DNAH6 (dynein axonemal heavy chain 6) is a 4158-residue axonemal dynein heavy chain of the inner dynein arms of motile cilia and sperm flagella. It has the typical heavy-chain architecture: an N-terminal stem that docks it in the axoneme and a C-terminal motor head of six AAA+ modules with a coiled-coil stalk and microtubule-binding domain, which converts ATP hydrolysis into minus-end-directed force on the neighbouring doublet. By sequence conservation and structural analysis DNAH6 is the heavy chain of IDAg, a single-headed, centrin (CETN2)-associated inner arm related to Chlamydomonas DHC2; IDAg and IDAd share a combined tail complex that associates with radial spoke 3. DNAH6 is expressed in testis, trachea and brain and lies along the respiratory ciliary axoneme and throughout the sperm flagellum; its axonemal assembly depends on the CCDC39/CCDC40 molecular ruler, and it is reduced in sperm lacking DNAH3 or DNAH7. Knockdown of DNAH6 disrupts motile cilia in human and mouse airway epithelium (with central-pair defects) and in the zebrafish left-right organizer, causing heterotaxy, and heterozygous DNAH6 variants have been proposed to act together with variants in other PCD genes in heterotaxy. Biallelic DNAH6 variants cause male infertility with multiple morphological abnormalities of the sperm flagella, with loss of inner dynein arms and radial spokes and, in some patients, sperm head and acrosome defects; ICSI can achieve pregnancy. Reports of DNAH6 in azoospermia and sperm head anomalies are single-family candidate findings.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005524 ATP binding | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: ATP binding from InterPro. Reason: Correct but uninformative relative to motor activity. |
| GO:0005930 axoneme | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt subcellular location mapping (cilium axoneme). Reason: DNAH6 is an axonemal inner arm heavy chain in respiratory cilia. Supporting Evidence: PMID:26918822 DNAH6 (red) antibody staining is lost in the ciliary axoneme (green) with shDNAH6 knockdown of human respiratory epithelia. |
| GO:0007018 microtubule-based movement | IEA GO_REF:0000002 | TOO GENERAL | Summary: InterPro mapping to microtubule-based movement. Reason: True but uninformative: cilium movement involved in cell motility (GO:0060294), ACCEPTed in this review, is_a cilium movement, which is_a microtubule-based movement, and so entails it. |
| GO:0008569 minus-end-directed microtubule motor activity | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT inference of minus-end-directed microtubule motor activity. Reason: DNAH6 retains a complete dynein motor domain; core molecular function. Supporting Evidence: file:human/DNAH6/DNAH6-uniprot.txt Produces force towards the minus ends of microtubules. |
| GO:0008569 minus-end-directed microtubule motor activity | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro mapping of minus-end-directed microtubule motor activity. Reason: Consistent with the IBA. |
| GO:0030286 dynein complex | IBA GO_REF:0000033 | MODIFY | Summary: PAINT IBD for dynein complex at the deep dynein heavy chain node PTN000743491. Reason: Correct but very general. DNAH6 is the heavy chain of the inner dynein arm IDAg. Unlike DNAH3 and DNAH7, DNAH6 (human Q9C0G6 and mouse E9Q0B6 alike) does not inherit the inner dynein arm IBA from PTN008503981, so this general term is all the phylogenetic inference gives it. Propagation Review Root cause: NO FAILURE CORE Failure modes: GRANULARITY MISMATCH Sources checked: PANTHER:PTN000743491 SUPPORTS TRANSFER Deep dynein heavy chain node; dynein complex is correct for DNAH6 but less specific than its inner dynein arm membership. Proposed replacements: inner dynein arm Supporting Evidence: PMID:39056782 DNAH6, the dynein heavy chain of IDAg PMID:37258679 the identities of only IDAf (DNAH2 and DNAH10), IDAd (DNAH1) and IDAg (DNAH6) had been confidently deduced on the basis of sequence conservation |
| GO:0030286 dynein complex | IEA GO_REF:0000002 | MODIFY | Summary: InterPro mapping to dynein complex. Reason: Too general; DNAH6 is an inner dynein arm (IDAg) heavy chain. Proposed replacements: inner dynein arm Supporting Evidence: PMID:39056782 DNAH6, the dynein heavy chain of IDAg |
| GO:0031514 motile cilium | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt flagellum location mapped to motile cilium. Reason: DNAH6 is in respiratory cilia and sperm flagella. |
| GO:0036126 sperm flagellum | IDA PMID:39503742 DNAH3 deficiency causes flagellar inner dynein arm loss and ... | ACCEPT | Summary: Immunofluorescence in the DNAH3 study shows DNAH6 in sperm flagella of controls, reduced in DNAH3-deficient sperm. Reason: Direct localization, independently confirmed by other groups; core location. The DNAH3 study stained DNAH6 in sperm from patients and normal controls; an independent DNAH6 study shows DNAH6 along the whole flagellum of normal sperm. Supporting Evidence: PMID:39503742 Immunofluorescence staining of DNAH1 (A), DNAH6 (B) and DNALI1 (C) in spermatozoa from patients and normal controls. PMID:37594300 DNAH6 was localized throughout the flagella of normal sperm |
| GO:0036126 sperm flagellum | IEA GO_REF:0000117 | ACCEPT | Summary: ARBA prediction of sperm flagellum localization. Reason: Consistent with immunofluorescence of human sperm. Supporting Evidence: PMID:37594300 DNAH6 was localized throughout the flagella of normal sperm, and the signals were reduced in patient AY0283 carrying a DNAH6 variant |
| GO:0045505 dynein intermediate chain binding | IBA GO_REF:0000033 | UNDECIDED | Summary: Family-level PAINT inference of dynein intermediate chain binding. Reason: IDAg is a single-headed, centrin-associated inner arm; no intermediate chain partner of DNAH6 is known. The IBD is seeded only by a cytoplasmic dynein, so the transfer is doubtful, but there are no DNAH6 data to refute it. Propagation Review Root cause: UNRESOLVED Failure modes: COMPARTMENT OR COMPLEX MISMATCH Sources checked: PANTHER:PTN000743491 UNRESOLVED Deep dynein heavy chain node spanning cytoplasmic and axonemal dyneins; the dynein intermediate chain binding IBD is seeded only by a Dictyostelium cytoplasmic dynein heavy chain. dictyBase:DDB_G0276355 SUPPORTS SOURCE BUT NOT TARGET Cytoplasmic dynein heavy chain; intermediate chain binding is well established there but single-headed axonemal inner arms are not known to carry intermediate chains. |
| GO:0045505 dynein intermediate chain binding | IEA GO_REF:0000002 | UNDECIDED | Summary: InterPro family mapping of dynein intermediate chain binding. Reason: Same considerations as the IBA. |
| GO:0051959 dynein light intermediate chain binding | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Family-level PAINT inference of dynein light intermediate chain binding, seeded by cytoplasmic dynein (DYNC1H1/Dync1h1) annotations. Reason: Not established for DNAH6. IDAg is centrin-associated rather than a DNALI1 (p28) arm, but structural work places the DNAH6 heavy chain in contact with the light intermediate chain of the neighbouring IDAd, so a light intermediate chain interaction is plausible. Kept as non-core pending direct data. Supporting Evidence: PMID:39056782 DNAH6, the dynein heavy chain of IDAg, is connected with the light intermediate chain of IDAd. |
| GO:0051959 dynein light intermediate chain binding | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: InterPro family mapping of dynein light intermediate chain binding. Reason: Same considerations as the IBA. |
| GO:0060294 cilium movement involved in cell motility | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT inference of cilium movement involved in cell motility. Reason: DNAH6 is required for normal sperm flagellar morphology and motility; patients with biallelic variants have MMAF with severely reduced motility. Supporting Evidence: PMID:31676830 This is the first report identifying novel recessive mutations in DNAH6 as a cause of MMAF. |
| GO:0097729 9+2 motile cilium | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT inference of 9+2 motile cilium localization. Reason: DNAH6 localizes to respiratory ciliary axonemes and sperm flagella. Supporting Evidence: PMID:26918822 DNAH6 (red) antibody staining is lost in the ciliary axoneme (green) with shDNAH6 knockdown of human respiratory epithelia. |
| GO:0003351 epithelial cilium movement involved in extracellular fluid movement | IMP PMID:26918822 DNAH6 and Its Interactions with PCD Genes in Heterotaxy and ... | NEW | Summary: shRNA knockdown of DNAH6 in human and mouse airway epithelia disrupted ciliary motion; dnah6 morpholino knockdown in zebrafish disrupted Kupffer's vesicle cilia and flow. Reason: DNAH6 is itself a motor subunit of the axonemal inner arms, so it does part of the work of airway ciliary beating, not merely being required for it. Not currently annotated in GOA. The evidence is knockdown-based and the authors note possible off-target effects, but it is consistent across species and with the CCDC39/40 ruler-defect data. Supporting Evidence: PMID:26918822 Functional analysis with gene knockdown in zebrafish embryos and in the human and mouse respiratory epithelia showed DNAH6 is required for left-right patterning and airway ciliary motion, respectively. |
| GO:0120316 sperm flagellum assembly | IMP PMID:37594300 Novel variants in DNAH6 cause male infertility associated wi... | NEW | Summary: Biallelic DNAH6 variants in several unrelated families cause MMAF, with absent inner dynein arms and radial spokes in patient sperm. Reason: DNAH6 is itself a structural inner dynein arm heavy chain, and its loss leaves both the inner arms and the radial spokes absent from patient sperm, so it does part of the work of building the flagellar axoneme rather than merely being required for it. Patient data from at least four independent groups show the same MMAF phenotype. Not currently annotated in GOA; the IBA that DNAH3 and DNAH7 receive for this term does not reach DNAH6, which sits outside PTN008951089, so the gap is phylogenetic rather than a curator decision. Supporting Evidence: PMID:37594300 The absence of inner dynein arms and radial spokes was observed in the sperm of patients with DNAH6 variants. |
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Download this section (compressed HTML)Q: Why does PAINT place DNAH6 (and DNAH14) outside the node that gives DNAH3 and DNAH7 the inner dynein arm, inner dynein arm assembly and sperm flagellum assembly IBAs? Human and mouse orthologs are treated consistently, so this is a tree-topology question rather than a classification error.
Q: Does DNAH6 deficiency cause primary ciliary dyskinesia on its own? The airway evidence is from knockdown and oligogenic heterotaxy cases; homozygous null DNAH6 individuals with respiratory phenotyping are needed.
Q: Are the sperm head, acrosome and azoospermia phenotypes reported in some DNAH6 patients direct roles of DNAH6 outside the axoneme, or secondary to flagellar failure or linked variants?
Experiment: Generate Dnah6 knockout mice and examine airway ciliary beat, ependymal flow, laterality and sperm axoneme ultrastructure by cryo-ET to confirm IDAg loss and its consequences.
Type: mouse knockout phenotyping and cryo-electron tomography
Experiment: Immunoprecipitation-mass spectrometry of DNAH6 from airway cilia to define its light chains (centrin, actin, DNALI1) and test the IBA-derived intermediate and light intermediate chain binding.
Type: IP-MS
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