{"gene":"DNAH6","run_date":"2026-04-28T17:46:02","timeline":{"discoveries":[{"year":2016,"finding":"DNAH6 is required for motile cilia function in left-right patterning; dnah6 morpholino knockdown in zebrafish disrupted motile cilia in Kupffer's vesicle causing heterotaxy with abnormal cardiac/gut looping, and DNAH6 shRNA knockdown disrupted motile cilia in human and mouse respiratory epithelia.","method":"Morpholino knockdown in zebrafish (cilia motility assay, organ laterality phenotype); shRNA knockdown in human and mouse respiratory epithelia","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 — reciprocal loss-of-function in two model systems (zebrafish and mammalian airway epithelia) with defined ciliary and laterality phenotypes, replicated across species","pmids":["26918822"],"is_preprint":false},{"year":2016,"finding":"Trans-heterozygous genetic interactions between DNAH6 and other PCD genes (DNAH5, DNAI1) can cause heterotaxy; subthreshold double-morpholino knockdown in zebrafish and siRNA knockdown in heterozygous Dnah5 or Dnai1 mutant mouse respiratory epithelia disrupted motile cilia function, establishing an oligogenic epistatic relationship.","method":"Subthreshold double-morpholino knockdown in zebrafish; siRNA knockdown in heterozygous mutant mouse respiratory epithelia; genetic epistasis","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 — epistasis demonstrated by double-knockdown rescue/enhancement experiments in two model systems with functional ciliary readout","pmids":["26918822"],"is_preprint":false},{"year":2018,"finding":"DNAH6 protein localizes to the neck region of spermatozoa in normal controls; compound heterozygous DNAH6 variants in an infertile male caused complete absence of DNAH6 protein and mRNA in spermatozoa, associated with sperm head anomalies (acephalic and globozoospermic sperm).","method":"Immunofluorescence localization in human spermatozoa; qRT-PCR; whole-exome sequencing with Sanger validation","journal":"Andrologia","confidence":"Medium","confidence_rationale":"Tier 3 — single patient, immunofluorescence localization with functional loss-of-expression link, no in vitro reconstitution","pmids":["29356036"],"is_preprint":false},{"year":2023,"finding":"DNAH6 variants cause absence of inner dynein arms and radial spokes in sperm flagella, as well as acrosome defects and abnormal chromatin compaction; decreased levels of component proteins in these defective structures were confirmed by Western blot, indicating DNAH6 is required for axonemal inner dynein arm and radial spoke assembly and acrosome biogenesis in sperm.","method":"Transmission electron microscopy of sperm ultrastructure; immunofluorescence; Western blot; whole-exome sequencing","journal":"Asian journal of andrology","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal methods (TEM, IF, WB) in human patients linking DNAH6 loss to specific axonemal structural defects","pmids":["37594300"],"is_preprint":false},{"year":2023,"finding":"A homozygous frameshift mutation in DNAH6 (c.2823dupT) causes abnormal DNAH6 mRNA expression (premature termination and NMD) and loss of DNAH6 protein in sperm, resulting in multiple morphological and ultrastructural abnormalities of spermatozoa (asthenoteratozoospermia).","method":"Whole-exome sequencing; Sanger sequencing; qRT-PCR; immunofluorescence; scanning and transmission electron microscopy","journal":"Frontiers in endocrinology","confidence":"Medium","confidence_rationale":"Tier 2 — multiple orthogonal methods linking frameshift mutation to mRNA decay and protein loss with ultrastructural sperm phenotype","pmids":["37424858"],"is_preprint":false},{"year":2024,"finding":"DNAH6 is an inner dynein arm (IDA) heavy chain component in sperm flagella; loss of DNAH3 in patients and Dnah3 knockout mice causes secondary loss of DNAH6 (along with DNAH1 and DNALI1) from sperm flagella, placing DNAH6 within a DNAH3-dependent IDA assembly pathway.","method":"Immunofluorescence of sperm flagella in DNAH3-deficient patients and Dnah3 KO mice; Western blot; whole-exome sequencing","journal":"eLife","confidence":"Medium","confidence_rationale":"Tier 2 — genetic epistasis via KO mouse and patient data with immunofluorescence showing DNAH6 as downstream IDA component of DNAH3","pmids":["39503742"],"is_preprint":false},{"year":2024,"finding":"DNAH6 is an IDA heavy chain in respiratory ciliary axonemes; disease-causing variants in CCDC39 and CCDC40 (components of the 96 nm axonemal ruler complex) cause conspicuous absence of DNAH6 (along with DNAH1 and DNAH7) from respiratory ciliary axonemes, demonstrating that DNAH6 assembly into cilia depends on the CCDC39/CCDC40 molecular ruler.","method":"Immunofluorescence analysis of respiratory ciliary axonemes in a cohort of 51 individuals with CCDC39/CCDC40 variants; next-generation sequencing","journal":"Cells","confidence":"High","confidence_rationale":"Tier 2 — large patient cohort (n=51) with immunofluorescence demonstrating DNAH6 axonemal absence dependent on the CCDC39/CCDC40 ruler complex, strong preponderance of evidence","pmids":["39056782"],"is_preprint":false},{"year":2024,"finding":"DNAH11 variants cause loss of outer dynein arm proteins and asthenoteratozoospermia but do not affect inner dynein arm proteins DNAH1 and DNAH6, establishing that DNAH6 resides specifically in the inner dynein arm compartment of sperm flagella and is not downstream of ODA assembly.","method":"Western blot and immunofluorescence of sperm from DNAH11-variant patients; scanning and transmission electron microscopy","journal":"Human genomics","confidence":"Medium","confidence_rationale":"Tier 2 — negative epistasis data from multiple patients placing DNAH6 specifically in IDA, supported by multiple orthogonal methods","pmids":["39256880"],"is_preprint":false},{"year":2024,"finding":"DNAH6 null deletion is significantly more frequent in asthenozoospermia patients than fertile controls (45% vs 11.7%), supporting a functional role of DNAH6 in sperm motility.","method":"PCR-based detection of null deletion in genomic DNA from asthenozoospermia patients vs. controls","journal":"BMC urology","confidence":"Low","confidence_rationale":"Tier 3 — single method (PCR deletion detection), association study without direct mechanistic validation","pmids":["39192248"],"is_preprint":false}],"current_model":"DNAH6 is a dynein axonemal heavy chain that functions as a component of the inner dynein arm (IDA) in both respiratory cilia and sperm flagella; it is required for motile cilia-driven left-right patterning and airway clearance, its axonemal assembly depends on the CCDC39/CCDC40 molecular ruler complex and on DNAH3, and loss-of-function mutations cause primary ciliary dyskinesia-like ciliary dysfunction, heterotaxy (via oligogenic interactions with DNAI1/DNAH5), and male infertility characterized by asthenoteratozoospermia with inner dynein arm, radial spoke, and acrosome defects."},"narrative":{"teleology":[{"year":2016,"claim":"Establishing DNAH6 as essential for motile cilia function and left-right patterning resolved its basic biological requirement: knockdown in zebrafish disrupted Kupffer's vesicle cilia and caused heterotaxy, while knockdown in mammalian respiratory epithelia impaired cilia motility, demonstrating a conserved role across vertebrates.","evidence":"Morpholino knockdown in zebrafish and shRNA knockdown in human/mouse respiratory epithelia with laterality and cilia motility phenotyping","pmids":["26918822"],"confidence":"High","gaps":["Whether DNAH6 functions in the outer or inner dynein arm was not resolved","Structural position of DNAH6 within the axonemal repeat was unknown","Mechanism by which DNAH6 loss disrupts cilia beat was not defined"]},{"year":2016,"claim":"Demonstrating oligogenic epistasis between DNAH6 and DNAH5/DNAI1 established that heterotaxy can arise from combinatorial subclinical defects in multiple dynein genes, expanding the genetic architecture of ciliopathies beyond monogenic models.","evidence":"Subthreshold double-morpholino knockdown in zebrafish and siRNA knockdown in heterozygous Dnah5/Dnai1 mutant mouse respiratory epithelia","pmids":["26918822"],"confidence":"High","gaps":["Physical basis for the epistatic interaction (e.g., shared complex or functional redundancy) was not determined","Whether oligogenic interactions extend to additional dynein or ciliary genes was untested"]},{"year":2018,"claim":"Localizing DNAH6 protein to the neck region of normal spermatozoa and linking compound heterozygous variants to complete protein loss and sperm head anomalies provided the first evidence of a sperm-specific role.","evidence":"Immunofluorescence and qRT-PCR in human spermatozoa from a single infertile patient with compound heterozygous DNAH6 variants","pmids":["29356036"],"confidence":"Medium","gaps":["Single patient without functional rescue or independent cohort replication","Mechanism linking a dynein heavy chain to sperm head/acrosome morphology was unexplained","Axonemal ultrastructure was not examined"]},{"year":2023,"claim":"Defining the ultrastructural consequences of DNAH6 loss in sperm — absence of inner dynein arms, radial spokes, and acrosome defects — placed DNAH6 within the IDA compartment and revealed an unexpectedly broad structural requirement extending beyond the dynein arm itself.","evidence":"Transmission electron microscopy, immunofluorescence, and Western blot in spermatozoa from DNAH6-variant patients","pmids":["37594300","37424858"],"confidence":"Medium","gaps":["Whether radial spoke and acrosome defects are direct or secondary consequences of IDA loss was not resolved","No animal knockout model confirmed these sperm phenotypes","Precise IDA isoform identity of DNAH6 (e.g., IDA-f vs. IDA-d) was not established"]},{"year":2024,"claim":"Establishing that DNAH6 axonemal assembly in respiratory cilia depends on the CCDC39/CCDC40 molecular ruler, and in sperm flagella depends on DNAH3, defined the hierarchical assembly pathway positioning DNAH6 downstream of specific scaffolding and co-heavy-chain components.","evidence":"Immunofluorescence of respiratory cilia in 51 CCDC39/CCDC40-variant individuals; immunofluorescence and Western blot of sperm from DNAH3-deficient patients and Dnah3 KO mice","pmids":["39056782","39503742"],"confidence":"High","gaps":["Whether DNAH6 directly binds CCDC39/CCDC40 or DNAH3, or is lost indirectly, is unknown","No biochemical reconstitution of the IDA assembly hierarchy exists","Whether the same assembly dependencies apply in embryonic nodal cilia was not tested"]},{"year":2024,"claim":"Negative epistasis data showing that DNAH11 (ODA) loss does not affect DNAH6 levels confirmed DNAH6 resides exclusively in the inner dynein arm compartment, independent of outer dynein arm integrity.","evidence":"Western blot and immunofluorescence of sperm from DNAH11-variant patients","pmids":["39256880"],"confidence":"Medium","gaps":["Only tested in sperm; whether IDA/ODA independence holds in respiratory or nodal cilia was not assessed","No direct structural data (cryo-ET) positioning DNAH6 within the 96 nm axonemal repeat"]},{"year":null,"claim":"The precise position of DNAH6 within the IDA substructure (specific IDA isoform), its direct binding partners within the dynein complex, and the mechanism by which its loss leads to secondary radial spoke and acrosome defects remain unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No cryo-electron tomography or high-resolution structural data for DNAH6 in the axoneme","No biochemical reconstitution of DNAH6-containing inner dynein arm complexes","Molecular mechanism of oligogenic epistasis with DNAH5/DNAI1 is unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003774","term_label":"cytoskeletal motor activity","supporting_discovery_ids":[0,3,5]}],"localization":[{"term_id":"GO:0005929","term_label":"cilium","supporting_discovery_ids":[0,3,5,6,7]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[3,5,6]}],"pathway":[{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[5,6]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[0,1]},{"term_id":"R-HSA-1474165","term_label":"Reproduction","supporting_discovery_ids":[3,4]}],"complexes":["Inner dynein arm (IDA)"],"partners":["DNAH3","DNAH1","DNALI1","CCDC39","CCDC40","DNAH5","DNAI1"],"other_free_text":[]},"mechanistic_narrative":"DNAH6 is an axonemal inner dynein arm (IDA) heavy chain required for motile cilia and sperm flagella function, with roles in left-right body patterning, airway mucociliary clearance, and sperm motility. In respiratory cilia, DNAH6 axonemal assembly depends on the CCDC39/CCDC40 molecular ruler complex, and in sperm flagella it is assembled through a DNAH3-dependent IDA pathway; loss of DNAH6 causes absence of inner dynein arms and radial spokes, acrosome defects, and asthenoteratozoospermia [PMID:39056782, PMID:39503742, PMID:37594300]. DNAH6 exhibits oligogenic epistatic interactions with other ciliary dynein genes (DNAH5, DNAI1), whereby trans-heterozygous loss produces heterotaxy through disrupted motile cilia in Kupffer's vesicle and respiratory epithelia [PMID:26918822]. Loss-of-function mutations in DNAH6 cause primary ciliary dyskinesia-like ciliary dysfunction with heterotaxy and male infertility [PMID:26918822, PMID:37424858]."},"prefetch_data":{"uniprot":{"accession":"Q9C0G6","full_name":"Dynein axonemal heavy chain 6","aliases":["Axonemal beta dynein heavy chain 6","Ciliary dynein heavy chain 6"],"length_aa":4158,"mass_kda":476.0,"function":"Force generating protein of respiratory cilia. Produces force towards the minus ends of microtubules. Dynein has ATPase activity; the force-producing power stroke is thought to occur on release of ADP (By similarity)","subcellular_location":"Cytoplasm, cytoskeleton, cilium axoneme; Cell projection, cilium, flagellum","url":"https://www.uniprot.org/uniprotkb/Q9C0G6/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/DNAH6","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/DNAH6","total_profiled":1310},"omim":[{"mim_id":"618801","title":"CILIARY DYSKINESIA, PRIMARY, 45; CILD45","url":"https://www.omim.org/entry/618801"},{"mim_id":"618063","title":"CILIARY DYSKINESIA, PRIMARY, 38; CILD38","url":"https://www.omim.org/entry/618063"},{"mim_id":"618058","title":"CILIA- AND FLAGELLA-ASSOCIATED PROTEIN 300; CFAP300","url":"https://www.omim.org/entry/618058"},{"mim_id":"610732","title":"TETRATRICOPEPTIDE REPEAT DOMAIN-CONTAINING PROTEIN 12; TTC12","url":"https://www.omim.org/entry/610732"},{"mim_id":"603336","title":"DYNEIN, AXONEMAL, HEAVY CHAIN 6; DNAH6","url":"https://www.omim.org/entry/603336"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Plasma membrane","reliability":"Approved"},{"location":"Centriolar satellite","reliability":"Approved"},{"location":"Basal body","reliability":"Approved"},{"location":"Connecting piece","reliability":"Approved"},{"location":"Mid piece","reliability":"Approved"},{"location":"Primary cilium tip","reliability":"Additional"},{"location":"Calyx","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in some","driving_tissues":[{"tissue":"choroid plexus","ntpm":5.0},{"tissue":"fallopian tube","ntpm":5.1}],"url":"https://www.proteinatlas.org/search/DNAH6"},"hgnc":{"alias_symbol":["Dnahc6","HL-2","FLJ37357"],"prev_symbol":["DNHL1"]},"alphafold":{"accession":"Q9C0G6","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9C0G6","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q9C0G6-4-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q9C0G6-4-F1-predicted_aligned_error_v6.png","plddt_mean":75.62},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=DNAH6","jax_strain_url":"https://www.jax.org/strain/search?query=DNAH6"},"sequence":{"accession":"Q9C0G6","fasta_url":"https://rest.uniprot.org/uniprotkb/Q9C0G6.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q9C0G6/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q9C0G6"}},"corpus_meta":[{"pmid":"26918822","id":"PMC_26918822","title":"DNAH6 and Its Interactions with PCD Genes in Heterotaxy and Primary Ciliary Dyskinesia.","date":"2016","source":"PLoS 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shRNA knockdown in human and mouse respiratory epithelia\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal loss-of-function in two model systems (zebrafish and mammalian airway epithelia) with defined ciliary and laterality phenotypes, replicated across species\",\n      \"pmids\": [\"26918822\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Trans-heterozygous genetic interactions between DNAH6 and other PCD genes (DNAH5, DNAI1) can cause heterotaxy; subthreshold double-morpholino knockdown in zebrafish and siRNA knockdown in heterozygous Dnah5 or Dnai1 mutant mouse respiratory epithelia disrupted motile cilia function, establishing an oligogenic epistatic relationship.\",\n      \"method\": \"Subthreshold double-morpholino knockdown in zebrafish; siRNA knockdown in heterozygous mutant mouse respiratory epithelia; genetic epistasis\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — epistasis demonstrated by double-knockdown rescue/enhancement experiments in two model systems with functional ciliary readout\",\n      \"pmids\": [\"26918822\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"DNAH6 protein localizes to the neck region of spermatozoa in normal controls; compound heterozygous DNAH6 variants in an infertile male caused complete absence of DNAH6 protein and mRNA in spermatozoa, associated with sperm head anomalies (acephalic and globozoospermic sperm).\",\n      \"method\": \"Immunofluorescence localization in human spermatozoa; qRT-PCR; whole-exome sequencing with Sanger validation\",\n      \"journal\": \"Andrologia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single patient, immunofluorescence localization with functional loss-of-expression link, no in vitro reconstitution\",\n      \"pmids\": [\"29356036\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"DNAH6 variants cause absence of inner dynein arms and radial spokes in sperm flagella, as well as acrosome defects and abnormal chromatin compaction; decreased levels of component proteins in these defective structures were confirmed by Western blot, indicating DNAH6 is required for axonemal inner dynein arm and radial spoke assembly and acrosome biogenesis in sperm.\",\n      \"method\": \"Transmission electron microscopy of sperm ultrastructure; immunofluorescence; Western blot; whole-exome sequencing\",\n      \"journal\": \"Asian journal of andrology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (TEM, IF, WB) in human patients linking DNAH6 loss to specific axonemal structural defects\",\n      \"pmids\": [\"37594300\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"A homozygous frameshift mutation in DNAH6 (c.2823dupT) causes abnormal DNAH6 mRNA expression (premature termination and NMD) and loss of DNAH6 protein in sperm, resulting in multiple morphological and ultrastructural abnormalities of spermatozoa (asthenoteratozoospermia).\",\n      \"method\": \"Whole-exome sequencing; Sanger sequencing; qRT-PCR; immunofluorescence; scanning and transmission electron microscopy\",\n      \"journal\": \"Frontiers in endocrinology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods linking frameshift mutation to mRNA decay and protein loss with ultrastructural sperm phenotype\",\n      \"pmids\": [\"37424858\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"DNAH6 is an inner dynein arm (IDA) heavy chain component in sperm flagella; loss of DNAH3 in patients and Dnah3 knockout mice causes secondary loss of DNAH6 (along with DNAH1 and DNALI1) from sperm flagella, placing DNAH6 within a DNAH3-dependent IDA assembly pathway.\",\n      \"method\": \"Immunofluorescence of sperm flagella in DNAH3-deficient patients and Dnah3 KO mice; Western blot; whole-exome sequencing\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis via KO mouse and patient data with immunofluorescence showing DNAH6 as downstream IDA component of DNAH3\",\n      \"pmids\": [\"39503742\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"DNAH6 is an IDA heavy chain in respiratory ciliary axonemes; disease-causing variants in CCDC39 and CCDC40 (components of the 96 nm axonemal ruler complex) cause conspicuous absence of DNAH6 (along with DNAH1 and DNAH7) from respiratory ciliary axonemes, demonstrating that DNAH6 assembly into cilia depends on the CCDC39/CCDC40 molecular ruler.\",\n      \"method\": \"Immunofluorescence analysis of respiratory ciliary axonemes in a cohort of 51 individuals with CCDC39/CCDC40 variants; next-generation sequencing\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — large patient cohort (n=51) with immunofluorescence demonstrating DNAH6 axonemal absence dependent on the CCDC39/CCDC40 ruler complex, strong preponderance of evidence\",\n      \"pmids\": [\"39056782\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"DNAH11 variants cause loss of outer dynein arm proteins and asthenoteratozoospermia but do not affect inner dynein arm proteins DNAH1 and DNAH6, establishing that DNAH6 resides specifically in the inner dynein arm compartment of sperm flagella and is not downstream of ODA assembly.\",\n      \"method\": \"Western blot and immunofluorescence of sperm from DNAH11-variant patients; scanning and transmission electron microscopy\",\n      \"journal\": \"Human genomics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — negative epistasis data from multiple patients placing DNAH6 specifically in IDA, supported by multiple orthogonal methods\",\n      \"pmids\": [\"39256880\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"DNAH6 null deletion is significantly more frequent in asthenozoospermia patients than fertile controls (45% vs 11.7%), supporting a functional role of DNAH6 in sperm motility.\",\n      \"method\": \"PCR-based detection of null deletion in genomic DNA from asthenozoospermia patients vs. controls\",\n      \"journal\": \"BMC urology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — single method (PCR deletion detection), association study without direct mechanistic validation\",\n      \"pmids\": [\"39192248\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"DNAH6 is a dynein axonemal heavy chain that functions as a component of the inner dynein arm (IDA) in both respiratory cilia and sperm flagella; it is required for motile cilia-driven left-right patterning and airway clearance, its axonemal assembly depends on the CCDC39/CCDC40 molecular ruler complex and on DNAH3, and loss-of-function mutations cause primary ciliary dyskinesia-like ciliary dysfunction, heterotaxy (via oligogenic interactions with DNAI1/DNAH5), and male infertility characterized by asthenoteratozoospermia with inner dynein arm, radial spoke, and acrosome defects.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"DNAH6 is an axonemal inner dynein arm (IDA) heavy chain required for motile cilia and sperm flagella function, with roles in left-right body patterning, airway mucociliary clearance, and sperm motility. In respiratory cilia, DNAH6 axonemal assembly depends on the CCDC39/CCDC40 molecular ruler complex, and in sperm flagella it is assembled through a DNAH3-dependent IDA pathway; loss of DNAH6 causes absence of inner dynein arms and radial spokes, acrosome defects, and asthenoteratozoospermia [PMID:39056782, PMID:39503742, PMID:37594300]. DNAH6 exhibits oligogenic epistatic interactions with other ciliary dynein genes (DNAH5, DNAI1), whereby trans-heterozygous loss produces heterotaxy through disrupted motile cilia in Kupffer's vesicle and respiratory epithelia [PMID:26918822]. Loss-of-function mutations in DNAH6 cause primary ciliary dyskinesia-like ciliary dysfunction with heterotaxy and male infertility [PMID:26918822, PMID:37424858].\",\n  \"teleology\": [\n    {\n      \"year\": 2016,\n      \"claim\": \"Establishing DNAH6 as essential for motile cilia function and left-right patterning resolved its basic biological requirement: knockdown in zebrafish disrupted Kupffer's vesicle cilia and caused heterotaxy, while knockdown in mammalian respiratory epithelia impaired cilia motility, demonstrating a conserved role across vertebrates.\",\n      \"evidence\": \"Morpholino knockdown in zebrafish and shRNA knockdown in human/mouse respiratory epithelia with laterality and cilia motility phenotyping\",\n      \"pmids\": [\"26918822\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether DNAH6 functions in the outer or inner dynein arm was not resolved\",\n        \"Structural position of DNAH6 within the axonemal repeat was unknown\",\n        \"Mechanism by which DNAH6 loss disrupts cilia beat was not defined\"\n      ]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Demonstrating oligogenic epistasis between DNAH6 and DNAH5/DNAI1 established that heterotaxy can arise from combinatorial subclinical defects in multiple dynein genes, expanding the genetic architecture of ciliopathies beyond monogenic models.\",\n      \"evidence\": \"Subthreshold double-morpholino knockdown in zebrafish and siRNA knockdown in heterozygous Dnah5/Dnai1 mutant mouse respiratory epithelia\",\n      \"pmids\": [\"26918822\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Physical basis for the epistatic interaction (e.g., shared complex or functional redundancy) was not determined\",\n        \"Whether oligogenic interactions extend to additional dynein or ciliary genes was untested\"\n      ]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Localizing DNAH6 protein to the neck region of normal spermatozoa and linking compound heterozygous variants to complete protein loss and sperm head anomalies provided the first evidence of a sperm-specific role.\",\n      \"evidence\": \"Immunofluorescence and qRT-PCR in human spermatozoa from a single infertile patient with compound heterozygous DNAH6 variants\",\n      \"pmids\": [\"29356036\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Single patient without functional rescue or independent cohort replication\",\n        \"Mechanism linking a dynein heavy chain to sperm head/acrosome morphology was unexplained\",\n        \"Axonemal ultrastructure was not examined\"\n      ]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defining the ultrastructural consequences of DNAH6 loss in sperm — absence of inner dynein arms, radial spokes, and acrosome defects — placed DNAH6 within the IDA compartment and revealed an unexpectedly broad structural requirement extending beyond the dynein arm itself.\",\n      \"evidence\": \"Transmission electron microscopy, immunofluorescence, and Western blot in spermatozoa from DNAH6-variant patients\",\n      \"pmids\": [\"37594300\", \"37424858\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Whether radial spoke and acrosome defects are direct or secondary consequences of IDA loss was not resolved\",\n        \"No animal knockout model confirmed these sperm phenotypes\",\n        \"Precise IDA isoform identity of DNAH6 (e.g., IDA-f vs. IDA-d) was not established\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Establishing that DNAH6 axonemal assembly in respiratory cilia depends on the CCDC39/CCDC40 molecular ruler, and in sperm flagella depends on DNAH3, defined the hierarchical assembly pathway positioning DNAH6 downstream of specific scaffolding and co-heavy-chain components.\",\n      \"evidence\": \"Immunofluorescence of respiratory cilia in 51 CCDC39/CCDC40-variant individuals; immunofluorescence and Western blot of sperm from DNAH3-deficient patients and Dnah3 KO mice\",\n      \"pmids\": [\"39056782\", \"39503742\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\n        \"Whether DNAH6 directly binds CCDC39/CCDC40 or DNAH3, or is lost indirectly, is unknown\",\n        \"No biochemical reconstitution of the IDA assembly hierarchy exists\",\n        \"Whether the same assembly dependencies apply in embryonic nodal cilia was not tested\"\n      ]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Negative epistasis data showing that DNAH11 (ODA) loss does not affect DNAH6 levels confirmed DNAH6 resides exclusively in the inner dynein arm compartment, independent of outer dynein arm integrity.\",\n      \"evidence\": \"Western blot and immunofluorescence of sperm from DNAH11-variant patients\",\n      \"pmids\": [\"39256880\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\n        \"Only tested in sperm; whether IDA/ODA independence holds in respiratory or nodal cilia was not assessed\",\n        \"No direct structural data (cryo-ET) positioning DNAH6 within the 96 nm axonemal repeat\"\n      ]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The precise position of DNAH6 within the IDA substructure (specific IDA isoform), its direct binding partners within the dynein complex, and the mechanism by which its loss leads to secondary radial spoke and acrosome defects remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\n        \"No cryo-electron tomography or high-resolution structural data for DNAH6 in the axoneme\",\n        \"No biochemical reconstitution of DNAH6-containing inner dynein arm complexes\",\n        \"Molecular mechanism of oligogenic epistasis with DNAH5/DNAI1 is unknown\"\n      ]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003774\", \"supporting_discovery_ids\": [0, 3, 5]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005929\", \"supporting_discovery_ids\": [0, 3, 5, 6, 7]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [3, 5, 6]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [5, 6]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"R-HSA-1474165\", \"supporting_discovery_ids\": [3, 4]}\n    ],\n    \"complexes\": [\n      \"Inner dynein arm (IDA)\"\n    ],\n    \"partners\": [\n      \"DNAH3\",\n      \"DNAH1\",\n      \"DNALI1\",\n      \"CCDC39\",\n      \"CCDC40\",\n      \"DNAH5\",\n      \"DNAI1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}