity and cause severe asthenozoospermia [PMID:33610189, PMID:39523437]. Loss of DNAH9 function in zebrafish and mouse models disturbs left-right body axis determination and cardiac development, confirming an evolutionarily conserved role in nodal cilia-dependent laterality signaling [PMID:35050399].\",\n  \"teleology\": [\n    {\n      \"year\": 2000,\n      \"claim\": \"Early ciliogenesis studies revealed that DNAH9 transcripts and protein appear in airway epithelial cells before visible ciliation, establishing that this dynein heavy chain is among the first axonemal components synthesized during differentiation.\",\n      \"evidence\": \"Northern blot, immunohistochemistry, and in vitro ciliogenesis model in human airway epithelium\",\n      \"pmids\": [\"11104725\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab observation without genetic perturbation\", \"Temporal data do not establish whether DNAH9 is functionally required at the earliest ciliogenesis steps\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Cloning of the full-length DNAH9 cDNA defined its domain architecture—an N-terminal stem and a C-terminal motor domain with four P-loops—placing it as a bona fide axonemal beta dynein heavy chain ortholog.\",\n      \"evidence\": \"5′ RACE, RT-PCR, BAC genomic sequencing, domain prediction\",\n      \"pmids\": [\"11247663\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No functional assays performed\", \"ATPase activity not directly measured\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"High-resolution immunofluorescence demonstrated that DNAH9 occupies a restricted axonemal region distinct from pan-axonemal DNAH5, providing the first evidence that human respiratory cilia contain at least two molecularly distinct ODA types.\",\n      \"evidence\": \"Immunofluorescence with specific antibodies on human ciliated airway epithelium and PCD patient samples\",\n      \"pmids\": [\"15750039\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Proximal vs. distal boundary not precisely defined\", \"Interaction partners not identified\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Analysis of DNAI2- and DNAH5-mutant cilia showed that DNAH9 axonemal assembly depends on the intermediate chain DNAI2 and the alpha heavy chain DNAH5, establishing an epistatic assembly hierarchy among ODA subunits.\",\n      \"evidence\": \"Immunofluorescence and electron microscopy across multiple PCD genotypes\",\n      \"pmids\": [\"18950741\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct physical interactions not tested in this study\", \"Whether DNAH9 reciprocally stabilizes DNAI2 was not addressed\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identification of DNAH11 as the proximal ODA beta heavy chain, together with demonstration that DNAH9 retains distal localization in DNAH11-mutant cilia, established that the two ODA subtypes assemble independently along the proximo-distal axis.\",\n      \"evidence\": \"Immunofluorescence with validated monoclonal antibodies, TEM tomography, GFP-LRD mouse model\",\n      \"pmids\": [\"26909801\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Signals determining positional identity of each ODA subtype remain unknown\", \"No structural model of the two ODA subtypes\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Two concurrent studies established DNAH9 as the disease gene for a PCD subtype characterized by distal-only ODA loss: direct interactions with DNAH5, DNAI2, and the docking component CCDC114 were confirmed by co-immunoprecipitation and yeast two-hybrid, and 3D electron tomography resolved regional ODA volume loss, while Paramecium RNAi validated evolutionary conservation.\",\n      \"evidence\": \"Patient genetics (multiple families), immunofluorescence, Co-IP, Y2H, 3D electron tomography, Paramecium RNAi\",\n      \"pmids\": [\"30471718\", \"30471717\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of DNAH9-CCDC114 docking interaction unresolved\", \"How distal positional cues target DNAH9 versus DNAH11 remains unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Comparative localization showed that DNAH9 is absent from human sperm axonemes (replaced by DNAH17/DNAH8), revealing cell-type-specific ODA heavy chain composition and explaining why DNAH9-PCD patients can retain normal sperm motility.\",\n      \"evidence\": \"Immunofluorescence and immunoblot on respiratory cilia and sperm from controls and DNAH17-mutant patients\",\n      \"pmids\": [\"31178125\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which different beta HCs are selected in sperm versus respiratory cilia is unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identification of biallelic DNAH9 variants causing nonsyndromic asthenozoospermia without respiratory disease indicated that DNAH9 contributes to sperm ODA integrity in some individuals despite its apparent absence from normal sperm axonemes, suggesting context- or allele-dependent effects.\",\n      \"evidence\": \"Whole exome sequencing, TEM, immunofluorescence, qRT-PCR on patient sperm\",\n      \"pmids\": [\"33610189\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Apparent contradiction with absence of DNAH9 in normal sperm not resolved\", \"Small cohort, single lab\", \"Functional rescue not performed\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Mouse and zebrafish loss-of-function models demonstrated that DNAH9 is required for left-right asymmetry determination and cardiac function, broadening its role beyond airway cilia to nodal cilia-dependent laterality signaling, and Dnah9 knockdown mice recapitulated PCD-like lung pathology including mucin accumulation.\",\n      \"evidence\": \"Zebrafish morpholino knockdown, Dnah9 KO and KD mouse models, Co-IP, lung function testing\",\n      \"pmids\": [\"35050399\", \"35729109\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Cardiac phenotype mechanism (direct versus secondary to laterality defect) not distinguished\", \"Single-lab studies for each model organism\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Further characterization of DNAH9-mutant sperm showed reduced axonemal incorporation of DNAI1, DNAH1, and DNAH10, indicating DNAH9 stabilizes additional ODA and inner dynein arm components in the flagellar context.\",\n      \"evidence\": \"TEM, immunofluorescence, whole exome and Sanger sequencing on asthenospermic patients\",\n      \"pmids\": [\"39523437\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Small cohort\", \"Whether DNAH9 directly binds DNAH1/DNAH10 or acts indirectly is untested\", \"Functional rescue not performed\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The positional cues that target DNAH9 to the distal axoneme while restricting DNAH11 to the proximal compartment remain unknown, and no high-resolution structural model of the human type 2 ODA complex exists.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No cryo-EM or X-ray structure of human DNAH9-containing ODA\", \"Distal targeting signal or adaptor not identified\", \"Reconciliation of DNAH9 absence in normal sperm with sperm phenotype in DNAH9-mutant patients unresolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140657\", \"supporting_discovery_ids\": [0]},\n      {\"term_id\": \"GO:0003774\", \"supporting_discovery_ids\": [0, 3, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [1, 3, 4, 6, 7]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [1, 3, 6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [2, 3, 4, 6]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [10]}\n    ],\n    \"complexes\": [\n      \"Outer dynein arm type 2 (distal ODA)\"\n    ],\n    \"partners\": [\n      \"DNAH5\",\n      \"DNAI2\",\n      \"CCDC114\",\n      \"GAS8\",\n      \"DNAI1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}