{"gene":"DNAI1","run_date":"2026-04-28T17:46:03","timeline":{"discoveries":[{"year":2001,"finding":"Compound heterozygous mutations in DNAI1 (encoding axonemal dynein intermediate chain 1) cause primary ciliary dyskinesia (PCD) with or without situs inversus (Kartagener syndrome), establishing that DNAI1 is essential for ciliary function and left-right axis determination.","method":"Genetic sequencing of DNAI1 in PCD/KS patients; identification of compound heterozygous mutations including a splice defect allele shared across families","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 2 — genetic evidence in multiple independent patients with defined mutations, replicated across families; mechanistic link between DNAI1 mutation and ciliary dysfunction/situs determination established","pmids":["11231901"],"is_preprint":false},{"year":2006,"finding":"DNAI1 mutations account for approximately 9-10% of PCD cases, predominantly occurring as a founder mutation (IVS1+2_3insT) affecting outer dynein arm (ODA) assembly; no DNAI1 mutations are found in PCD patients without ODA defects, indicating DNAI1 is specifically required for ODA function.","method":"Full coding region sequencing of DNAI1 in 179 unrelated PCD families; RT-PCR on nasal epithelial RNA; marker haplotype analysis for founder effect","journal":"American journal of respiratory and critical care medicine","confidence":"High","confidence_rationale":"Tier 2 — large cohort sequencing with functional correlation to ODA defect phenotype; founder effect confirmed by haplotype analysis","pmids":["16858015"],"is_preprint":false},{"year":1991,"finding":"The ODA6 locus in Chlamydomonas (ortholog of DNAI1) encodes the 70 kDa dynein intermediate chain protein that is essential for assembly of stable outer dynein arms; loss of this protein prevents assembly of all major outer arm dynein subunits.","method":"Genetic rescue by transformation with wild-type genomic clone; restriction fragment length polymorphism mapping; complementation analysis","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1 — genetic rescue with wild-type gene in defined mutant, confirming gene identity and essential role in ODA assembly","pmids":["1673970"],"is_preprint":false},{"year":2010,"finding":"DNAI1 population-specific mutation spectrum analysis shows IVS1+2_3insT accounts for 54% of mutant alleles worldwide; MLPA analysis indicates no large exonic deletions contribute to PCD pathogenesis; the global involvement of DNAI1 mutations ranges from 7-10% in unselected families.","method":"SSCP analysis, direct sequencing of DNAI1 coding sequence in 157 PCD families; MLPA for copy number variation; SNP haplotype analysis for founder effect","journal":"Respiratory research","confidence":"Medium","confidence_rationale":"Tier 2 — large cohort with multiple methods; single lab study but large sample size with orthogonal approaches","pmids":["21143860"],"is_preprint":false},{"year":2008,"finding":"DNAI1 mutations are identified in only 2% of an unselected PCD cohort, with specific missense variants (p.Trp568Ser, p.Glu174Lys) and the IVS1+2_3insT splice mutation; loss-of-function DNAI1 mutations cause ciliary dysmotility consistent with an outer dynein arm structural role.","method":"Denaturing HPLC and direct sequencing of DNAI1 coding and splice site sequences in 104 unrelated PCD patients","journal":"Respiration; international review of thoracic diseases","confidence":"Medium","confidence_rationale":"Tier 2 — systematic sequencing in a clinically heterogeneous cohort; single lab but consistent with prior studies","pmids":["18434704"],"is_preprint":false},{"year":2016,"finding":"Trans-heterozygous interactions between DNAH6 and DNAI1 can cause heterotaxy; subthreshold double-morpholino knockdown of Dnah6 in heterozygous Dnai1 mutant mouse respiratory epithelia disrupts motile cilia function, demonstrating an oligogenic epistatic interaction between DNAI1 and DNAH6 in cilia-driven left-right patterning.","method":"Zebrafish subthreshold double morpholino knockdown; siRNA knockdown in heterozygous Dnai1 mutant mouse respiratory epithelial cells; cilia beat analysis","journal":"PLoS genetics","confidence":"Medium","confidence_rationale":"Tier 2 — functional epistasis demonstrated in two model organisms with defined cellular phenotype (disrupted motile cilia)","pmids":["26918822"],"is_preprint":false}],"current_model":"DNAI1 encodes an axonemal dynein intermediate chain protein that is an essential structural component of the outer dynein arm (ODA) of motile cilia and flagella; loss-of-function mutations in DNAI1 abolish ODA assembly, causing ciliary dysmotility that underlies primary ciliary dyskinesia (with or without situs inversus), and DNAI1 participates in oligogenic interactions with other ODA components (e.g., DNAH6, DNAH5) to regulate cilia-driven left-right axis determination."},"narrative":{"teleology":[{"year":1991,"claim":"The identity of the gene encoding the 70 kDa ODA intermediate chain was established: Chlamydomonas ODA6, the DNAI1 ortholog, was shown to be absolutely required for stable outer dynein arm assembly, answering whether a single intermediate chain is sufficient for ODA biogenesis.","evidence":"Genetic rescue of oda6 mutant Chlamydomonas by transformation with wild-type genomic clone; complementation and RFLP mapping","pmids":["1673970"],"confidence":"High","gaps":["Whether the human ortholog performs an identical role was not yet tested","Mechanism by which the intermediate chain scaffolds other ODA subunits was not resolved","No structural model for intermediate chain–heavy chain interaction"]},{"year":2001,"claim":"The first direct genetic link between human DNAI1 and disease was established: compound heterozygous mutations in DNAI1 cause primary ciliary dyskinesia with or without situs inversus, demonstrating that the ODA intermediate chain is essential for ciliary motility and left-right axis determination in humans.","evidence":"Sequencing of DNAI1 in PCD/Kartagener syndrome patients; identification of compound heterozygous mutations including a shared splice defect allele across families","pmids":["11231901"],"confidence":"High","gaps":["Mutation frequency and allelic spectrum across diverse populations were unknown","Whether DNAI1 mutations could cause ciliary defects beyond the ODA phenotype was unclear"]},{"year":2006,"claim":"Large-cohort sequencing defined the contribution and allelic architecture of DNAI1 in PCD: DNAI1 mutations account for ~9–10% of cases, with the founder allele IVS1+2_3insT predominating, and mutations segregate exclusively with ODA defects, confirming DNAI1 is dispensable when ODA structure is intact.","evidence":"Full coding region sequencing in 179 unrelated PCD families; RT-PCR on nasal epithelial RNA; haplotype analysis","pmids":["16858015"],"confidence":"High","gaps":["Contribution of large structural rearrangements to DNAI1 pathogenesis had not been assessed","Genotype–phenotype correlations for specific missense variants were limited"]},{"year":2016,"claim":"The discovery of oligogenic epistasis between DNAI1 and DNAH6 expanded the mechanistic model from simple Mendelian loss-of-function to combinatorial dosage sensitivity: trans-heterozygous reduction of both ODA components disrupts cilia-driven laterality, explaining some heterotaxy cases without biallelic mutations in a single gene.","evidence":"Subthreshold double morpholino knockdown in zebrafish; siRNA knockdown in heterozygous Dnai1 mutant mouse respiratory epithelia with cilia beat analysis","pmids":["26918822"],"confidence":"Medium","gaps":["Physical interaction between DNAI1 and DNAH6 proteins was not demonstrated biochemically","Whether DNAI1 engages in epistatic interactions with additional ODA or IDA genes is untested","Morpholino-based evidence in zebrafish requires genetic confirmation"]},{"year":null,"claim":"The precise mechanism by which DNAI1 scaffolds or chaperones ODA heavy and light chains during cytoplasmic pre-assembly and axonemal docking remains structurally unresolved, and the full epistatic network governing DNAI1-dependent left-right patterning is incomplete.","evidence":"","pmids":[],"confidence":"Low","gaps":["No high-resolution structural model of DNAI1 within the ODA complex","Cytoplasmic pre-assembly and transport mechanism of DNAI1-containing ODA subcomplexes not characterized","Complete set of oligogenic partners modifying DNAI1-associated phenotypes is unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[2,0,1]}],"localization":[{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[0,1,2,5]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[2]}],"pathway":[{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[2,0,1]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[0,5]}],"complexes":["Outer dynein arm (ODA)"],"partners":["DNAH6","DNAH5"],"other_free_text":[]},"mechanistic_narrative":"DNAI1 encodes an axonemal dynein intermediate chain that is essential for the assembly of outer dynein arms (ODAs) in motile cilia and flagella; loss of the Chlamydomonas ortholog ODA6 prevents assembly of all major outer arm dynein subunits [PMID:1673970]. Compound heterozygous loss-of-function mutations in DNAI1 cause primary ciliary dyskinesia (PCD), with or without situs inversus, accounting for approximately 7–10% of PCD cases and segregating exclusively with ODA-defective phenotypes [PMID:11231901, PMID:16858015]. DNAI1 also participates in oligogenic epistatic interactions with other ODA components such as DNAH6, whereby trans-heterozygous perturbation of both genes disrupts cilia-driven left-right patterning and causes heterotaxy [PMID:26918822]."},"prefetch_data":{"uniprot":{"accession":"Q9UI46","full_name":"Dynein axonemal intermediate chain 1","aliases":["Axonemal dynein intermediate chain 1"],"length_aa":699,"mass_kda":79.3,"function":"Component of dynein, a family of motor proteins essential for movement along microtubules (By similarity). Required for structural and functional integrity of cilia (By similarity). Part of the dynein complex of respiratory cilia","subcellular_location":"Dynein axonemal particle; Cytoplasm, cytoskeleton, cilium axoneme; Cell projection, cilium, flagellum; Cytoplasm, cytoskeleton","url":"https://www.uniprot.org/uniprotkb/Q9UI46/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/DNAI1","classification":"Not Classified","n_dependent_lines":3,"n_total_lines":1208,"dependency_fraction":0.0024834437086092716},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/DNAI1","total_profiled":1310},"omim":[{"mim_id":"620642","title":"CILIARY DYSKINESIA, PRIMARY, 53; CILD53","url":"https://www.omim.org/entry/620642"},{"mim_id":"619564","title":"CALAXIN; CLXN","url":"https://www.omim.org/entry/619564"},{"mim_id":"618801","title":"CILIARY DYSKINESIA, PRIMARY, 45; CILD45","url":"https://www.omim.org/entry/618801"},{"mim_id":"618300","title":"CILIARY DYSKINESIA, PRIMARY, 40; CILD40","url":"https://www.omim.org/entry/618300"},{"mim_id":"614790","title":"WT1-INTERACTING PROTEIN; WTIP","url":"https://www.omim.org/entry/614790"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Primary cilium","reliability":"Supported"},{"location":"Mid piece","reliability":"Supported"},{"location":"End piece","reliability":"Supported"},{"location":"Vesicles","reliability":"Additional"},{"location":"Principal piece","reliability":"Additional"}],"tissue_specificity":"Group enriched","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"choroid plexus","ntpm":65.4},{"tissue":"fallopian tube","ntpm":31.9},{"tissue":"testis","ntpm":31.3}],"url":"https://www.proteinatlas.org/search/DNAI1"},"hgnc":{"alias_symbol":["DIC1","PCD","CILD1","oda6"],"prev_symbol":[]},"alphafold":{"accession":"Q9UI46","domains":[{"cath_id":"2.130.10.10","chopping":"308-483_492-666_674-697","consensus_level":"high","plddt":92.1964,"start":308,"end":697}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UI46","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UI46-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9UI46-F1-predicted_aligned_error_v6.png","plddt_mean":79.0},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=DNAI1","jax_strain_url":"https://www.jax.org/strain/search?query=DNAI1"},"sequence":{"accession":"Q9UI46","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9UI46.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9UI46/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9UI46"}},"corpus_meta":[{"pmid":"11193023","id":"PMC_11193023","title":"Programmed cell death (PCD). 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identification of compound heterozygous mutations including a splice defect allele shared across families\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic evidence in multiple independent patients with defined mutations, replicated across families; mechanistic link between DNAI1 mutation and ciliary dysfunction/situs determination established\",\n      \"pmids\": [\"11231901\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"DNAI1 mutations account for approximately 9-10% of PCD cases, predominantly occurring as a founder mutation (IVS1+2_3insT) affecting outer dynein arm (ODA) assembly; no DNAI1 mutations are found in PCD patients without ODA defects, indicating DNAI1 is specifically required for ODA function.\",\n      \"method\": \"Full coding region sequencing of DNAI1 in 179 unrelated PCD families; RT-PCR on nasal epithelial RNA; marker haplotype analysis for founder effect\",\n      \"journal\": \"American journal of respiratory and critical care medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — large cohort sequencing with functional correlation to ODA defect phenotype; founder effect confirmed by haplotype analysis\",\n      \"pmids\": [\"16858015\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1991,\n      \"finding\": \"The ODA6 locus in Chlamydomonas (ortholog of DNAI1) encodes the 70 kDa dynein intermediate chain protein that is essential for assembly of stable outer dynein arms; loss of this protein prevents assembly of all major outer arm dynein subunits.\",\n      \"method\": \"Genetic rescue by transformation with wild-type genomic clone; restriction fragment length polymorphism mapping; complementation analysis\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — genetic rescue with wild-type gene in defined mutant, confirming gene identity and essential role in ODA assembly\",\n      \"pmids\": [\"1673970\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"DNAI1 population-specific mutation spectrum analysis shows IVS1+2_3insT accounts for 54% of mutant alleles worldwide; MLPA analysis indicates no large exonic deletions contribute to PCD pathogenesis; the global involvement of DNAI1 mutations ranges from 7-10% in unselected families.\",\n      \"method\": \"SSCP analysis, direct sequencing of DNAI1 coding sequence in 157 PCD families; MLPA for copy number variation; SNP haplotype analysis for founder effect\",\n      \"journal\": \"Respiratory research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — large cohort with multiple methods; single lab study but large sample size with orthogonal approaches\",\n      \"pmids\": [\"21143860\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"DNAI1 mutations are identified in only 2% of an unselected PCD cohort, with specific missense variants (p.Trp568Ser, p.Glu174Lys) and the IVS1+2_3insT splice mutation; loss-of-function DNAI1 mutations cause ciliary dysmotility consistent with an outer dynein arm structural role.\",\n      \"method\": \"Denaturing HPLC and direct sequencing of DNAI1 coding and splice site sequences in 104 unrelated PCD patients\",\n      \"journal\": \"Respiration; international review of thoracic diseases\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — systematic sequencing in a clinically heterogeneous cohort; single lab but consistent with prior studies\",\n      \"pmids\": [\"18434704\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Trans-heterozygous interactions between DNAH6 and DNAI1 can cause heterotaxy; subthreshold double-morpholino knockdown of Dnah6 in heterozygous Dnai1 mutant mouse respiratory epithelia disrupts motile cilia function, demonstrating an oligogenic epistatic interaction between DNAI1 and DNAH6 in cilia-driven left-right patterning.\",\n      \"method\": \"Zebrafish subthreshold double morpholino knockdown; siRNA knockdown in heterozygous Dnai1 mutant mouse respiratory epithelial cells; cilia beat analysis\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional epistasis demonstrated in two model organisms with defined cellular phenotype (disrupted motile cilia)\",\n      \"pmids\": [\"26918822\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"DNAI1 encodes an axonemal dynein intermediate chain protein that is an essential structural component of the outer dynein arm (ODA) of motile cilia and flagella; loss-of-function mutations in DNAI1 abolish ODA assembly, causing ciliary dysmotility that underlies primary ciliary dyskinesia (with or without situs inversus), and DNAI1 participates in oligogenic interactions with other ODA components (e.g., DNAH6, DNAH5) to regulate cilia-driven left-right axis determination.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"DNAI1 encodes an axonemal dynein intermediate chain that is essential for the assembly of outer dynein arms (ODAs) in motile cilia and flagella; loss of the Chlamydomonas ortholog ODA6 prevents assembly of all major outer arm dynein subunits [PMID:1673970]. Compound heterozygous loss-of-function mutations in DNAI1 cause primary ciliary dyskinesia (PCD), with or without situs inversus, accounting for approximately 7–10% of PCD cases and segregating exclusively with ODA-defective phenotypes [PMID:11231901, PMID:16858015]. DNAI1 also participates in oligogenic epistatic interactions with other ODA components such as DNAH6, whereby trans-heterozygous perturbation of both genes disrupts cilia-driven left-right patterning and causes heterotaxy [PMID:26918822].\",\n  \"teleology\": [\n    {\n      \"year\": 1991,\n      \"claim\": \"The identity of the gene encoding the 70 kDa ODA intermediate chain was established: Chlamydomonas ODA6, the DNAI1 ortholog, was shown to be absolutely required for stable outer dynein arm assembly, answering whether a single intermediate chain is sufficient for ODA biogenesis.\",\n      \"evidence\": \"Genetic rescue of oda6 mutant Chlamydomonas by transformation with wild-type genomic clone; complementation and RFLP mapping\",\n      \"pmids\": [\"1673970\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether the human ortholog performs an identical role was not yet tested\",\n        \"Mechanism by which the intermediate chain scaffolds other ODA subunits was not resolved\",\n        \"No structural model for intermediate chain–heavy chain interaction\"\n      ]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"The first direct genetic link between human DNAI1 and disease was established: compound heterozygous mutations in DNAI1 cause primary ciliary dyskinesia with or without situs inversus, demonstrating that the ODA intermediate chain is essential for ciliary motility and left-right axis determination in humans.\",\n      \"evidence\": \"Sequencing of DNAI1 in PCD/Kartagener syndrome patients; identification of compound heterozygous mutations including a shared splice defect allele across families\",\n      \"pmids\": [\"11231901\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Mutation frequency and allelic spectrum across diverse populations were unknown\",\n        \"Whether DNAI1 mutations could cause ciliary defects beyond the ODA phenotype was unclear\"\n      ]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Large-cohort sequencing defined the contribution and allelic architecture of DNAI1 in PCD: DNAI1 mutations account for ~9–10% of cases, with the founder allele IVS1+2_3insT predominating, and mutations segregate exclusively with ODA defects, confirming DNAI1 is dispensable when ODA structure is intact.\",\n      \"evidence\": \"Full coding region sequencing in 179 unrelated PCD families; RT-PCR on nasal epithelial RNA; haplotype analysis\",\n      \"pmids\": [\"16858015\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Contribution of large structural rearrangements to DNAI1 pathogenesis had not been assessed\",\n        \"Genotype–phenotype correlations for specific missense variants were limited\"\n      ]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"The discovery of oligogenic epistasis between DNAI1 and DNAH6 expanded the mechanistic model from simple Mendelian loss-of-function to combinatorial dosage sensitivity: trans-heterozygous reduction of both ODA components disrupts cilia-driven laterality, explaining some heterotaxy cases without biallelic mutations in a single gene.\",\n      \"evidence\": \"Subthreshold double morpholino knockdown in zebrafish; siRNA knockdown in heterozygous Dnai1 mutant mouse respiratory epithelia with cilia beat analysis\",\n      \"pmids\": [\"26918822\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Physical interaction between DNAI1 and DNAH6 proteins was not demonstrated biochemically\",\n        \"Whether DNAI1 engages in epistatic interactions with additional ODA or IDA genes is untested\",\n        \"Morpholino-based evidence in zebrafish requires genetic confirmation\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The precise mechanism by which DNAI1 scaffolds or chaperones ODA heavy and light chains during cytoplasmic pre-assembly and axonemal docking remains structurally unresolved, and the full epistatic network governing DNAI1-dependent left-right patterning is incomplete.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No high-resolution structural model of DNAI1 within the ODA complex\",\n        \"Cytoplasmic pre-assembly and transport mechanism of DNAI1-containing ODA subcomplexes not characterized\",\n        \"Complete set of oligogenic partners modifying DNAI1-associated phenotypes is unknown\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [2, 0, 1]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [0, 1, 2, 5]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [2]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [2, 0, 1]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [0, 5]}\n    ],\n    \"complexes\": [\n      \"Outer dynein arm (ODA)\"\n    ],\n    \"partners\": [\n      \"DNAH6\",\n      \"DNAH5\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}