Affinage

DNAH12

Dynein axonemal heavy chain 12 · UniProt Q6ZR08

Round 2 corrected
Length
3092 aa
Mass
356.9 kDa
Annotated
2026-04-28
70 papers in source corpus 5 papers cited in narrative 6 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

DNAH12 is an atypical axonemal dynein heavy chain that lacks a microtubule-binding domain and functions specifically in sperm flagella, where it is essential for inner dynein arm (IDA) assembly and central pair (CP) stability. DNAH12 physically interacts with IDA components DNAH1 and DNALI1, recruiting them to the axoneme, and also binds radial spoke head proteins RSPH1, RSPH9, and DNAJB13 to stabilize the central pair apparatus (PMID:40146200). Biallelic loss-of-function mutations in DNAH12 cause asthenoteratozoospermia with IDA defects and CP loss in both humans and knockout mice, a phenotype rescuable by intracytoplasmic sperm injection; notably, DNAH12 deficiency does not impair ciliary structure or function, indicating a flagella-restricted role (PMID:39071892, PMID:40146200).

Mechanistic history

Synthesis pass · year-by-year structured walk · 4 steps
  1. 2014 Medium

    The question of where DNAH12 protein is expressed was addressed by the serendipitous finding that a BRAF V600E antibody cross-reacts with DNAH12, establishing its localization to axonemal structures of cilia and sperm flagella across multiple tissues.

    Evidence ELISA and immunohistochemistry using VE1 antibody with sequence homology analysis in human tissues

    PMID:25412847

    Open questions at the time
    • Localization inferred from antibody cross-reactivity rather than a DNAH12-specific reagent
    • No functional or ultrastructural role established at this stage
    • Tissue-specific versus ubiquitous axonemal function not distinguished
  2. 2024 High

    The central question of DNAH12's biological requirement was answered: biallelic loss-of-function mutations cause asthenoteratozoospermia in humans, and Dnah12 knockout mice show IDA impairment and central pair loss specifically in sperm flagella without ciliary defects, establishing a flagella-restricted essential function.

    Evidence Whole-exome sequencing in patient families, Dnah12 knockout mouse, TEM ultrastructural analysis, semen analysis

    PMID:39071892

    Open questions at the time
    • Molecular partners mediating IDA assembly and CP stability not yet identified at this stage
    • Mechanism by which DNAH12 functions without a microtubule-binding domain not resolved
    • Whether the flagella-specific phenotype reflects expression restriction or functional redundancy in cilia not determined
  3. 2025 High

    The mechanistic basis of DNAH12 function was elucidated: DNAH12 directly interacts with IDA components DNAH1 and DNALI1 (recruiting them to the axoneme) and with radial spoke head proteins RSPH1, RSPH9, and DNAJB13 (stabilizing the central pair), explaining how loss of this atypical dynein—which lacks a microtubule-binding domain—causes both IDA and CP defects.

    Evidence Reciprocal co-immunoprecipitation, Dnah12 KO and point-mutant mouse models, TEM, immunofluorescence, and ICSI rescue in human patients across six families

    PMID:40146200

    Open questions at the time
    • Structural basis of DNAH12 interactions with DNAH1/DNALI1 and radial spoke proteins not resolved
    • How DNAH12 achieves axonemal function without a microtubule-binding domain remains mechanistically unclear
    • Whether DNAH12 has additional partners beyond those tested by Co-IP is unknown
  4. 2025 Low

    Proteomic analysis of IQUB/RS1-deficient sperm flagella revealed secondary loss of DNAH12, providing independent evidence that DNAH12-containing IDAs are physically proximal to radial spoke 1 in the axonemal repeat.

    Evidence Protein mass spectrometry and western blotting in Iqub knockout mouse sperm

    PMID:39849482

    Open questions at the time
    • DNAH12 reduction is a secondary effect of RS1 loss, not direct evidence of DNAH12–RS1 interaction
    • Precise positioning of DNAH12-containing IDA subspecies within the 96-nm axonemal repeat not mapped
    • Single study without independent replication

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the structural mechanism by which DNAH12 functions without a microtubule-binding domain, the precise position of DNAH12-containing IDA subspecies within the 96-nm axonemal repeat, and whether DNAH12 plays any role in tissues beyond the male germline under stress or pathological conditions.
  • No structural model of DNAH12 or its complexes exists
  • The basis for flagella-specific versus ciliary function is unexplained
  • No high-resolution mapping of DNAH12 within the axonemal repeat

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0008092 cytoskeletal protein binding 2
Localization
GO:0005929 cilium 3
Pathway
R-HSA-1474165 Reproduction 2 R-HSA-1852241 Organelle biogenesis and maintenance 2
Partners
DNAH1DNAJB13DNALI1RSPH1RSPH9

Evidence

Reading pass · 6 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2014 DNAH12 protein is a major component of axonemal structures in cilia and flagella; the VE1 antibody (anti-BRAF V600E) cross-reacts with DNAH12 epitopes due to sequence homology between amino acids 596–606 of BRAF V600E and regions of DNAH12, confirming DNAH12 localization to cilia of bronchial airways, fallopian tubes, nasopharynx, epididymis, and sperm flagella, as demonstrated by ELISA and immunohistochemistry. ELISA, immunohistochemistry, targeted sequencing, sequence homology analysis Modern Pathology Medium 25412847
2024 Biallelic loss-of-function mutations in DNAH12 cause asthenoteratozoospermia in humans; Dnah12 knockout mice recapitulate severe spermatogenesis failure with inner dynein arm (IDA) impairment and central pair (CP) loss in sperm flagella, but DNAH12 deficiency does not affect cilium organization or function, demonstrating a sperm flagella-specific role. Whole-exome sequencing, Sanger sequencing, Dnah12 knockout mouse model, transmission electron microscopy (TEM), semen analysis iScience High 39071892
2025 DNAH12 physically interacts with inner dynein arm (IDA) components DNALI1 and DNAH1; loss of DNAH12 causes failed recruitment of DNALI1 and DNAH1 to IDAs in sperm flagella, leading to compromised sperm development. DNAH12 also interacts with radial spoke head proteins RSPH1, RSPH9, and DNAJB13 to regulate central pair (CP) stability. DNAH12 is characterized as a special dynein lacking a microtubule-binding domain. Co-immunoprecipitation, whole-exome sequencing, Sanger sequencing, Dnah12 knockout and Dnah12 mutant mouse models, transmission electron microscopy, immunofluorescence, ICSI rescue experiments eLife High 40146200
2025 DNAH12 deficiency in sperm flagella causes significant downregulation of inner dynein arm components DNAH7 and DNAH12 in the context of radial spoke 1 (RS1) deficiency caused by IQUB mutation, highlighting the physical proximity of DNAH12-containing IDAs to RS1 in the axoneme. Protein mass spectrometry, western blotting, Iqub knockout mouse model, transmission electron microscopy Cell Communication and Signaling Low 39849482
2024 In a mouse model of occlusal disharmony-induced anxiety, hippocampal Sirt1 downregulation leads to increased histone H3 acetylation and decreased Dnah12 transcription, while resveratrol-mediated Sirt1 upregulation increases Dnah12 expression; this suggests Dnah12 transcription in the hippocampus is regulated by Sirt1-dependent histone deacetylation. Mouse behavioral model, RT-qPCR, western blotting, resveratrol pharmacological intervention, mRNA expression profiling Clinical Oral Investigations Low 39276172
2024 DNAH12 is identified as a novel preprint-confirmed candidate gene for male infertility; six biallelic mutations in DNAH12 co-segregate recessively with asthenoteratozoospermia in six families; the protein is a component of inner dynein arms in sperm flagella and recruits DNAH1 and DNALI1 to IDAs, while also interacting with radial spoke proteins RSPH1, RSPH9, and DNAJB13. Whole-exome sequencing, Sanger sequencing, Dnah12 KO and mutant mouse models, TEM, co-immunoprecipitation, immunofluorescence, ICSI bioRxivpreprint High

Source papers

Stage 0 corpus · 70 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2001 The sequence of the human genome. Science (New York, N.Y.) 8428 11181995
2003 Complete sequencing and characterization of 21,243 full-length human cDNAs. Nature genetics 754 14702039
2011 Phylogenetic-based propagation of functional annotations within the Gene Ontology consortium. Briefings in bioinformatics 656 21873635
2007 Global proteomic profiling of phosphopeptides using electron transfer dissociation tandem mass spectrometry. Proceedings of the National Academy of Sciences of the United States of America 426 17287340
2007 Activation of endosomal dynein motors by stepwise assembly of Rab7-RILP-p150Glued, ORP1L, and the receptor betalll spectrin. The Journal of cell biology 384 17283181
1998 Kinesin and dynein superfamily proteins in organelle transport and cell division. Current opinion in cell biology 272 9484596
2006 Dynein is required for receptor sorting and the morphogenesis of early endosomes. Nature cell biology 159 17173037
1996 Mammalian cells express three distinct dynein heavy chains that are localized to different cytoplasmic organelles. The Journal of cell biology 158 8666668
1996 Holliday junction resolvases encoded by homologous rusA genes in Escherichia coli K-12 and phage 82. Journal of molecular biology 130 8648624
2009 Genetic risk profiling and prediction of disease course in Crohn's disease patients. Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association 117 19422935
2021 Protein interaction landscapes revealed by advanced in vivo cross-linking-mass spectrometry. Proceedings of the National Academy of Sciences of the United States of America 113 34349018
2009 Confirmation of multiple Crohn's disease susceptibility loci in a large Dutch-Belgian cohort. The American journal of gastroenterology 113 19174780
2010 Personalized smoking cessation: interactions between nicotine dose, dependence and quit-success genotype score. Molecular medicine (Cambridge, Mass.) 108 20379614
2018 Histone Interaction Landscapes Visualized by Crosslinking Mass Spectrometry in Intact Cell Nuclei. Molecular & cellular proteomics : MCP 101 30021884
2009 Control and benefits of CP4-57 prophage excision in Escherichia coli biofilms. The ISME journal 96 19458652
2009 Identification of dyneins that localize exclusively to the proximal portion of Chlamydomonas flagella. Journal of cell science 89 19351714
2020 Kinase Interaction Network Expands Functional and Disease Roles of Human Kinases. Molecular cell 88 32707033
2019 The midbody interactome reveals unexpected roles for PP1 phosphatases in cytokinesis. Nature communications 74 31586073
1996 Multiple mouse chromosomal loci for dynein-based motility. Genomics 71 8812413
2021 Histone deacetylase inhibitors inhibit cervical cancer growth through Parkin acetylation-mediated mitophagy. Acta pharmaceutica Sinica. B 66 35256949
2015 Deep resequencing of 131 Crohn's disease associated genes in pooled DNA confirmed three reported variants and identified eight novel variants. Gut 64 25731871
1989 Characterization of the cryptic lambdoid prophage DLP12 of Escherichia coli and overlap of the DLP12 integrase gene with the tRNA gene argU. Journal of bacteriology 63 2553674
2016 Complex Sources of Variation in Tissue Expression Data: Analysis of the GTEx Lung Transcriptome. American journal of human genetics 54 27588449
2006 Novel mechanism of Escherichia coli porin regulation. Journal of bacteriology 53 16385048
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 51 25412847
2021 Exome sequencing reveals variants in known and novel candidate genes for severe sperm motility disorders. Human reproduction (Oxford, England) 50 34089056
2017 Intratumoral Genetic Heterogeneity in Rectal Cancer: Are Single Biopsies representative of the entirety of the tumor? Annals of surgery 49 27479130
2019 TNF-α inhibits glucocorticoid receptor-induced gene expression by reshaping the GR nuclear cofactor profile. Proceedings of the National Academy of Sciences of the United States of America 48 31182584
1997 Isolation of several human axonemal dynein heavy chain genes: genomic structure of the catalytic site, phylogenetic analysis and chromosomal assignment. FEBS letters 48 9256245
1997 Identification of dynein heavy chain genes expressed in human and mouse testis: chromosomal localization of an axonemal dynein gene. Gene 41 9373155
2020 Mutation of CFAP57, a protein required for the asymmetric targeting of a subset of inner dynein arms in Chlamydomonas, causes primary ciliary dyskinesia. PLoS genetics 39 32764743
2006 The DNA sequence, annotation and analysis of human chromosome 3. Nature 39 16641997
2011 The retrograde IFT machinery of C. elegans cilia: two IFT dynein complexes? PloS one 38 21695221
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) 37 34791246
2012 A genome-wide search for loci interacting with known prostate cancer risk-associated genetic variants. Carcinogenesis 36 22219177
2016 Contribution of Heritability and Epigenetic Factors to Skeletal Muscle Mass Variation in United Kingdom Twins. The Journal of clinical endocrinology and metabolism 35 27144936
2023 PAICS ubiquitination recruits UBAP2 to trigger phase separation for purinosome assembly. Molecular cell 27 37848033
2007 Subclassification and targeted characterization of prophage-encoded two-component cell lysis cassette. Journal of biosciences 27 17914239
2010 Molecular reclassification of Crohn's disease by cluster analysis of genetic variants. PloS one 25 20886065
2020 Hypermethylation of UCHL1 Promotes Metastasis of Nasopharyngeal Carcinoma by Suppressing Degradation of Cortactin (CTTN). Cells 24 32120844
2020 Improvement of sabinene tolerance of Escherichia coli using adaptive laboratory evolution and omics technologies. Biotechnology for biofuels 23 32346395
1999 Identification of three aspartic acid residues essential for catalysis by the RusA holliday junction resolvase. Journal of molecular biology 23 9973560
2023 FBXO22 promotes leukemogenesis by targeting BACH1 in MLL-rearranged acute myeloid leukemia. Journal of hematology & oncology 22 36774506
2011 Role of DLP12 lysis genes in Escherichia coli biofilm formation. Microbiology (Reading, England) 22 21415116
2019 Impaired plasma membrane localization of ubiquitin ligase complex underlies 3-M syndrome development. The Journal of clinical investigation 21 31343991
2021 Modulation of OMV Production by the Lysis Module of the DLP12 Defective Prophage of Escherichia coli K12. Microorganisms 20 33673345
2002 RusA proteins from the extreme thermophile Aquifex aeolicus and lactococcal phage r1t resolve Holliday junctions. Molecular microbiology 19 11972790
2022 Engagement of the G3BP2-TRIM25 Interaction by Nucleocapsid Protein Suppresses the Type I Interferon Response in SARS-CoV-2-Infected Cells. Vaccines 14 36560452
2024 Whole exome sequencing analysis of 167 men with primary infertility. BMC medical genomics 12 39267058
2015 Comparison of 10,11-Dehydrocurvularin Polyketide Synthases from Alternaria cinerariae and Aspergillus terreus Highlights Key Structural Motifs. Chembiochem : a European journal of chemical biology 12 26493380
1998 tRNA(Arg) (fimU) and expression of SEF14 and SEF21 in Salmonella enteritidis. Journal of bacteriology 12 9473037
2023 The prophage-encoded transcriptional regulator AppY has pleiotropic effects on E. coli physiology. PLoS genetics 11 36930675
2013 Comparative genome sequencing identifies a prophage-associated genomic island linked to host adaptation of Lawsonia intracellularis infections. Veterinary research 11 23826661
2024 Further evidence from DNAH12 supports favorable fertility outcomes of infertile males with dynein axonemal heavy chain gene family variants. iScience 10 39071892
2022 Interaction of LATS1 with SMAC links the MST2/Hippo pathway with apoptosis in an IAP-dependent manner. Cell death & disease 10 35941108
2025 Deficiency in DNAH12 causes male infertility by impairing DNAH1 and DNALI1 recruitment in humans and mice. eLife 9 40146200
2020 What Happened in the Hippocampal Axon in a Rat Model of Posttraumatic Stress Disorder. Cellular and molecular neurobiology 9 32930942
2024 DSBSO-Based XL-MS Analysis of Breast Cancer PDX Tissues to Delineate Protein Interaction Network in Clinical Samples. Journal of proteome research 7 38334954
2023 Comparative transcriptome analysis identified crucial genes and pathways affecting sperm motility in the reproductive tract of drakes with different libido. Poultry science 7 36881978
2022 CRISPR-Cas Controls Cryptic Prophages. International journal of molecular sciences 7 36555835
2014 Phage ORF family recombinases: conservation of activities and involvement of the central channel in DNA binding. PloS one 6 25083707
2025 IQUB mutation induces radial spoke 1 deficiency causing asthenozoospermia with normal sperm morphology in humans and mice. Cell communication and signaling : CCS 5 39849482
2017 The structure of DLP12 endolysin exhibiting alternate loop conformation and comparative analysis with other endolysins. Proteins 5 29179254
2015 The lysis cassette of DLP12 defective prophage is regulated by RpoE. Microbiology (Reading, England) 5 25998262
2013 A Q-like transcription factor regulates biofilm development in Escherichia coli by controlling expression of the DLP12 lysis cassette. Microbiology (Reading, England) 4 23378572
2012 Characterization of DLP12 Prophage Membrane Associated Protein: HolinGFP. Indian journal of microbiology 3 23997340
2024 Occlusal disharmony promotes anxiety-like behaviours by suppressing Sirt1. Clinical oral investigations 2 39276172
2025 Potential for Clinical Management of Pancreatic Cancer Through Whole Exome Profiling of Site-Specific Metastases and Matched Primary Tumors. Laboratory investigation; a journal of technical methods and pathology 0 40545177
2025 The essential role of cytoskeleton and ciliary abnormalities in the development of congenital pulmonary airway malformations. Pediatric surgery international 0 41264116
2025 Genetic Insights into Familial Hypospadias Identifying Rare Variants and Their Potential Role in Urethral Development. Genes 0 41300791