Affinage

DNAI2

Dynein axonemal intermediate chain 2 · UniProt Q9GZS0

Length
605 aa
Mass
68.8 kDa
Annotated
2026-04-28
69 papers in source corpus 14 papers cited in narrative 15 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

DNAI2 is an intermediate chain subunit of the axonemal outer dynein arm (ODA) that is essential for the assembly and structural integrity of both proximal and distal ODA complexes in motile cilia and flagella. DNAI2 is stabilized in the cytoplasm through a hierarchical pre-assembly pathway in which ZMYND10 stabilizes DNAI1, which in turn stabilizes DNAI2, with upstream factors including Pontin (R2TP complex), HEATR2, LRRC56, and CFAP70 also required for proper DNAI2 stabilization and ciliary delivery (PMID:29601588, PMID:29113992, PMID:25232951, PMID:39912490, PMID:37458246). Loss of DNAI2 causes complete absence of ODA heavy chains DNAH5 and DNAH9 from ciliary axonemes, abolishing ODA-dependent motility and nodal flow required for left–right axis determination (PMID:18950741, PMID:20707998). Biallelic loss-of-function mutations in DNAI2 cause primary ciliary dyskinesia with outer dynein arm defects, situs abnormalities, and male infertility (PMID:18950741, PMID:36303540).

Mechanistic history

Synthesis pass · year-by-year structured walk · 8 steps
  1. 2000 Medium

    Identification of DNAI2 as the human ortholog of Chlamydomonas IC69 (ODA6), mapping to 17q25 with trachea- and testis-enriched expression, established it as a candidate axonemal dynein intermediate chain.

    Evidence cDNA cloning, chromosomal mapping, and Northern blot in human tissues

    PMID:11153919

    Open questions at the time
    • No functional data; role in ODA assembly not yet tested
    • Protein-level expression and localization not determined
  2. 2008 High

    Loss-of-function mutations in DNAI2 patients demonstrated that DNAI2 is essential for ODA assembly along the entire axoneme, with its absence causing concomitant loss of heavy chains DNAH5 and DNAH9, and reciprocal experiments showed interdependence among ODA subunits for axonemal targeting.

    Evidence Patient mutation analysis with immunofluorescence, TEM, and Western blot on human respiratory cilia across multiple PCD genotypes

    PMID:18950741

    Open questions at the time
    • Mechanism by which DNAI2 loss prevents heavy chain assembly unknown
    • Cytoplasmic pre-assembly steps not yet characterized
  3. 2010 High

    Medaka genetic models established that DNAI2 is required for ODA formation in node cilia, directly linking DNAI2-dependent ODA function to nodal flow generation and left–right axis determination, and revealed tissue-specific redundancy between DNAI2 paralogs.

    Evidence Positional cloning of medaka mii mutant, TEM ultrastructure, nodal flow imaging, and double-mutant analysis

    PMID:20707998 PMID:20709053

    Open questions at the time
    • Whether paralog redundancy applies in mammals unclear
    • Whether DNAI2 has cilia-independent roles not addressed
  4. 2014 Medium

    Discovery that HEATR2 physically interacts with DNAI2 and is required for cytoplasmic dynein arm pre-assembly identified the first cytoplasmic assembly factor directly associated with DNAI2.

    Evidence Co-immunoprecipitation in human cells plus genetic loss-of-function in Drosophila and human

    PMID:25232951

    Open questions at the time
    • Stoichiometry and directness of HEATR2–DNAI2 interaction not resolved
    • Whether HEATR2 acts as a chaperone or scaffold unclear
  5. 2017 Medium

    Pontin (Ruvbl1), an R2TP complex ATPase, was placed upstream of DNAI2 stabilization, showing that AAA-ATPase-dependent remodeling is an early prerequisite for ODA intermediate chain accumulation.

    Evidence Pontin conditional knockout mice and zebrafish mutants with Western blot quantification of DNAI1/DNAI2 levels

    PMID:29113992

    Open questions at the time
    • Whether Pontin acts directly on DNAI2 or via DNAI1 stabilization not distinguished
    • Single-lab finding
  6. 2018 High

    Elucidation of the hierarchical stabilization cascade ZMYND10→DNAI1→DNAI2 revealed that DNAI2 does not directly contact ZMYND10 but depends on DNAI1 for cytoplasmic stabilization during ODA pre-assembly.

    Evidence Zmynd10-knockout mice, reciprocal co-IP, and co-expression stability assays

    PMID:29601588

    Open questions at the time
    • Whether additional chaperones bridge DNAI1–DNAI2 interaction unknown
    • Structural basis of DNAI1-dependent DNAI2 stabilization not determined
  7. 2023 Medium

    CFAP70 was identified as a physical interactor of both DNAI1 and DNAI2 in mouse testis, and CLXN/ODAD5 was shown to be required for distal ODA assembly including DNAI2 targeting, expanding the network of ODA docking and transport factors upstream of DNAI2.

    Evidence Co-IP from mouse testis (CFAP70), immunofluorescence on CLXN-mutant patient respiratory cilia, TEM

    PMID:36727596 PMID:37458246

    Open questions at the time
    • Whether CFAP70 functions in transport versus stabilization of DNAI2 not resolved
    • Direct versus indirect role of CLXN in DNAI2 axonemal targeting unclear
  8. 2025 Medium

    LRRC56 knockout mice confirmed another upstream assembly factor required for DNAI2 ciliary localization, further defining the multi-step pathway from cytoplasmic pre-assembly to axonemal docking.

    Evidence CRISPR/Cas9 LRRC56-KO mice with immunofluorescence and TEM

    PMID:39912490

    Open questions at the time
    • Order of LRRC56 action relative to HEATR2 and Pontin not established
    • Single-lab finding

Open questions

Synthesis pass · forward-looking unresolved questions
  • The structural basis of DNAI2 integration into the ODA complex, the complete order of cytoplasmic pre-assembly steps, and whether DNAI2 has functions independent of the axonemal ODA remain unresolved.
  • No high-resolution structure of DNAI2 within the human ODA complex
  • Complete temporal ordering of all assembly factors (Pontin, HEATR2, ZMYND10, LRRC56, CFAP70, CLXN) not established
  • Potential non-ciliary roles (e.g., oocyte surface localization) not mechanistically characterized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005198 structural molecule activity 3
Localization
GO:0005929 cilium 7 GO:0005829 cytosol 3
Pathway
R-HSA-1852241 Organelle biogenesis and maintenance 5
Partners
CFAP70DNAH5DNAH9DNAI1HEATR2RUVBL1ZMYND10
Complex memberships
Outer dynein arm (ODA)

Evidence

Reading pass · 15 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2008 DNAI2 encodes an outer dynein arm (ODA) intermediate chain protein that localizes throughout respiratory cilia; loss-of-function mutations cause complete absence of DNAI2 protein and ODA defects, with concomitant absence of ODA heavy chains DNAH5 and DNAH9 from all ciliary axonemes, establishing DNAI2 as essential for assembly of both proximal and distal ODA complexes. Patient mutation analysis, immunofluorescence imaging, electron microscopy, Western blot/protein expression analysis American journal of human genetics High 18950741
2008 DNAI2 is absent from ciliary axonemes in patients with mutations in DNAH5 (complete absence) and DNAI1 (distal absence), indicating interdependence among ODA chain proteins for axonemal assembly; DNAI1 mutations mainly disrupt proximal ODA complexes while DNAI2 and DNAH5 mutations affect both proximal and distal ODA complexes. High-resolution immunofluorescence imaging of respiratory cells from PCD patients with defined mutations American journal of human genetics High 18950741
2000 DNAI2 (human gene related to Chlamydomonas IC69/ODA6) is composed of 14 exons located at chromosomal locus 17q25 and is highly expressed in trachea and testis, consistent with its role as an axonemal dynein intermediate chain. cDNA cloning, chromosomal mapping, Northern blot expression analysis Human genetics Medium 11153919
2018 ZMYND10 stabilizes DNAI1 in the cytoplasm during dynein arm pre-assembly; DNAI2 does not directly interact with ZMYND10 but is stabilized indirectly through DNAI1—co-expression of DNAI2 with DNAI1 and ZMYND10 stabilizes DNAI2, whereas ZMYND10 alone does not stabilize DNAI2. Zmynd10 knockout mouse model, co-immunoprecipitation, co-expression stability assays, immunofluorescence PLoS genetics High 29601588
2014 HEATR2 interacts with DNAI2 by immunoprecipitation and is required for dynein arm assembly in the cytoplasm; this distinguishes HEATR2 from HSP70/HSP90-dependent chaperone mechanisms, placing it in a cytoplasmic pre-assembly network that delivers functional dynein to the ciliary compartment. Immunoprecipitation (Co-IP), Drosophila and human genetic analysis, immunofluorescence PLoS genetics Medium 25232951
2017 Pontin (Ruvbl1), an R2TP complex AAA-ATPase, is required in mouse testis for stabilization of both DNAI1 and DNAI2 as an early step in axonemal dynein arm assembly, placing Pontin upstream of DNAI2 stabilization in the dynein pre-assembly pathway. Zebrafish and mouse genetic models (pontin mutant/conditional knockout), Western blot for DNAI1 and DNAI2 protein levels, immunofluorescence Development (Cambridge, England) Medium 29113992
2010 In medaka (Oryzias latipes), dnai2a is required for outer dynein arm (ODA) formation in Kupffer's vesicle cilia; loss of dnai2a alone causes left-right patterning defects but not polycystic kidney disease, while simultaneous loss of both dnai2 paralogs (dnai2a and dnai2b) leads to PKD, demonstrating redundant and distinct roles of Dnai2 paralogs in different ciliated tissues. Medaka positional cloning, transmission electron microscopy (ODA ultrastructure), nodal flow analysis, genetic double-mutant analysis Developmental biology High 20707998 20709053
2010 Dnai2a (medaka ortholog) is required for outer dynein arm formation in Kupffer's vesicle (node-equivalent) cilia; loss causes loss of nodal flow and randomized left-right organ asymmetry, establishing a direct mechanistic link between DNAI2-dependent ODA function and left-right axis determination. Medaka mutant (mii) analysis, TEM, nodal flow imaging, left-specific gene expression analysis Developmental biology High 20707998
2019 IP6K3 (inositol hexakisphosphate kinase 3) associates with dynein intermediate chain 2 (DIC2/DNAI2 cytoplasmic isoform) at the leading edge of migrating cells; both proteins are recruited interdependently to the leading edge and cooperate to promote focal adhesion turnover and cell motility. Co-immunoprecipitation, immunofluorescence microscopy, TIRF microscopy, IP6K3 deletion cell lines Proceedings of the National Academy of Sciences of the United States of America Medium 30718399
2023 CFAP70 physically interacts with both DNAI1 and DNAI2 in mouse testis; Cfap70 deficiency in mice reduces the level of AKAP3 in sperm flagella and causes multiple morphological abnormalities of the flagella, suggesting CFAP70 participates in flagellum assembly and transport of flagellar components including DNAI2. CRISPR/Cas9 Cfap70-knockout mice, co-immunoprecipitation (CFAP70-DNAI1/DNAI2 interaction), Western blot, immunofluorescence Biology of reproduction Medium 37458246
2013 ARMC4 loss-of-function causes PCD with absence of distal outer dynein arm motors and a predicted interaction with DNAI2, suggesting ARMC4 functions in the same ODA assembly pathway as DNAI2. Whole-exome and whole-genome sequencing, immunofluorescence (ARMC4 protein absence in cilia), bioinformatic interaction prediction Journal of medical genetics Low 24203976
2023 CLXN (EFCAB1/ODAD5) is required for assembly of distal outer dynein arms; immunofluorescence shows that DNAI2 (along with DNAH5 and DNAI1) is absent from distal axonemes in CLXN-mutant patients, and CLXN itself is absent in patients with ODA-docking complex mutations (ODAD1-4), placing CLXN within the ODA-docking machinery upstream of DNAI2 distal assembly. Clinical exome sequencing, immunofluorescence microscopy on patient respiratory cilia, TEM Genetics in medicine Medium 36727596
2008 Mouse Dnai2 (Dnaic2) protein (~70 kDa) is predominantly expressed in ovary, testis, and lung; in mouse ovaries it shows developmentally regulated expression with peak levels at day 10, and the protein localizes to the surface of oocytes in secondary and antral follicles, suggesting a role in ovarian follicular development. Differential display RT-PCR, RACE cloning, Northern blot, Western blot, immunofluorescence on mouse ovary sections DNA and cell biology Medium 18547164
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 lack of outer dynein arms, confirming the pathogenic mechanism of this DNAI2 variant. Whole exome sequencing, immunofluorescence microscopy on nasal brush biopsies, transmission electron microscopy Frontiers in genetics Medium 36303540
2025 LRRC56 (DNAAF12) knockout in mice results in absence of DNAI2 (and DNALI1) from cilia as shown by immunofluorescence, with TEM-confirmed dynein arm defects, placing LRRC56 upstream of DNAI2 in the dynein arm assembly pathway. CRISPR/Cas9 LRRC56-knockout mice, immunofluorescence, transmission electron microscopy Biology open Medium 39912490

Source papers

Stage 0 corpus · 69 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 191 18950741
1998 The role of preassembled cytoplasmic complexes in assembly of flagellar dynein subunits. Molecular biology of the cell 162 9725897
1991 Identification of oda6 as a Chlamydomonas dynein mutant by rescue with the wild-type gene. The Journal of cell biology 134 1673970
1992 Homology of the 74-kD cytoplasmic dynein subunit with a flagellar dynein polypeptide suggests an intracellular targeting function. The Journal of cell biology 111 1387402
2012 Exome sequencing identifies mutations in CCDC114 as a cause of primary ciliary dyskinesia. American journal of human genetics 110 23261302
1996 Inner dynein arms but not outer dynein arms require the activity of kinesin homologue protein KHP1(FLA10) to reach the distal part of flagella in Chlamydomonas. The Journal of cell biology 107 8609169
2008 Molecular identification of three Arabidopsis thaliana mitochondrial dicarboxylate carrier isoforms: organ distribution, bacterial expression, reconstitution into liposomes and functional characterization. The Biochemical journal 103 18039180
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 74 22385203
2009 Ciliary defects and genetics of primary ciliary dyskinesia. Paediatric respiratory reviews 70 19410201
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
2012 Respiratory syncytial virus inhibits ciliagenesis in differentiated normal human bronchial epithelial cells: effectiveness of N-acetylcysteine. PloS one 67 23118923
2014 HEATR2 plays a conserved role in assembly of the ciliary motile apparatus. PLoS genetics 52 25232951
2001 Transport and arrangement of the outer-dynein-arm docking complex in the flagella of Chlamydomonas mutants that lack outer dynein arms. Cell motility and the cytoskeleton 47 11276076
1996 DNA structural features responsible for sequence-dependent binding geometries of Hoechst 33258. Biopolymers 45 8722229
1993 Reversion analysis of dynein intermediate chain function. Journal of cell science 45 8227195
2021 The versatility of plant organic acid metabolism in leaves is underpinned by mitochondrial malate-citrate exchange. The Plant cell 43 34498076
2018 ZMYND10 stabilizes intermediate chain proteins in the cytoplasmic pre-assembly of dynein arms. PLoS genetics 42 29601588
2019 Bioinformatic identification of candidate biomarkers and related transcription factors in nasopharyngeal carcinoma. World journal of surgical oncology 41 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 41 26399381
2018 In vivo analysis of outer arm dynein transport reveals cargo-specific intraflagellar transport properties. Molecular biology of the cell 40 30133350
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
2005 Differential light chain assembly influences outer arm dynein motor function. Molecular biology of the cell 31 16195342
1997 Beat frequency difference between the two flagella of Chlamydomonas depends on the attachment site of outer dynein arms on the outer-doublet microtubules. Cell motility and the cytoskeleton 29 8986378
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
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
2020 A novel genetic variant in DNAI2 detected by custom gene panel in a newborn with Primary Ciliary Dyskinesia: case report. BMC medical genetics 12 33167880
2017 IL-13 regulates human nasal epithelial cell differentiation via H3K4me3 modification. Journal of inflammation research 12 29386911
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
2017 The Role of the Notch Signal Pathway in Mucosal Cell Metaplasia in Mouse Acute Otitis Media. Scientific reports 9 28676722
1998 An intronic enhancer is required for deflagellation-induced transcriptional regulation of a Chlamydomonas reinhardtii dynein gene. Molecular biology of the cell 9 9802898
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 8 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 8 34736257
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 Comparative transcriptome analysis identified crucial genes and pathways affecting sperm motility in the reproductive tract of drakes with different libido. Poultry science 7 36881978
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
2024 PTEN decreases NR2F1 expression to inhibit ciliogenesis during EGFRL858R-induced lung cancer progression. Cell death & disease 3 38499532
2025 Rhinovirus C15 infection induces airway epithelial cell remodeling and robust inflammatory responses: Potential implications for airway obstruction in children. Mucosal immunology 2 40975321
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
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
2025 Endometrial Signatures of Subfertility in Beef Heifers Reveal Dysregulation of MAPK Signaling and Ciliary Function. Genes 0 41300775