Affinage

DNAH2

Dynein axonemal heavy chain 2 · UniProt Q9P225

Length
4427 aa
Mass
507.7 kDa
Annotated
2026-06-09
31 papers in source corpus 11 papers cited in narrative 11 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

DNAH2 is an axonemal dynein heavy chain that serves as the motor subunit of the double-headed inner dynein arm-f (Dynein-f) complex driving microtubule sliding in motile cilia and sperm flagella (PMID:31178125, PMID:25412847). It assembles into Dynein-f by associating with the intermediate chains WDR78 (IC138 orthologue) and WDR63 (IC140 orthologue), an interaction required for axonemal localization of the complex; depletion of DNAH2 or its partners paralyzes ciliary beat (PMID:30060180). DNAH2 is essential for sperm flagellum biogenesis: loss of DNAH2 in human patients and Dnah2-null mice produces inner dynein arm absence, central-pair loss, severely disorganized flagellar ultrastructure, and compromised assembly of other axonemal components (DNAH1, RSPH3), manifesting as the multiple morphological abnormalities of the flagella (MMAF) phenotype and male infertility (PMID:30811583, PMID:33968937, PMID:33771466). Bi-allelic DNAH2 variants are a cause of human MMAF-associated male infertility (PMID:30811583, PMID:33771466). Proper incorporation of DNAH2 into the flagellar compartment depends on CEP76-mediated transition zone gating, since CEP76 loss causes DNAH2 to accumulate at the sperm neck rather than the tail (PMID:38570187). Beyond its axonemal role, DNAH2 promotes homologous recombination repair in the Fanconi anemia pathway by facilitating FANCD2 ubiquitination and its recruitment to DNA damage sites (PMID:35402838).

Mechanistic history

Synthesis pass · year-by-year structured walk · 10 steps
  1. 2014 Medium

    Established that DNAH2 is a major axonemal component of cilia and flagella involved in microtubule sliding, providing the first functional placement of the protein.

    Evidence ELISA cross-reactivity of the VE1 antibody with DNAH2 epitopes plus sequence homology analysis

    PMID:25412847

    Open questions at the time
    • Inference of motor function rests on antibody cross-reactivity and homology, not direct motility assay
    • No localization to a specific dynein arm subtype shown
  2. 2019 Medium

    Resolved which axonemal compartment DNAH2 occupies, placing it specifically in the inner dynein arm rather than the outer arm.

    Evidence Immunofluorescence and immunoblot on human sperm from DNAH17 (ODA)-mutant patients

    PMID:31178125

    Open questions at the time
    • Single lab, correlative localization
    • Does not define the molecular subcomplex DNAH2 belongs to
  3. 2019 High

    Defined DNAH2's molecular complex by showing it forms Dynein-f with intermediate chains WDR78 and WDR63 and that this assembly is required for ciliary motility.

    Evidence Co-immunoprecipitation plus RNAi/morpholino knockdown in mouse ependymal cells and zebrafish with ciliary beat analysis

    PMID:30060180

    Open questions at the time
    • Stoichiometry and structural architecture of Dynein-f not resolved
    • Direct ATPase/motor activity of DNAH2 not measured
  4. 2019 High

    Linked DNAH2 loss-of-function to human disease, establishing it as a cause of MMAF with absent inner dynein arms.

    Evidence Whole-exome sequencing, TEM ultrastructure, and immunofluorescence on patient sperm

    PMID:30811583

    Open questions at the time
    • Causality not confirmed by genetic rescue
    • Mechanism connecting DNAH2 loss to broader axonemal disarray unclear
  5. 2021 High

    Confirmed in vivo requirement for DNAH2 in flagellogenesis and showed it influences centriolar, annulus, and other axonemal protein organization.

    Evidence CRISPR/Cas9 Dnah2-null mice with SEM/TEM, immunofluorescence, and Western blot; bi-allelic patient variants with TEM showing central-pair and IDA loss

    PMID:33771466 PMID:33968937

    Open questions at the time
    • How DNAH2 loss causes central-pair absence is not mechanistically explained
    • Order of assembly events upstream/downstream of DNAH2 undefined
  6. 2021 Medium

    Identified an unexpected non-axonemal role for DNAH2 in DNA repair, placing it in the Fanconi anemia homologous recombination pathway.

    Evidence HR repair assay, mitomycin C sensitivity, FANCD2 immunofluorescence, and ubiquitination assays in U2OS/DR-U2OS cells

    PMID:35402838

    Open questions at the time
    • Direct physical interaction of DNAH2 with FANCD2 or the FA core complex not shown
    • Mechanism by which a dynein heavy chain promotes FANCD2 ubiquitination unknown
    • Single lab, not independently replicated
  7. 2022 Low

    Showed DNAH2 axonemal localization depends on the dynein regulatory complex assembly factor CCDC40.

    Evidence Immunofluorescence on respiratory cilia and sperm from a CCDC40-mutant PCD patient

    PMID:35449766

    Open questions at the time
    • Single patient case with one method
    • No direct manipulation of DNAH2
    • Correlative loss does not prove direct dependency
  8. 2024 Medium

    Defined how DNAH2 reaches the flagellar compartment, implicating CEP76-mediated transition zone gating in its trafficking.

    Evidence Cep76-mutant mouse with immunofluorescence localization of DNAH2 in sperm

    PMID:38570187

    Open questions at the time
    • Direct interaction between CEP76 and DNAH2 not demonstrated
    • Whether gating is selective for DNAH2 versus general cargo unclear
  9. 2026 Low

    Distinguished DNAH2 assembly dependencies from other IDA subtypes, showing it is preserved in ZMYND10-related PCD.

    Evidence Immunofluorescence on respiratory cilia from a ZMYND10-mutant PCD patient

    PMID:42180707

    Open questions at the time
    • Single patient case, single method
    • No quantification or functional readout
  10. 2028 Low

    Proposed a link between DNAH2 and SHH signaling and a female reproductive phenotype, extending DNAH2 function beyond sperm.

    Evidence Dnah2-null mice and siRNA silencing in hMSCs with Western blot for SMO/GLI2

    PMID:42228139

    Open questions at the time
    • Preliminary single-lab study with small sample
    • Mechanistic link between DNAH2 and SHH pathway proteins not established
    • SHH connection not independently corroborated

Open questions

Synthesis pass · forward-looking unresolved questions
  • The direct motor/ATPase activity of DNAH2, the structural architecture of the Dynein-f complex, and the molecular basis of its non-axonemal role in FANCD2-dependent DNA repair remain undefined.
  • No biochemical reconstitution of DNAH2 motor activity
  • No structural model of Dynein-f
  • Mechanism connecting a dynein heavy chain to Fanconi anemia repair unresolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003774 cytoskeletal motor activity 2 GO:0140657 ATP-dependent activity 1
Localization
GO:0005929 cilium 3 GO:0005856 cytoskeleton 2
Pathway
R-HSA-1474165 Reproduction 3 R-HSA-73894 DNA Repair 1
Partners
WDR63WDR78
Complex memberships
Dynein-f (inner dynein arm-f)

Evidence

Reading pass · 11 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2019 DNAH2 is a component of the inner dynein arms (IDA) in sperm flagella axonemes, as demonstrated by immunofluorescence showing DNAH2 and DNALI (inner dynein arm components) were present in sperm cells lacking DNAH17 (an outer dynein arm component), establishing DNAH2's localization to the inner dynein arm compartment. Immunofluorescence and immunoblot on human sperm cells from patients with DNAH17 mutations American journal of human genetics Medium 31178125
2019 Mutations in DNAH2 cause multiple morphological abnormalities of the sperm flagella (MMAF) in humans. Patient sperm show severely disarranged axonemal structures with mitochondrial sheath defects, significantly decreased DNAH2 protein, and absence of inner dynein arms, establishing DNAH2 as required for inner dynein arm assembly in sperm flagella. Whole-exome sequencing, Sanger sequencing validation, transmission electron microscopy, immunofluorescence on patient sperm Clinical genetics High 30811583
2019 DNAH2 (as a heavy chain subunit of vertebrate Dynein-f/inner dynein arm-f) associates with the intermediate chain Wdr78 (vertebrate IC138 orthologue) and Wdr63 (IC140 orthologue), forming a complex required for axonemal localization; RNAi depletion of either Wdr78 or Dnah2 paralyzed mouse ependymal cilia, and Wdr78 depletion caused loss of all Dynein-f subunits from cilia. Co-immunoprecipitation (association assay), RNAi knockdown in mouse ependymal cells, zebrafish morpholino knockdown, ciliary beat analysis Journal of molecular cell biology High 30060180
2014 DNAH2 protein contains a region of significant sequence homology to the synthetic BRAF V600E peptide (residues 596–606: GLATEKSRWSG), and the VE1 antibody cross-reacts with DNAH2 epitopes as demonstrated by ELISA, confirming DNAH2 is a major component of axonemes in cilia and flagella where it drives microtubule sliding. ELISA cross-reactivity assay, sequence homology analysis Modern pathology Medium 25412847
2021 DNAH2 is essential for multiple steps in sperm flagella formation: Dnah2-null male mice (CRISPR/Cas9 knockout) are infertile with MMAF phenotype (absent, short, bent, coiled flagella); null spermatids show misexpression of centriolar proteins, delocalization of annulus proteins, severely disorganized flagellar ultrastructure, and compromised expression of other axonemal components DNAH1 and RSPH3. CRISPR/Cas9 knockout mice, scanning and transmission electron microscopy, immunofluorescence, Western blot Frontiers in cell and developmental biology High 33968937
2021 Bi-allelic DNAH2 variants in human patients cause absence of the central pair of microtubules and inner dynein arms in sperm axonemes, as revealed by transmission electron microscopy, with reduced DNAH2 protein by immunofluorescence. Whole-exome sequencing, Sanger sequencing, TEM, scanning electron microscopy, immunofluorescence Reproductive biomedicine online High 33771466
2021 DNAH2 modulates homologous recombination repair in the Fanconi anemia pathway: DNAH2 knockdown in U2OS cells increased sensitivity to mitomycin C (DNA inter-strand crosslinks), reduced enrichment of FANCD2 at DNA damage sites, and decreased ubiquitination of FANCD2, suggesting DNAH2 promotes FANCD2 ubiquitination and recruitment to damage foci. Homologous recombination repair assay, mitomycin C sensitivity assay, immunofluorescence, ubiquitination modification assay in U2OS and DR-U2OS cell lines Blood science Medium 35402838
2022 In a patient with CCDC40 mutations causing PCD, immunofluorescence showed loss of DNAH2 in both respiratory cilia and sperm, establishing that DNAH2 localization in inner dynein arms depends on intact CCDC40-mediated dynein regulatory complex assembly. Immunofluorescence on respiratory cilia and sperm from a patient with compound heterozygous CCDC40 variants Pharmacogenomics and personalized medicine Low 35449766
2024 CEP76 mutation in mice leads to accumulation of DNAH2 (along with AKAP4) at the sperm neck rather than proper incorporation into the sperm tail, indicating that CEP76-mediated transition zone gating is required for DNAH2 entry into the ciliary/flagellar compartment. Genetic mouse knockout (Cep76 mutant), immunofluorescence localization of DNAH2 in sperm Life science alliance Medium 38570187
2026 In ZMYND10-related PCD, immunofluorescence showed that the double-headed IDA-f component DNAH2 was preserved despite loss of single-headed IDA components (DNALI1) and outer dynein arms (DNAH5), indicating DNAH2 assembly is not dependent on ZMYND10 and that different IDA subtypes have distinct assembly dependencies. Immunofluorescence on respiratory cilia from a PCD patient with ZMYND10 splice-site variant Frontiers in medicine Low 42180707
2028 In Dnah2-null mice, DNAH2 silencing in human mesenchymal stem cells reduced SMO protein levels by 53.1% and GLI2 by 66.4%, suggesting DNAH2 modulates the SHH signaling pathway; Dnah2-null female mice showed vaginal atresia consistent with ciliary dysfunction. CRISPR/Cas9 Dnah2 knockout mice, siRNA silencing in hMSCs, Western blot for SHH pathway proteins Pediatric surgery international Low 42228139

Source papers

Stage 0 corpus · 31 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2019 Mutations in DNAH17, Encoding a Sperm-Specific Axonemal Outer Dynein Arm Heavy Chain, Cause Isolated Male Infertility Due to Asthenozoospermia. American journal of human genetics 149 31178125
2015 Age-related mutations and chronic myelomonocytic leukemia. Leukemia 112 26648538
2019 DNAH2 is a novel candidate gene associated with multiple morphological abnormalities of the sperm flagella. Clinical genetics 82 30811583
2014 Cross-reactivity of the BRAF VE1 antibody with epitopes in axonemal dyneins leads to staining of cilia. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc 53 25412847
2021 Genetic Defects in DNAH2 Underlie Male Infertility With Multiple Morphological Abnormalities of the Sperm Flagella in Humans and Mice. Frontiers in cell and developmental biology 51 33968937
2021 Whole-exome sequencing of a cohort of infertile men reveals novel causative genes in teratozoospermia that are chiefly related to sperm head defects. Human reproduction (Oxford, England) 42 34791246
2021 Novel bi-allelic variants in DNAH2 cause severe asthenoteratozoospermia with multiple morphological abnormalities of the flagella. Reproductive biomedicine online 37 33771466
2015 Alterations of the spindle checkpoint pathway in clinicopathologically aggressive CpG island methylator phenotype clear cell renal cell carcinomas. International journal of cancer 37 26061684
2019 Vertebrate Dynein-f depends on Wdr78 for axonemal localization and is essential for ciliary beat. Journal of molecular cell biology 34 30060180
2024 Genetic etiological spectrum of sperm morphological abnormalities. Journal of assisted reproduction and genetics 17 39417902
2021 Phenotypes and genotypes in non-consanguineous and consanguineous primary microcephaly: High incidence of epilepsy. Molecular genetics & genomic medicine 17 34402213
2024 Systematic molecular analyses for 115 karyotypically normal men with isolated non-obstructive azoospermia. Human reproduction (Oxford, England) 16 38511217
2020 Transcriptomic analysis of female and male gonads in juvenile snakeskin gourami (Trichopodus pectoralis). Scientific reports 14 32251302
2022 Novel Compound Heterozygous Variants in CCDC40 Associated with Primary Ciliary Dyskinesia and Multiple Morphological Abnormalities of the Sperm Flagella. Pharmacogenomics and personalized medicine 12 35449766
2024 Genetic mutation of Cep76 results in male infertility due to abnormal sperm tail composition. Life science alliance 7 38570187
2024 Genomic variants associated with age at diagnosis of childhood-onset type 1 diabetes. Journal of human genetics 5 38982180
2021 Identification of candidate genes encoding tumor-specific neoantigens in early- and late-stage colon adenocarcinoma. Aging 5 33428592
2023 Identification of novel rare variants for anxiety: an exome-wide association study in the UK Biobank. Progress in neuro-psychopharmacology & biological psychiatry 4 38154517
2025 Genetic and transcriptional insights into immune checkpoint blockade response and survival: lessons from melanoma and beyond. Journal of translational medicine 3 40269853
2025 Prepubertal exposure to 17β-estradiol downregulates motor protein genes, impairs sperm flagella formation, and reduces fertility in Nile tilapia (Oreochromis niloticus). Aquatic toxicology (Amsterdam, Netherlands) 3 40412113
2024 Unraveling the Genetic Basis of Combined Deafness and Male Infertility Phenotypes through High-Throughput Sequencing in a Unique Cohort from South India. Advanced genetics (Hoboken, N.J.) 3 38884051
2021 DNAH2 facilitates the homologous recombination repair of Fanconi anemia pathway through modulating FANCD2 ubiquitination. Blood science (Baltimore, Md.) 3 35402838
2017 [Knocking out of human DNAH2 gene in U2OS cells by CRISPR/Cas9n double nick system]. Sheng wu gong cheng xue bao = Chinese journal of biotechnology 2 28956384
2025 Identification of candidate genes harboring pathogenic variants in congenital heart disease and laterality defects in Chinese population. Frontiers in genetics 1 40406060
2025 Identifying potential genetic biomarkers for sperm dysfunction through whole-genome sequencing. Scientific reports 1 41115892
2025 Endometrial Signatures of Subfertility in Beef Heifers Reveal Dysregulation of MAPK Signaling and Ciliary Function. Genes 1 41300775
2024 Retrotransposon involves in photoperiodic spermatogenesis in Brandt's voles (Lasiopodomys brandtii) by co-transcription with flagellar genes. International journal of biological macromolecules 1 39362423
2026 A homozygous splice-site variant in ZMYND10 causes primary ciliary dyskinesia with primary infertility in a Chinese family. Frontiers in medicine 0 42180707
2026 A novel compound heterozygous variant in DNAH2: preliminary evidence of a potential genetic modifier for persistent cloaca in a Chinese family. Pediatric surgery international 0 42228139
2025 Establishment and clinical significance of genetic factor screening method for patients with nonobstructive azoospermia based on whole exon sequencing technology. Translational andrology and urology 0 40376536
2025 Comparing Ovarian Clear Cell Carcinoma and High-Grade Serous Carcinoma Based on the SEER Database and Analyzing the Significantly Mutated Genes. Current cancer drug targets 0 40910240

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