Affinage

DNAI2

Dynein axonemal intermediate chain 2 · UniProt Q9GZS0

Length
605 aa
Mass
68.8 kDa
Annotated
2026-06-09
58 papers in source corpus 13 papers cited in narrative 13 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

DNAI2 is an outer dynein arm (ODA) intermediate chain that distributes throughout the ciliary axoneme and is required for assembly of both proximal and distal ODA complexes; loss-of-function mutations abolish DNAI2 from cilia and eliminate the ODA heavy chains DNAH5 and DNAH9 along the entire axoneme, distinguishing it from DNAI1, whose loss mainly affects proximal ODAs (PMID:18950741, PMID:36303540). Its identity as a structural ODA component related to Chlamydomonas IC69, with expression concentrated in trachea and testis, was established by molecular cloning (PMID:11153919). Axonemal incorporation of DNAI2 depends on a cytoplasmic pre-assembly cascade in which the R2TP-associated AAA ATPase Pontin stabilizes the dynein intermediate chains (PMID:29113992), and a hierarchical ZMYND10→DNAI1→DNAI2 stabilization pathway operates such that DNAI2 is stabilized by co-expression with DNAI1 and ZMYND10 rather than by direct ZMYND10 binding; HEATR2 and CFAP70 also participate in this cytoplasmic assembly and transport network through direct binding to DNAI2 (PMID:25232951, PMID:29601588, PMID:37458246). Beyond pre-assembly, axonemal docking of DNAI2 requires the ODA-docking complex, since defects in CLXN/ODAD5 and ODAD1-4 leave DNAI2 absent from the axoneme (PMID:36727596). In vertebrate models, Dnai2 is required for ODA formation in motile cilia, and its loss disrupts nodal flow to produce left-right axis defects and, with paralog loss, polycystic kidney disease (PMID:20707998, PMID:20709053). Separately, DNAI2 (as DIC2) localizes to the leading edge of migrating cells, where it is recruited interdependently with IP6K3 to promote focal adhesion turnover and cell motility (PMID:30718399).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 2000 Medium

    Identifying the gene as a homolog of an ODA intermediate chain established DNAI2 as a candidate structural component of the ciliary dynein motor.

    Evidence cDNA cloning, chromosomal mapping, and Northern blot showing tracheal/testis expression and relatedness to Chlamydomonas IC69

    PMID:11153919

    Open questions at the time
    • No functional demonstration of axonemal incorporation
    • No in vivo loss-of-function phenotype
  2. 2008 High

    Patient genetics defined DNAI2 as required for assembly of both proximal and distal ODA complexes, distinguishing its role from DNAI1.

    Evidence Immunofluorescence, EM, and Western blot in respiratory cells from patients with loss-of-function DNAI2 mutations across multiple families

    PMID:18950741

    Open questions at the time
    • Does not resolve the molecular interaction map within the ODA
    • Mechanism by which DNAI2 organizes heavy-chain assembly not defined
  3. 2008 Low

    Expression and oocyte-surface localization data raised a possible role beyond cilia, in ovarian follicular development.

    Evidence Northern/Western blot and immunofluorescence in mouse ovary sections

    PMID:18547164

    Open questions at the time
    • Localization without a functional consequence established
    • Single lab, single study
    • No link to a motile-cilia mechanism demonstrated
  4. 2010 High

    Vertebrate genetics connected Dnai2-dependent ODA assembly to ciliary motility, nodal flow, and left-right and kidney development.

    Evidence Positional cloning, EM ultrastructure, double-mutant epistasis, and live nodal-flow imaging in medaka

    PMID:20707998 PMID:20709053

    Open questions at the time
    • Paralog redundancy versus tissue-specific roles only partly resolved
    • Does not address human pre-assembly factors
  5. 2014 Medium

    Identifying HEATR2 as a DNAI2 binding partner placed DNAI2 within a cytoplasmic dynein pre-assembly network distinct from generic HSP70/HSP90 chaperoning.

    Evidence Co-immunoprecipitation of HEATR2 with DNAI2 plus genetic analysis in Drosophila and PCD patients

    PMID:25232951

    Open questions at the time
    • Single Co-IP without reciprocal validation detailed
    • Direct versus indirect binding not resolved
  6. 2017 Medium

    Pontin/R2TP was shown to stabilize DNAI2, defining an early co-chaperone-dependent step of dynein arm assembly.

    Evidence Pontin conditional knockout mouse testis with Western blot for DNAI2 levels and cytosolic puncta localization

    PMID:29113992

    Open questions at the time
    • Whether Pontin acts directly on DNAI2 not established
    • Single lab
  7. 2018 High

    A hierarchical ZMYND10→DNAI1→DNAI2 stabilization cascade was defined, showing DNAI2 stability is governed indirectly through DNAI1 rather than by direct ZMYND10 binding.

    Evidence Zmynd10 knockout mouse, reciprocal Co-IP, and co-expression stability assays with cilia EM

    PMID:29601588

    Open questions at the time
    • Stoichiometry and order of subunit incorporation not fully defined
    • Structural basis of DNAI1-DNAI2 stabilization unknown
  8. 2019 Medium

    A cilia-independent function emerged: DNAI2/DIC2 partners with IP6K3 at the leading edge to drive focal adhesion turnover and motility.

    Evidence Co-IP, immunofluorescence/TIRF imaging, and IP6K3 deletion cell lines

    PMID:30718399

    Open questions at the time
    • Molecular basis of focal adhesion turnover by DIC2 unclear
    • Relationship to canonical axonemal role not addressed
  9. 2022 Medium

    An additional PCD-causing DNAI2 missense variant confirmed the requirement of DNAI2 for ODA assembly with co-loss of DNAI1 and DNAH5.

    Evidence Whole exome sequencing, TEM, and immunofluorescence of patient nasal brushings

    PMID:36303540

    Open questions at the time
    • Single family
    • Effect of missense on protein folding/interaction not biochemically dissected
  10. 2023 Medium

    Genetics of docking and flagellar factors placed DNAI2 axonemal localization downstream of the ODA-docking complex (CLXN/ODAD5, ODAD1-4) and the flagellar assembly factor CFAP70.

    Evidence Immunofluorescence/TEM in ODAD-mutant patient cells; CRISPR knockout mouse plus Co-IP for CFAP70-DNAI2

    PMID:36727596 PMID:37458246

    Open questions at the time
    • Direct docking interactions of DNAI2 not mapped
    • Distal-specific docking mechanism incompletely defined
  11. 2025 Low

    An ex vivo human airway model of DNAI2 loss was established to recapitulate the PCD phenotype.

    Evidence CRISPR-Cas9 knockout in clonal primary nasal epithelial cultures (preprint)

    PMID:bio_10.1101_2025.09.15.675861

    Open questions at the time
    • Preprint without detailed DNAI2-specific phenotyping
    • Mechanistic readouts beyond model establishment not reported

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the same intermediate chain is partitioned between an axonemal dynein-assembly role and a leading-edge motility/focal-adhesion role remains unresolved.
  • No structural model of DNAI2 within the ODA
  • Direct binding partners within ODA not biochemically mapped
  • Regulation distinguishing ciliary versus cytoplasmic pools unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005198 structural molecule activity 2 GO:0008092 cytoskeletal protein binding 1
Localization
GO:0005929 cilium 4 GO:0005829 cytosol 2 GO:0005886 plasma membrane 1
Pathway
R-HSA-1852241 Organelle biogenesis and maintenance 3 R-HSA-1266738 Developmental Biology 1
Partners
CFAP70DNAI1HEATR2IP6K3RUVBL1ZMYND10
Complex memberships
outer dynein arm

Evidence

Reading pass · 13 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2008 DNAI2 is an outer dynein arm (ODA) intermediate chain that localizes throughout respiratory cilia axonemes. Loss-of-function DNAI2 mutations cause complete absence of DNAI2 protein from ciliary axonemes and result in ODA defects. High-resolution immunofluorescence showed absence of ODA heavy chains DNAH5 and DNAH9 from all DNAI2-mutant ciliary axonemes, demonstrating DNAI2 is required for assembly of both proximal and distal ODA complexes. Conversely, DNAI1 mutations mainly disrupt proximal ODA complexes, while DNAH5 mutations affect both proximal and distal ODA complexes. Immunofluorescence microscopy, electron microscopy, protein expression analysis in patient respiratory cells with loss-of-function mutations American journal of human genetics High 18950741
2000 DNAI2 (human dynein axonemal intermediate chain 2) is encoded by a gene of 14 exons located at chromosome 17q25, is highly expressed in trachea and testis, and the protein is related to Chlamydomonas IC69 (an outer dynein arm intermediate chain). This established DNAI2 as a structural component of the outer dynein arm. cDNA cloning, chromosomal mapping, Northern blot, expression analysis Human genetics Medium 11153919
2010 In medaka fish, dnai2a (ortholog of human DNAI2) is required for outer dynein arm (ODA) formation in Kupffer's vesicle cilia, and loss of dnai2a causes loss of nodal flow and left-right axis defects. Combined loss of both dnai2 paralogs (dnai2a and dnai2b) leads to polycystic kidney disease, demonstrating that Dnai2 proteins control left-right polarity and kidney formation through regulation of ciliary motility. Positional cloning of medaka mutant, ultrastructural analysis (ODA defects by EM), genetic epistasis (double mutant), live imaging of nodal flow Developmental biology High 20707998 20709053
2010 In medaka, a second dnai2 paralog exists and the two dnai2 genes function either redundantly or distinctly in different tissues with motile cilia. The jaodori (joi) mutant in dnai2 shows severe reduction in outer dynein arms in Kupffer's vesicle cilia with disrupted cilia motility and left-right defects. Positional cloning, transposon insertion identification, ultrastructural electron microscopy, cilia motility analysis Developmental biology High 20709053
2014 HEATR2 interacts with DNAI2 (by immunoprecipitation) and is required for dynein arm assembly in the cytoplasm prior to axonemal incorporation. This interaction is distinct from HSP70/HSP90 chaperone interactions, implicating HEATR2 and DNAI2 in a cytoplasmic pre-assembly and transport network for dynein machinery. Immunoprecipitation (IP) of HEATR2 with DNAI2; genetic analysis in Drosophila and human PCD patients PLoS genetics Medium 25232951
2017 Pontin (Ruvbl1), an AAA ATPase component of the R2TP co-chaperone complex, is essential for stabilization of axonemal dynein intermediate chain 2 (DNAI2) in mouse testis, representing an early step in dynein arm assembly. Loss of Pontin in mouse testis reduces DNAI2 protein levels, and Pontin localizes to cytosolic puncta in ciliated cells where pre-assembly occurs. Mouse knockout (Pontin conditional KO), Western blot for DNAI2 protein levels, immunofluorescence localization in zebrafish embryos Development (Cambridge, England) Medium 29113992
2018 ZMYND10 stabilizes DNAI1 during cytoplasmic pre-assembly of dynein arms; DNAI1 in turn stabilizes DNAI2. DNAI2 does not directly interact with ZMYND10, but is stabilized by co-expression with both DNAI1 and ZMYND10, establishing a hierarchical stabilization cascade: ZMYND10→DNAI1→DNAI2. In Zmynd10 knockout mice, both inner and outer dynein arms are absent from cilia axonemes. Zmynd10 knockout mouse, co-immunoprecipitation, co-expression stability assays, immunofluorescence/electron microscopy of cilia PLoS genetics High 29601588
2019 IP6K3 (inositol hexakisphosphate kinase 3) associates with dynein intermediate chain 2 (DIC2/DNAI2) at the leading edge of migrating cells. DIC2 and IP6K3 are recruited interdependently to the leading edge, where they function coordinately to promote focal adhesion turnover and cell motility. Deletion of IP6K3 causes defects in cell motility and neuronal dendritic growth. Immunofluorescence microscopy, TIRF microscopy, co-immunoprecipitation, IP6K3 deletion cell lines Proceedings of the National Academy of Sciences of the United States of America Medium 30718399
2023 CFAP70 interacts with both DNAI1 and DNAI2 in mouse testis (by co-immunoprecipitation). Loss of CFAP70 in Cfap70-deficient mice reduces AKAP3 levels in sperm flagella and leads to multiple morphological abnormalities of the flagella, implicating CFAP70 in flagellum assembly and transport of flagellar components including DNAI2. CRISPR/Cas9 knockout mouse, co-immunoprecipitation, immunofluorescence, Western blot Biology of reproduction Medium 37458246
2022 A homozygous missense variant in DNAI2 (c.740G>A; p.Arg247Gln) causes PCD with complete absence of DNAI1, DNAI2, and DNAH5 from ciliary axonemes as shown by immunofluorescence, and TEM demonstrates absence of outer dynein arms, establishing that DNAI2 is required for proper ODA assembly in the ciliary axoneme. Whole exome sequencing, TEM, immunofluorescence analysis of patient nasal brushings Frontiers in genetics Medium 36303540
2023 Pathogenic variants in CLXN (ODAD5) cause absence of DNAI2 (along with DNAH5 and DNAI1) from distal ciliary axonemes, placing CLXN upstream of or required for distal ODA assembly that includes DNAI2. Additionally, DNAI2 is absent from ciliary axonemes of individuals with defects in ODA-docking machinery components ODAD1-4, demonstrating that DNAI2 axonemal localization depends on the ODA-docking complex. Immunofluorescence microscopy on patient respiratory cells, TEM Genetics in medicine Medium 36727596
2008 Mouse Dnai2 (Dnaic2) protein is approximately 70 kDa, encoded by an ~3 kb mRNA predominantly expressed in ovary, testis, and lung. In mouse ovaries, Dnai2 protein localizes to the surface of oocytes, with strong expression on secondary and antral follicle oocytes, suggesting a role in ovarian follicular development. Northern blot, Western blot, immunofluorescence localization in mouse ovary sections DNA and cell biology Low 18547164
2025 CRISPR-Cas9 knockout of DNAI2 in primary nasal epithelial cultures creates a primary ciliary dyskinesia disease model, demonstrating that targeted loss of DNAI2 in human airway epithelial cells recapitulates PCD phenotype ex vivo. CRISPR-Cas9 genome editing in clonal nasal epithelial cultures bioRxivpreprint Low bio_10.1101_2025.09.15.675861

Source papers

Stage 0 corpus · 58 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2008 DNAI2 mutations cause primary ciliary dyskinesia with defects in the outer dynein arm. American journal of human genetics 194 18950741
2012 Exome sequencing identifies mutations in CCDC114 as a cause of primary ciliary dyskinesia. American journal of human genetics 112 23261302
2012 Roflumilast N-oxide, a PDE4 inhibitor, improves cilia motility and ciliated human bronchial epithelial cells compromised by cigarette smoke in vitro. British journal of pharmacology 75 22385203
2009 Ciliary defects and genetics of primary ciliary dyskinesia. Paediatric respiratory reviews 70 19410201
2012 Respiratory syncytial virus inhibits ciliagenesis in differentiated normal human bronchial epithelial cells: effectiveness of N-acetylcysteine. PloS one 68 23118923
2013 Combined exome and whole-genome sequencing identifies mutations in ARMC4 as a cause of primary ciliary dyskinesia with defects in the outer dynein arm. Journal of medical genetics 67 24203976
2014 HEATR2 plays a conserved role in assembly of the ciliary motile apparatus. PLoS genetics 52 25232951
1996 DNA structural features responsible for sequence-dependent binding geometries of Hoechst 33258. Biopolymers 45 8722229
2021 The versatility of plant organic acid metabolism in leaves is underpinned by mitochondrial malate-citrate exchange. The Plant cell 44 34498076
2018 ZMYND10 stabilizes intermediate chain proteins in the cytoplasmic pre-assembly of dynein arms. PLoS genetics 43 29601588
2019 Bioinformatic identification of candidate biomarkers and related transcription factors in nasopharyngeal carcinoma. World journal of surgical oncology 42 30935420
2016 Role of IFN-γ, IL-13, and IL-17 on mucociliary differentiation of nasal epithelial cells in chronic rhinosinusitis with nasal polyps. Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology 42 26399381
2000 The human dynein intermediate chain 2 gene (DNAI2): cloning, mapping, expression pattern, and evaluation as a candidate for primary ciliary dyskinesia. Human genetics 36 11153919
2013 Roflumilast inhibits respiratory syncytial virus infection in human differentiated bronchial epithelial cells. PloS one 34 23936072
2017 Axonemal dynein assembly requires the R2TP complex component Pontin. Development (Cambridge, England) 31 29113992
2016 Genotyping by Sequencing Using Specific Allelic Capture to Build a High-Density Genetic Map of Durum Wheat. PloS one 22 27171472
1995 The Bacillus subtilis dnaI gene is part of the dnaB operon. Microbiology (Reading, England) 22 7773414
1988 Functional analysis of the dna (Ts) mutants of Bacillus subtilis: plasmid pUB110 replication as a model system. Molecular & general genetics : MGG 21 3146018
2010 Gain of chromosome 2p in chronic lymphocytic leukemia: significant heterogeneity and a new recurrent dicentric rearrangement. Leukemia & lymphoma 16 20078324
2019 Inositol hexakisphosphate kinase 3 promotes focal adhesion turnover via interactions with dynein intermediate chain 2. Proceedings of the National Academy of Sciences of the United States of America 15 30718399
2021 Integrative bioinformatics approaches for identifying potential biomarkers and pathways involved in non-obstructive azoospermia. Translational andrology and urology 14 33532314
2003 Enantioselective binding of S- and R-ofloxacin to various synthetic polynucleotides. European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences 14 12594014
2020 A novel genetic variant in DNAI2 detected by custom gene panel in a newborn with Primary Ciliary Dyskinesia: case report. BMC medical genetics 13 33167880
2017 IL-13 regulates human nasal epithelial cell differentiation via H3K4me3 modification. Journal of inflammation research 13 29386911
2008 Real-time detection of Fe.EDTA/H2O2-induced DNA cleavage by linear dichroism. Nucleic acids research 13 18567909
2000 Amine group of guanine enhances the binding of norfloxacin antibiotics to DNA. European journal of biochemistry 13 10998063
2023 Experimental and molecular support for Cfap70 as a causative gene of 'multiple morphological abnormalities of the flagella' with male infertility†. Biology of reproduction 11 37458246
2014 Carrier frequencies of eleven mutations in eight genes associated with primary ciliary dyskinesia in the Ashkenazi Jewish population. Molecular genetics & genomic medicine 11 25802884
2000 [Resistance to therapy in primary nephrotic syndrome: effect of MDR1 gene activity]. Polski merkuriusz lekarski : organ Polskiego Towarzystwa Lekarskiego 11 10897619
2023 Pathogenic variants in CLXN encoding the outer dynein arm docking-associated calcium-binding protein calaxin cause primary ciliary dyskinesia. Genetics in medicine : official journal of the American College of Medical Genetics 10 36727596
2022 Identification of a novel founder variant in DNAI2 cause primary ciliary dyskinesia in five consanguineous families derived from a single tribe descendant of Arabian Peninsula. Frontiers in genetics 10 36303540
2017 Activation of the coagulation cascade in patients with scrub typhus. Diagnostic microbiology and infectious disease 10 28679481
2008 Mouse dynein axonemal intermediate chain 2: cloning and expression. DNA and cell biology 10 18547164
2023 Naringenin attenuated airway cilia structural and functional injury induced by cigarette smoke extract via IL-17 and cAMP pathways. Phytomedicine : international journal of phytotherapy and phytopharmacology 9 38359483
2021 PM2.5 Upregulates the Expression of MUC5AC via the EGFR-PI3K Pathway in Human Sinonasal Epithelial Cells. International archives of allergy and immunology 9 34736257
2017 The Role of the Notch Signal Pathway in Mucosal Cell Metaplasia in Mouse Acute Otitis Media. Scientific reports 9 28676722
2023 Comparative transcriptome analysis identified crucial genes and pathways affecting sperm motility in the reproductive tract of drakes with different libido. Poultry science 8 36881978
2010 Dynein axonemal intermediate chain 2 is required for formation of the left-right body axis and kidney in medaka. Developmental biology 8 20707998
2010 Characterization of the medaka (Oryzias latipes) primary ciliary dyskinesia mutant, jaodori: Redundant and distinct roles of dynein axonemal intermediate chain 2 (dnai2) in motile cilia. Developmental biology 8 20709053
2009 Dic2 and Dic3 loci confer osmotic adaptation and fungicidal sensitivity independent of the HOG pathway in Cochliobolus heterostrophus. Mycological research 8 19682577
2003 Anomalous excitonic CD of meso-tetrakis(3-N-methylpyridiniumyl)porphyrin bound to poly[d(A-T)(2)]. Journal of biochemistry 8 12761170
2024 Association of novel DNAH11 variants with asthenoteratozoospermia lead to male infertility. Human genomics 7 39256880
2023 Clinical and Genetic Characterization of Patients with Primary Ciliary Dyskinesia in Southwest Saudi Arabia: A Cross Sectional Study. Children (Basel, Switzerland) 6 37892347
2025 LRRC56 deletion causes primary ciliary dyskinesia in mice characterized by dynein arms defects. Biology open 5 39912490
2016 Alterations in oviductal cilia morphology and reduced expression of axonemal dynein in diabetic NOD mice. Tissue & cell 4 27823762
2005 Binding modes of V(=O)meso-tetrakis(N-methylpyridinium-4-yl)porphyrin to various synthetic DNAs studied by polarized spectroscopy. Biochimica et biophysica acta 4 16386850
2025 Rhinovirus C15 infection induces airway epithelial cell remodeling and robust inflammatory responses: Potential implications for airway obstruction in children. Mucosal immunology 3 40975321
2024 PTEN decreases NR2F1 expression to inhibit ciliogenesis during EGFRL858R-induced lung cancer progression. Cell death & disease 3 38499532
2024 Exploring nasopharyngeal carcinoma genetics: Bioinformatics insights into pathways and gene associations. The Medical journal of Malaysia 2 39352166
2025 Identified Candidate Genes of Semen Trait in Three Pig Breeds Through Weighted GWAS and Multi-Tissue Transcriptome Analysis. Animals : an open access journal from MDPI 1 39943208
2025 Transcriptomic Features of Recurrence Rates in Idiopathic Subglottic Stenosis. The Laryngoscope 1 40326273
2025 Endometrial Signatures of Subfertility in Beef Heifers Reveal Dysregulation of MAPK Signaling and Ciliary Function. Genes 1 41300775
2024 Primary Ciliary Dyskinesia with Identical Genotype but Distinct Phenotypes in Two Siblings. The Tohoku journal of experimental medicine 1 38811211
2022 Subtyping children with asthma by clustering analysis of mRNA expression data. Frontiers in genetics 1 36159986
2021 IFT46 Expression in the Nasal Mucosa of Primary Ciliary Dyskinesia Patients: Preliminary Study. Allergy & rhinology (Providence, R.I.) 1 33628615
2021 CCDC114, DNAI2 and TOP2A involves in the effects of tibolone treatment on postmenopausal endometrium. BMC women's health 1 34116668
2026 Beneficial fungal root endophyte Piriformospora indica inhibits bitter gourd mosaic complex disease incited by combined infection of tomato leaf curl, papaya ringspot, and cucumber mosaic viruses without compromising crop growth and yield by orchestrating ROS production and scavenging through retrograde signaling. Frontiers in microbiology 0 41929680
2025 First report of DNAI2-associated primary ciliary dyskinesia in Libya: A case from a nonconsanguineous marriage. Respiratory medicine case reports 0 41018726

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