{"gene":"DNAH3","run_date":"2026-06-09T23:54:42","timeline":{"discoveries":[{"year":2024,"finding":"DNAH3 is a component of the inner dynein arm (IDA) in sperm flagella; biallelic loss-of-function variants cause loss of IDA-associated proteins DNAH1, DNAH6, and DNALI1 in sperm flagella, leading to abnormal flagellar morphology and asthenoteratozoospermia in both patients and Dnah3 knockout mice.","method":"Whole-exome sequencing, Dnah3 knockout mouse generation, transmission electron microscopy, immunofluorescence staining, ICSI rescue","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal knockout phenotype in humans and mice, multiple orthogonal methods (TEM, immunostaining, CASA), with IDA protein loss documented; replicated across independent patient cohorts","pmids":["39503742"],"is_preprint":false},{"year":2024,"finding":"Biallelic DNAH3 variants in infertile men cause asthenoteratozoospermia characterized by loss of the central pair of microtubules, dislocated mitochondrial sheath and fibrous sheath, and partial absence of inner dynein arms in sperm flagella; Dnah3 knockout mice recapitulate the AT phenotype.","method":"Whole-exome sequencing, Dnah3 knockout mouse generation (two independent lines), H&E staining, transmission electron microscopy, immunostaining, CASA, ICSI rescue","journal":"Human reproduction open","confidence":"High","confidence_rationale":"Tier 2 / Strong — two independent knockout mouse lines, multiple orthogonal methods, human patient data corroborated by mouse model","pmids":["38312775"],"is_preprint":false},{"year":2026,"finding":"DNAH3 forms a protein complex with DNALI1 (inner dynein arm light intermediate chain 1), as demonstrated by co-immunoprecipitation and mass spectrometry; this interaction is required for flagellum IDA assembly and sperm motility.","method":"Co-immunoprecipitation, mass spectrometry, comparative proteomics, scRNA-seq, CRISPR/Cas9 knockout mouse, electron microscopy, immunofluorescence","journal":"Reproductive biology and endocrinology : RB&E","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — direct Co-IP plus mass spectrometry identifying the complex, supported by knockout phenotype and proteomics in a single rigorous study","pmids":["41731497"],"is_preprint":false},{"year":2025,"finding":"DNAH3 deficiency in Dnah3 knockout mice causes asthenozoospermia without morphological flagellar abnormalities; sperm metabolomics revealed that DNAH3 deficiency disturbs energy metabolism, specifically reducing L-palmitoylcarnitine and glycocholic acid levels, indicating a role for DNAH3 in sperm energy metabolism.","method":"Dnah3 knockout mouse generation, CASA, H&E staining, TEM, sperm metabolomics, ICSI rescue","journal":"Biology of reproduction","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knockout mouse with defined metabolomics phenotype, single lab, multiple methods but metabolomics finding is novel and not yet replicated","pmids":["39774634"],"is_preprint":false},{"year":2024,"finding":"Novel biallelic DNAH3 variants (including premature stop codons) cause oligoasthenoteratozoospermia with fibrous sheath dysplasia and multiple tail malformations, with significantly reduced DNAH3 protein expression confirmed by Western blot; loss of DNAH3 alters expression of related flagellar proteins.","method":"Whole-exome sequencing, Papanicolaou staining, scanning electron microscopy, transmission electron microscopy, RT-qPCR, Western blotting, protein structure prediction","journal":"Frontiers in endocrinology","confidence":"Medium","confidence_rationale":"Tier 2–3 / Moderate — human patient study with multiple structural and molecular methods, single lab, no mouse model","pmids":["39588341"],"is_preprint":false},{"year":2008,"finding":"Retroviral insertional mutagenesis in APC-mutant mouse colon epithelial cells identified Dnah3 as a candidate cooperative oncogene; upregulation and truncation of Dnah3 due to viral integration were observed, and Dnah3-overexpressing IMCE cells showed impairment of microtubule function.","method":"Retroviral insertional mutagenesis, identification of common integration sites, Dnah3 overexpression in IMCE cells with microtubule function assay","journal":"Cancer science","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, single overexpression experiment with microtubule readout, no mechanistic dissection of how DNAH3 impairs microtubule function","pmids":["18294281"],"is_preprint":false},{"year":2025,"finding":"In Aphis citricidus, DNAH3 (dynein axonemal heavy chain 3) is a target of miR-3050; RNAi-mediated knockdown of DNAH3 caused wing deformities, and circ-379 acts as a molecular sponge for miR-3050 to maintain DNAH3 expression during wing development. (Note: this finding is from an insect, not the human/mammalian protein, and is relevant only as evidence for DNAH3 function in cilia/flagella-related structures in non-mammalian organisms.)","method":"RNA sequencing, RT-PCR, dual-luciferase reporter assay, biotin-avidin RNA pull-down, RNAi knockdown phenotype","journal":"Insect biochemistry and molecular biology","confidence":"Low","confidence_rationale":"Tier 3 / Weak — insect model (non-mammalian ortholog), single lab, RNAi knockdown with phenotypic readout but limited mechanistic depth for the mammalian protein","pmids":["40850515"],"is_preprint":false},{"year":2025,"finding":"DNAH7 loss-of-function causes inner dynein arm deficiency in sperm flagella; immunofluorescent staining showed a marked reduction of IDA-associated proteins including DNAH3 in patients with DNAH7 mutations, indicating that DNAH3 localizes to the IDA and its expression depends on DNAH7 integrity.","method":"Whole-exome sequencing, transmission electron microscopy, immunofluorescence staining in human patient sperm","journal":"Human genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — DNAH3 protein localization within IDA established by immunofluorescence in the context of DNAH7 KO, corroborating IDA localization shown in other papers; single lab","pmids":["40810911"],"is_preprint":false}],"current_model":"DNAH3 is an axonemal dynein heavy chain that localizes to the inner dynein arm (IDA) of sperm flagella, where it forms a protein complex with DNALI1 and is required for IDA assembly; biallelic loss-of-function variants in humans and knockout in mice cause asthenoteratozoospermia characterized by IDA deficiency, loss of co-IDA proteins (DNAH1, DNAH6, DNALI1), and disrupted sperm energy metabolism, all leading to male infertility that can be overcome by ICSI."},"narrative":{"mechanistic_narrative":"DNAH3 is an axonemal dynein heavy chain that functions as a structural component of the inner dynein arm (IDA) in sperm flagella, where it is required for proper axonemal assembly and sperm motility [PMID:39503742, PMID:38312775]. DNAH3 forms a protein complex with the inner dynein arm light intermediate chain DNALI1, an interaction necessary for IDA assembly and motility [PMID:41731497]. Biallelic loss-of-function variants in humans, and knockout in mice, produce asthenoteratozoospermia: IDA deficiency accompanied by loss of co-resident IDA proteins DNAH1, DNAH6, and DNALI1, abnormal flagellar morphology including central-pair, mitochondrial-sheath, and fibrous-sheath defects, and male infertility that can be overcome by ICSI [PMID:39503742, PMID:38312775]. DNAH3's residence in the IDA is corroborated by its dependence on DNAH7 integrity, as DNAH7 loss markedly reduces flagellar DNAH3 [PMID:40810911]. Beyond its structural role, DNAH3 deficiency perturbs sperm energy metabolism, reducing L-palmitoylcarnitine and glycocholic acid levels [PMID:39774634]. This timeline establishes a sperm-flagellar IDA function as the dominant, well-evidenced role of human DNAH3.","teleology":[{"year":2024,"claim":"Established DNAH3 as a bona fide inner dynein arm component whose loss disrupts the axonemal machinery, answering whether DNAH3 has a causal role in sperm motility and male fertility.","evidence":"Whole-exome sequencing of infertile men plus Dnah3 knockout mice analyzed by TEM, immunofluorescence, and CASA, with ICSI rescue","pmids":["39503742","38312775"],"confidence":"High","gaps":["Atomic/structural placement of DNAH3 within the IDA not resolved","Whether loss of DNAH1/DNAH6/DNALI1 is due to direct interaction or secondary destabilization not dissected","Mechanism linking IDA loss to specific flagellar morphological defects (central pair, sheaths) not defined"]},{"year":2024,"claim":"Extended the human phenotypic spectrum to oligoasthenoteratozoospermia with fibrous sheath dysplasia and confirmed that pathogenic variants reduce DNAH3 protein, addressing the molecular consequence of the variants.","evidence":"Whole-exome sequencing, electron microscopy, RT-qPCR, and Western blotting in a human patient cohort","pmids":["39588341"],"confidence":"Medium","gaps":["No mouse model in this study to confirm causality","Which flagellar proteins are altered and by what mechanism not fully resolved"]},{"year":2025,"claim":"Revealed a metabolic dimension to DNAH3 function by showing its loss disturbs sperm energy metabolism independent of overt structural defects, broadening the mechanistic picture beyond axonemal architecture.","evidence":"Dnah3 knockout mice analyzed by CASA, TEM, and sperm metabolomics with ICSI rescue","pmids":["39774634"],"confidence":"Medium","gaps":["Metabolomics finding novel and not independently replicated","Causal link between DNAH3 loss and specific metabolite changes not established","Apparent absence of morphological abnormality conflicts with structural defects reported elsewhere; reconciliation unclear"]},{"year":2025,"claim":"Independently corroborated DNAH3's IDA localization by demonstrating its flagellar abundance depends on DNAH7 integrity, placing DNAH3 within an interdependent network of IDA dynein heavy chains.","evidence":"Immunofluorescence and TEM of sperm from patients with DNAH7 loss-of-function variants","pmids":["40810911"],"confidence":"Medium","gaps":["Whether DNAH3-DNAH7 dependence reflects direct interaction or shared assembly pathway not determined","Single-lab observation in human patients only"]},{"year":2026,"claim":"Identified DNALI1 as a direct DNAH3 binding partner required for IDA assembly, providing the first defined molecular interaction underpinning DNAH3's structural role.","evidence":"Co-immunoprecipitation and mass spectrometry with comparative proteomics, scRNA-seq, CRISPR/Cas9 knockout mice, and electron microscopy","pmids":["41731497"],"confidence":"High","gaps":["Stoichiometry and structural architecture of the DNAH3-DNALI1 complex unresolved","Whether DNALI1 binding is required for DNAH3 stability or vice versa not separated"]},{"year":null,"claim":"How DNAH3 mechanically couples to the axoneme to generate motility, and how its structural role connects to the observed energy-metabolism disturbances, remain unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No high-resolution structure of DNAH3 within the assembled IDA","Mechanistic basis of metabolic phenotype not connected to axonemal function","Generality of findings beyond sperm flagella (e.g., motile cilia) not characterized"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003774","term_label":"cytoskeletal motor activity","supporting_discovery_ids":[0,1,2]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,1,2]}],"localization":[{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[0,1,7]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[0,2]}],"pathway":[{"term_id":"R-HSA-397014","term_label":"Muscle contraction","supporting_discovery_ids":[0,1]},{"term_id":"R-HSA-1474165","term_label":"Reproduction","supporting_discovery_ids":[0,1]}],"complexes":["inner dynein arm"],"partners":["DNALI1","DNAH1","DNAH6","DNAH7"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q8TD57","full_name":"Dynein axonemal heavy chain 3","aliases":["Axonemal beta dynein heavy chain 3","HsADHC3","Ciliary dynein heavy chain 3","Dnahc3-b"],"length_aa":4116,"mass_kda":470.8,"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 (By similarity). Essential for the assembly and structural organization of the sperm flagellum's axoneme, including its inner dynein arms and accessory components, which are critical for maintaining flagellar integrity and motility (PubMed:39503742, PubMed:38312775)","subcellular_location":"Cytoplasm, cytoskeleton, cilium axoneme; Cytoplasm; Cell projection, cilium, flagellum","url":"https://www.uniprot.org/uniprotkb/Q8TD57/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/DNAH3","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/DNAH3","total_profiled":1310},"omim":[{"mim_id":"603334","title":"DYNEIN, AXONEMAL, HEAVY CHAIN 3; DNAH3","url":"https://www.omim.org/entry/603334"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Mid piece","reliability":"Approved"},{"location":"Principal piece","reliability":"Approved"},{"location":"Equatorial segment","reliability":"Additional"},{"location":"Flagellar centriole","reliability":"Additional"}],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"fallopian tube","ntpm":5.1},{"tissue":"testis","ntpm":3.2}],"url":"https://www.proteinatlas.org/search/DNAH3"},"hgnc":{"alias_symbol":["Dnahc3b","DLP3","Hsadhc3","DKFZp434N074"],"prev_symbol":[]},"alphafold":{"accession":"Q8TD57","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8TD57","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q8TD57-3-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q8TD57-3-F1-predicted_aligned_error_v6.png","plddt_mean":76.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=DNAH3","jax_strain_url":"https://www.jax.org/strain/search?query=DNAH3"},"sequence":{"accession":"Q8TD57","fasta_url":"https://rest.uniprot.org/uniprotkb/Q8TD57.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q8TD57/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q8TD57"}},"corpus_meta":[{"pmid":"10839998","id":"PMC_10839998","title":"Defensin-like peptide-2 from platypus venom: member of a class of peptides with a distinct structural fold.","date":"2000","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/10839998","citation_count":51,"is_preprint":false},{"pmid":"3656451","id":"PMC_3656451","title":"Spectroscopic studies on histone-DNA interactions. II. Three transitions in nucleosomes resolved by salt-titration.","date":"1987","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/3656451","citation_count":48,"is_preprint":false},{"pmid":"30109710","id":"PMC_30109710","title":"Genetic dissection of bull fertility in US Jersey dairy cattle.","date":"2018","source":"Animal genetics","url":"https://pubmed.ncbi.nlm.nih.gov/30109710","citation_count":41,"is_preprint":false},{"pmid":"33710394","id":"PMC_33710394","title":"Exome sequencing reveals predominantly de novo variants in disorders with intellectual disability (ID) in the founder population of Finland.","date":"2021","source":"Human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/33710394","citation_count":38,"is_preprint":false},{"pmid":"17760420","id":"PMC_17760420","title":"Stable DNA-protein cross-links are products of DNA charge transport in a nucleosome core particle.","date":"2007","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/17760420","citation_count":34,"is_preprint":false},{"pmid":"29879995","id":"PMC_29879995","title":"Family specific genetic predisposition to breast cancer: results from Tunisian whole exome sequenced breast cancer cases.","date":"2018","source":"Journal of translational medicine","url":"https://pubmed.ncbi.nlm.nih.gov/29879995","citation_count":33,"is_preprint":false},{"pmid":"3216389","id":"PMC_3216389","title":"Association of nucleosome core particle DNA with different histone oligomers. Transfer of histones between DNA-(H2A,H2B) and DNA-(H3,H4) complexes.","date":"1988","source":"Journal of molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/3216389","citation_count":29,"is_preprint":false},{"pmid":"32670234","id":"PMC_32670234","title":"Characterization of Novel Broad-Host-Range Bacteriophage DLP3 Specific to Stenotrophomonas maltophilia as a Potential Therapeutic Agent.","date":"2020","source":"Frontiers in microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/32670234","citation_count":21,"is_preprint":false},{"pmid":"38312775","id":"PMC_38312775","title":"Bi-allelic variants in DNAH3 cause male infertility with asthenoteratozoospermia in humans and mice.","date":"2024","source":"Human reproduction open","url":"https://pubmed.ncbi.nlm.nih.gov/38312775","citation_count":20,"is_preprint":false},{"pmid":"30084009","id":"PMC_30084009","title":"MicroRNA Alternations in the Testes Related to the Sterility of Triploid Fish.","date":"2018","source":"Marine biotechnology (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/30084009","citation_count":17,"is_preprint":false},{"pmid":"18294281","id":"PMC_18294281","title":"Identification of candidate cooperative genes of the Apc mutation in transformation of the colon epithelial cell by retroviral insertional mutagenesis.","date":"2008","source":"Cancer science","url":"https://pubmed.ncbi.nlm.nih.gov/18294281","citation_count":17,"is_preprint":false},{"pmid":"36364468","id":"PMC_36364468","title":"Isolation of a New Polysaccharide from Dandelion Leaves and Evaluation of Its Antioxidant, Antibacterial, and Anticancer Activities.","date":"2022","source":"Molecules (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/36364468","citation_count":17,"is_preprint":false},{"pmid":"27581094","id":"PMC_27581094","title":"Detection of Missing Proteins Using the PRIDE Database as a Source of Mass Spectrometry Evidence.","date":"2016","source":"Journal of proteome research","url":"https://pubmed.ncbi.nlm.nih.gov/27581094","citation_count":15,"is_preprint":false},{"pmid":"23663090","id":"PMC_23663090","title":"Genetic drift or natural selection? Hybridization and asymmetric mitochondrial introgression in two Caribbean lizards (Anolis pulchellus and Anolis krugi).","date":"2013","source":"Journal of evolutionary biology","url":"https://pubmed.ncbi.nlm.nih.gov/23663090","citation_count":13,"is_preprint":false},{"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},{"pmid":"33352926","id":"PMC_33352926","title":"A Biomarker Panel of Radiation-Upregulated miRNA as Signature for Ionizing Radiation Exposure.","date":"2020","source":"Life (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/33352926","citation_count":11,"is_preprint":false},{"pmid":"38572415","id":"PMC_38572415","title":"The genetic landscape of autism spectrum disorder in the Middle Eastern population.","date":"2024","source":"Frontiers in genetics","url":"https://pubmed.ncbi.nlm.nih.gov/38572415","citation_count":9,"is_preprint":false},{"pmid":"36881978","id":"PMC_36881978","title":"Comparative transcriptome analysis identified crucial genes and pathways affecting sperm motility in the reproductive tract of drakes with different libido.","date":"2023","source":"Poultry science","url":"https://pubmed.ncbi.nlm.nih.gov/36881978","citation_count":8,"is_preprint":false},{"pmid":"8485137","id":"PMC_8485137","title":"Unfolded structure and reactivity of nucleosome core DNA-histone H2A,H2B complexes in solution as studied by synchrotron radiation X-ray scattering.","date":"1993","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/8485137","citation_count":7,"is_preprint":false},{"pmid":"21804483","id":"PMC_21804483","title":"Soluble intercellular cell adhesion molecule-1 and vascular cell adhesion molecule-1 in asymptomatic dyslipidemic subjects.","date":"2011","source":"International angiology : a journal of the International Union of Angiology","url":"https://pubmed.ncbi.nlm.nih.gov/21804483","citation_count":6,"is_preprint":false},{"pmid":"21475379","id":"PMC_21475379","title":"Total adiponectin levels in dyslipidemic individuals: relationship to metabolic parameters and intima-media thickness.","date":"2011","source":"Biomedical papers of the Medical Faculty of the University Palacky, Olomouc, Czechoslovakia","url":"https://pubmed.ncbi.nlm.nih.gov/21475379","citation_count":6,"is_preprint":false},{"pmid":"39774634","id":"PMC_39774634","title":"Impact of DNAH3 deficiency on sperm energy metabolism and motility leading to asthenozoospermia†.","date":"2025","source":"Biology of reproduction","url":"https://pubmed.ncbi.nlm.nih.gov/39774634","citation_count":5,"is_preprint":false},{"pmid":"37662916","id":"PMC_37662916","title":"DNA and histones impair the mechanical stability and lytic susceptibility of fibrin formed by staphylocoagulase.","date":"2023","source":"Frontiers in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/37662916","citation_count":5,"is_preprint":false},{"pmid":"29110840","id":"PMC_29110840","title":"Immunohistochemical and genetic characteristics of lung cancer mimicking organizing pneumonia.","date":"2017","source":"Lung cancer (Amsterdam, Netherlands)","url":"https://pubmed.ncbi.nlm.nih.gov/29110840","citation_count":4,"is_preprint":false},{"pmid":"40850515","id":"PMC_40850515","title":"Circ-379-miR-3050-DNAH3/RNF8 axis modulates wing development in Aphis citricidus.","date":"2025","source":"Insect biochemistry and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/40850515","citation_count":3,"is_preprint":false},{"pmid":"38928079","id":"PMC_38928079","title":"The Role of Z Chromosome Localization Gene psmd9 in Spermatogenesis of Cynoglossus semilaevis.","date":"2024","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/38928079","citation_count":3,"is_preprint":false},{"pmid":"39588341","id":"PMC_39588341","title":"Novel bi-allelic DNAH3 variants cause oligoasthenoteratozoospermia.","date":"2024","source":"Frontiers in endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/39588341","citation_count":2,"is_preprint":false},{"pmid":"40810911","id":"PMC_40810911","title":"Biallelic loss-of-function variants of DNAH7 cause male infertility associated with asthenozoospermia in humans.","date":"2025","source":"Human genetics","url":"https://pubmed.ncbi.nlm.nih.gov/40810911","citation_count":2,"is_preprint":false},{"pmid":"26624456","id":"PMC_26624456","title":"A new species of bright-eyed treefrog (Mantellidae) from Madagascar, with comments on call evolution and patterns of syntopy in the Boophis ankaratra complex.","date":"2015","source":"Zootaxa","url":"https://pubmed.ncbi.nlm.nih.gov/26624456","citation_count":1,"is_preprint":false},{"pmid":"41731497","id":"PMC_41731497","title":"DNAH3 interacts with DNALI1 and is required for sperm flagellum function and male fertility.","date":"2026","source":"Reproductive biology and endocrinology : RB&E","url":"https://pubmed.ncbi.nlm.nih.gov/41731497","citation_count":0,"is_preprint":false},{"pmid":"41751509","id":"PMC_41751509","title":"Narrow Versus Broad Phenotype Definitions Affect Genetic Analysis of Language More than Other Broad Autism Phenotype Traits.","date":"2026","source":"Genes","url":"https://pubmed.ncbi.nlm.nih.gov/41751509","citation_count":0,"is_preprint":false},{"pmid":"41430479","id":"PMC_41430479","title":"Sex-biased Expression of Genes and Transposable Elements in Hybrids from Drosophila mojavensis and Drosophila arizonae.","date":"2026","source":"Genome biology and evolution","url":"https://pubmed.ncbi.nlm.nih.gov/41430479","citation_count":0,"is_preprint":false},{"pmid":"40694934","id":"PMC_40694934","title":"Gonadal sex differentiation in Eleutheronema tetradactylum: Histological features and transcriptomic insights from mature gonads.","date":"2025","source":"Comparative biochemistry and physiology. Part D, Genomics & proteomics","url":"https://pubmed.ncbi.nlm.nih.gov/40694934","citation_count":0,"is_preprint":false},{"pmid":"40678843","id":"PMC_40678843","title":"In vitro Nucleosome Assembly Facilitated by the Histone Chaperone SRCAP.","date":"2025","source":"Current protocols","url":"https://pubmed.ncbi.nlm.nih.gov/40678843","citation_count":0,"is_preprint":false},{"pmid":"40913757","id":"PMC_40913757","title":"Concurrent developmental language level change for children with autism spectrum disorder using alternative and augmentative communication systems: a cross-sectional study in Cyprus.","date":"2025","source":"Disability and rehabilitation. Assistive technology","url":"https://pubmed.ncbi.nlm.nih.gov/40913757","citation_count":0,"is_preprint":false},{"pmid":null,"id":"bio_10.1101_2025.06.16.659550","title":"Biosynthesis of glycosylated 5-hydroxycytosine in the DNA of diverse viruses","date":"2025-06-16","source":"bioRxiv","url":"https://doi.org/10.1101/2025.06.16.659550","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":22309,"output_tokens":2098,"usd":0.049198,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":9090,"output_tokens":2352,"usd":0.052125,"stage2_stop_reason":"end_turn"},"total_usd":0.101323,"stage1_batch_id":"msgbatch_01AsR7g8dGTEiEw9U83bJeWn","stage2_batch_id":"msgbatch_01YV5ZyxtFNUZEjxRcpd9jzb","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2024,\n      \"finding\": \"DNAH3 is a component of the inner dynein arm (IDA) in sperm flagella; biallelic loss-of-function variants cause loss of IDA-associated proteins DNAH1, DNAH6, and DNALI1 in sperm flagella, leading to abnormal flagellar morphology and asthenoteratozoospermia in both patients and Dnah3 knockout mice.\",\n      \"method\": \"Whole-exome sequencing, Dnah3 knockout mouse generation, transmission electron microscopy, immunofluorescence staining, ICSI rescue\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal knockout phenotype in humans and mice, multiple orthogonal methods (TEM, immunostaining, CASA), with IDA protein loss documented; replicated across independent patient cohorts\",\n      \"pmids\": [\"39503742\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Biallelic DNAH3 variants in infertile men cause asthenoteratozoospermia characterized by loss of the central pair of microtubules, dislocated mitochondrial sheath and fibrous sheath, and partial absence of inner dynein arms in sperm flagella; Dnah3 knockout mice recapitulate the AT phenotype.\",\n      \"method\": \"Whole-exome sequencing, Dnah3 knockout mouse generation (two independent lines), H&E staining, transmission electron microscopy, immunostaining, CASA, ICSI rescue\",\n      \"journal\": \"Human reproduction open\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — two independent knockout mouse lines, multiple orthogonal methods, human patient data corroborated by mouse model\",\n      \"pmids\": [\"38312775\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"DNAH3 forms a protein complex with DNALI1 (inner dynein arm light intermediate chain 1), as demonstrated by co-immunoprecipitation and mass spectrometry; this interaction is required for flagellum IDA assembly and sperm motility.\",\n      \"method\": \"Co-immunoprecipitation, mass spectrometry, comparative proteomics, scRNA-seq, CRISPR/Cas9 knockout mouse, electron microscopy, immunofluorescence\",\n      \"journal\": \"Reproductive biology and endocrinology : RB&E\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — direct Co-IP plus mass spectrometry identifying the complex, supported by knockout phenotype and proteomics in a single rigorous study\",\n      \"pmids\": [\"41731497\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"DNAH3 deficiency in Dnah3 knockout mice causes asthenozoospermia without morphological flagellar abnormalities; sperm metabolomics revealed that DNAH3 deficiency disturbs energy metabolism, specifically reducing L-palmitoylcarnitine and glycocholic acid levels, indicating a role for DNAH3 in sperm energy metabolism.\",\n      \"method\": \"Dnah3 knockout mouse generation, CASA, H&E staining, TEM, sperm metabolomics, ICSI rescue\",\n      \"journal\": \"Biology of reproduction\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockout mouse with defined metabolomics phenotype, single lab, multiple methods but metabolomics finding is novel and not yet replicated\",\n      \"pmids\": [\"39774634\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Novel biallelic DNAH3 variants (including premature stop codons) cause oligoasthenoteratozoospermia with fibrous sheath dysplasia and multiple tail malformations, with significantly reduced DNAH3 protein expression confirmed by Western blot; loss of DNAH3 alters expression of related flagellar proteins.\",\n      \"method\": \"Whole-exome sequencing, Papanicolaou staining, scanning electron microscopy, transmission electron microscopy, RT-qPCR, Western blotting, protein structure prediction\",\n      \"journal\": \"Frontiers in endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2–3 / Moderate — human patient study with multiple structural and molecular methods, single lab, no mouse model\",\n      \"pmids\": [\"39588341\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Retroviral insertional mutagenesis in APC-mutant mouse colon epithelial cells identified Dnah3 as a candidate cooperative oncogene; upregulation and truncation of Dnah3 due to viral integration were observed, and Dnah3-overexpressing IMCE cells showed impairment of microtubule function.\",\n      \"method\": \"Retroviral insertional mutagenesis, identification of common integration sites, Dnah3 overexpression in IMCE cells with microtubule function assay\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, single overexpression experiment with microtubule readout, no mechanistic dissection of how DNAH3 impairs microtubule function\",\n      \"pmids\": [\"18294281\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"In Aphis citricidus, DNAH3 (dynein axonemal heavy chain 3) is a target of miR-3050; RNAi-mediated knockdown of DNAH3 caused wing deformities, and circ-379 acts as a molecular sponge for miR-3050 to maintain DNAH3 expression during wing development. (Note: this finding is from an insect, not the human/mammalian protein, and is relevant only as evidence for DNAH3 function in cilia/flagella-related structures in non-mammalian organisms.)\",\n      \"method\": \"RNA sequencing, RT-PCR, dual-luciferase reporter assay, biotin-avidin RNA pull-down, RNAi knockdown phenotype\",\n      \"journal\": \"Insect biochemistry and molecular biology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — insect model (non-mammalian ortholog), single lab, RNAi knockdown with phenotypic readout but limited mechanistic depth for the mammalian protein\",\n      \"pmids\": [\"40850515\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"DNAH7 loss-of-function causes inner dynein arm deficiency in sperm flagella; immunofluorescent staining showed a marked reduction of IDA-associated proteins including DNAH3 in patients with DNAH7 mutations, indicating that DNAH3 localizes to the IDA and its expression depends on DNAH7 integrity.\",\n      \"method\": \"Whole-exome sequencing, transmission electron microscopy, immunofluorescence staining in human patient sperm\",\n      \"journal\": \"Human genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — DNAH3 protein localization within IDA established by immunofluorescence in the context of DNAH7 KO, corroborating IDA localization shown in other papers; single lab\",\n      \"pmids\": [\"40810911\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"DNAH3 is an axonemal dynein heavy chain that localizes to the inner dynein arm (IDA) of sperm flagella, where it forms a protein complex with DNALI1 and is required for IDA assembly; biallelic loss-of-function variants in humans and knockout in mice cause asthenoteratozoospermia characterized by IDA deficiency, loss of co-IDA proteins (DNAH1, DNAH6, DNALI1), and disrupted sperm energy metabolism, all leading to male infertility that can be overcome by ICSI.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"DNAH3 is an axonemal dynein heavy chain that functions as a structural component of the inner dynein arm (IDA) in sperm flagella, where it is required for proper axonemal assembly and sperm motility [#0, #1]. DNAH3 forms a protein complex with the inner dynein arm light intermediate chain DNALI1, an interaction necessary for IDA assembly and motility [#2]. Biallelic loss-of-function variants in humans, and knockout in mice, produce asthenoteratozoospermia: IDA deficiency accompanied by loss of co-resident IDA proteins DNAH1, DNAH6, and DNALI1, abnormal flagellar morphology including central-pair, mitochondrial-sheath, and fibrous-sheath defects, and male infertility that can be overcome by ICSI [#0, #1]. DNAH3's residence in the IDA is corroborated by its dependence on DNAH7 integrity, as DNAH7 loss markedly reduces flagellar DNAH3 [#7]. Beyond its structural role, DNAH3 deficiency perturbs sperm energy metabolism, reducing L-palmitoylcarnitine and glycocholic acid levels [#3]. This timeline establishes a sperm-flagellar IDA function as the dominant, well-evidenced role of human DNAH3.\",\n  \"teleology\": [\n    {\n      \"year\": 2024,\n      \"claim\": \"Established DNAH3 as a bona fide inner dynein arm component whose loss disrupts the axonemal machinery, answering whether DNAH3 has a causal role in sperm motility and male fertility.\",\n      \"evidence\": \"Whole-exome sequencing of infertile men plus Dnah3 knockout mice analyzed by TEM, immunofluorescence, and CASA, with ICSI rescue\",\n      \"pmids\": [\"39503742\", \"38312775\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Atomic/structural placement of DNAH3 within the IDA not resolved\",\n        \"Whether loss of DNAH1/DNAH6/DNALI1 is due to direct interaction or secondary destabilization not dissected\",\n        \"Mechanism linking IDA loss to specific flagellar morphological defects (central pair, sheaths) not defined\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Extended the human phenotypic spectrum to oligoasthenoteratozoospermia with fibrous sheath dysplasia and confirmed that pathogenic variants reduce DNAH3 protein, addressing the molecular consequence of the variants.\",\n      \"evidence\": \"Whole-exome sequencing, electron microscopy, RT-qPCR, and Western blotting in a human patient cohort\",\n      \"pmids\": [\"39588341\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"No mouse model in this study to confirm causality\",\n        \"Which flagellar proteins are altered and by what mechanism not fully resolved\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Revealed a metabolic dimension to DNAH3 function by showing its loss disturbs sperm energy metabolism independent of overt structural defects, broadening the mechanistic picture beyond axonemal architecture.\",\n      \"evidence\": \"Dnah3 knockout mice analyzed by CASA, TEM, and sperm metabolomics with ICSI rescue\",\n      \"pmids\": [\"39774634\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Metabolomics finding novel and not independently replicated\",\n        \"Causal link between DNAH3 loss and specific metabolite changes not established\",\n        \"Apparent absence of morphological abnormality conflicts with structural defects reported elsewhere; reconciliation unclear\"\n      ]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Independently corroborated DNAH3's IDA localization by demonstrating its flagellar abundance depends on DNAH7 integrity, placing DNAH3 within an interdependent network of IDA dynein heavy chains.\",\n      \"evidence\": \"Immunofluorescence and TEM of sperm from patients with DNAH7 loss-of-function variants\",\n      \"pmids\": [\"40810911\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether DNAH3-DNAH7 dependence reflects direct interaction or shared assembly pathway not determined\",\n        \"Single-lab observation in human patients only\"\n      ]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Identified DNALI1 as a direct DNAH3 binding partner required for IDA assembly, providing the first defined molecular interaction underpinning DNAH3's structural role.\",\n      \"evidence\": \"Co-immunoprecipitation and mass spectrometry with comparative proteomics, scRNA-seq, CRISPR/Cas9 knockout mice, and electron microscopy\",\n      \"pmids\": [\"41731497\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Stoichiometry and structural architecture of the DNAH3-DNALI1 complex unresolved\",\n        \"Whether DNALI1 binding is required for DNAH3 stability or vice versa not separated\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How DNAH3 mechanically couples to the axoneme to generate motility, and how its structural role connects to the observed energy-metabolism disturbances, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No high-resolution structure of DNAH3 within the assembled IDA\",\n        \"Mechanistic basis of metabolic phenotype not connected to axonemal function\",\n        \"Generality of findings beyond sperm flagella (e.g., motile cilia) not characterized\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003774\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 1, 2]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [0, 1, 7]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [0, 2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-397014\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"R-HSA-1474165\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"complexes\": [\"inner dynein arm\"],\n    \"partners\": [\"DNALI1\", \"DNAH1\", \"DNAH6\", \"DNAH7\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":4,"faith_total":5,"faith_pct":80.0}}