DNAH1 (dynein axonemal heavy chain 1; also HDHC7/DNAHC1, mouse ortholog Mdhc7/Dnah1) is a 4265-residue heavy chain of a single-headed inner dynein arm (IDA) of the motile axoneme. It has the usual dynein heavy chain layout: an N-terminal stem that anchors it within the arm, and a motor head of six AAA modules (four with ATP-binding P-loops) with a coiled-coil stalk that carries the microtubule-binding domain. Like other axonemal dyneins it is expected to use ATP to generate force toward microtubule minus ends, driving doublet sliding. DNAH1 is expressed mainly in testis and trachea. In human sperm it lies along the whole flagellum, and in respiratory epithelium along the full length of the ciliary axoneme, where PCD studies assign it to IDA d. It associates with the axonemal light intermediate chain DNALI1, and with the flagellar proteins TTC29 and ZMYND12; DNALI1, DNAH3 and DNAH12 are each needed for DNAH1 to reach the sperm flagellum. Biallelic DNAH1 loss of function in men causes asthenoteratozoospermia with multiple morphological abnormalities of the sperm flagella (MMAF; spermatogenic failure 18), with loss of inner dynein arms, disorganized doublets and frequent loss of the central pair, usually without respiratory disease. One consanguineous family with a homozygous missense variant had primary ciliary dyskinesia (CILD37). Dnah1-null mice are infertile, with poorly progressive sperm and a roughly 50% reduction in tracheal ciliary beat frequency, but their axonemes look grossly normal, possibly because a shorter Dnah1 isoform partly substitutes. DNAH1 therefore acts as a force-generating IDA motor whose loss most strongly affects the sperm flagellum.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0003777 microtubule motor activity | NAS PMID:9373155 Identification of dynein heavy chain genes expressed in huma... | MODIFY | Summary: Early cloning paper classifying the human DHC7 (DNAH1) fragment as an axonemal inner-arm dynein heavy chain by sequence similarity; motor activity was not measured. Reason: Motor activity is the expected function of an axonemal dynein heavy chain with intact P-loops and stalk, but the more informative term is minus-end-directed microtubule motor activity, which is also supported by the IBA and UniProt function text. Proposed replacements: minus-end-directed microtubule motor activity Supporting Evidence: PMID:9373155 Two of these clones, gHDHC7 and gMDHC7, are homologous genes encoding axonemal inner arm dyneins. file:human/DNAH1/DNAH1-uniprot.txt Produces force towards the minus ends of |
| GO:0005524 ATP binding | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: InterPro-based ATP binding. UniProt annotates ATP-binding P-loops in the AAA modules of the DNAH1 motor head. Reason: Structurally sound but uninformative; ATP binding is part of the motor activity captured by the core molecular function. Supporting Evidence: file:human/DNAH1/DNAH1-uniprot.txt FT BINDING 1581..1588 |
| GO:0005858 axonemal dynein complex | NAS PMID:9373155 Identification of dynein heavy chain genes expressed in huma... | MODIFY | Summary: Sequence-based assignment of DNAH1 to the axonemal dynein complex. Reason: Correct but less specific than the experimentally supported inner dynein arm (GO:0036156); DNAH1 is an inner-arm, not outer-arm, heavy chain. Proposed replacements: inner dynein arm Supporting Evidence: PMID:9373155 Two of these clones, gHDHC7 and gMDHC7, are homologous genes encoding axonemal inner arm dyneins. |
| GO:0005930 axoneme | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt subcellular-location mapping to axoneme. Reason: DNAH1 is detected along sperm flagellar and respiratory ciliary axonemes. Supporting Evidence: PMID:39056782 IF staining against DNAH1 demonstrated the localization along the full-length ciliary axoneme. |
| GO:0005930 axoneme | IMP PMID:24360805 Mutations in DNAH1, which encodes an inner arm heavy chain d... | ACCEPT | Summary: DNAH1 antisera decorate the full length of control sperm flagella, and the staining is lost in sperm from a patient with a splice-site mutation. Reason: Localization along the axoneme is shown directly (and its loss in the mutant); the location is correct. Supporting Evidence: PMID:24360805 In control individuals, DNAH1 antisera decorated the full length of the sperm flagellum |
| GO:0007018 microtubule-based movement | IEA GO_REF:0000002 | TOO GENERAL | Summary: InterPro dynein heavy chain mapping to microtubule-based movement. Reason: True for an axonemal dynein heavy chain, but entailed by the more specific flagellated sperm motility (GO:0030317), which this review ACCEPTs; flagellated sperm motility is a descendant of microtubule-based movement via cilium movement involved in cell motility. |
| GO:0007288 sperm axoneme assembly | IEA GO_REF:0000117 | KEEP AS NON CORE | Summary: ARBA prediction of sperm axoneme assembly. Reason: Consistent with the human IMP data (axonemal disorganization in DNAH1 mutant sperm), but the defect is not seen in Dnah1-null mice and likely reflects loss of a structural IDA component rather than a dedicated assembly role. Supporting Evidence: PMID:24360805 A general axonemal disorganization including mislocalization of the microtubule doublets and loss of the inner dynein arms was observed. |
| GO:0007288 sperm axoneme assembly | IMP PMID:24360805 Mutations in DNAH1, which encodes an inner arm heavy chain d... | KEEP AS NON CORE | Summary: Sperm from men with homozygous DNAH1 mutations show general axonemal disorganization, mislocalized doublets and loss of inner dynein arms. Reason: The phenotype is real and DNAH1 is a structural component of the axoneme, so the annotation stands, but it is secondary to the motor role. Dnah1 knockout mice have reduced motility without gross axonemal defects, so the assembly requirement is not universal. Supporting Evidence: PMID:24360805 A general axonemal disorganization including mislocalization of the microtubule doublets and loss of the inner dynein arms was observed. PMID:11371505 The reduction in both ciliary and flagellar motility is not correlated with any gross defects in the axonemal structure. |
| GO:0008569 minus-end-directed microtubule motor activity | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT inference at the deep dynein heavy chain node PTN000743491, seeded by cytoplasmic and axonemal dyneins from yeasts, Dictyostelium and Tetrahymena. Reason: Minus-end-directed motor activity is ancestral to the whole dynein heavy chain family, and DNAH1 retains the full motor domain (AAA1-AAA6 with P-loops and stalk), so there is no sign of loss of function on this branch. Supporting Evidence: file:human/DNAH1/DNAH1-uniprot.txt Produces force towards the minus ends of |
| GO:0008569 minus-end-directed microtubule motor activity | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro dynein heavy chain mapping to minus-end-directed motor activity. Reason: Consistent with the IBA and the intact motor domain. Supporting Evidence: file:human/DNAH1/DNAH1-uniprot.txt Produces force towards the minus ends of |
| GO:0030286 dynein complex | IBA GO_REF:0000033 | TOO GENERAL | Summary: PAINT inference that DNAH1 is part of a dynein complex. Reason: True, but entailed by inner dynein arm (GO:0036156), which this review ACCEPTs on direct experimental evidence; inner dynein arm is a descendant of dynein complex. |
| GO:0030286 dynein complex | IEA GO_REF:0000002 | TOO GENERAL | Summary: InterPro mapping to dynein complex. Reason: True, but entailed by inner dynein arm (GO:0036156), which this review ACCEPTs; inner dynein arm is a descendant of dynein complex. |
| GO:0030317 flagellated sperm motility | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT inference at PTN002580741, seeded by mouse Dnah1 and human DNAH1 experimental annotations. Reason: The node is grounded in direct mutant data on both orthologs (human DNAH1 appears among its own sources because its IMP data helped place the node). Sperm motility is the best-established process for DNAH1. Supporting Evidence: PMID:11371505 In comparison to MDHC7(+/-) and wild-type mice the spermatozoa of MDHC7(-/-) mice revealed a dramatic reduced straight line velocity and progressive movement |
| GO:0030317 flagellated sperm motility | IMP PMID:24360805 Mutations in DNAH1, which encodes an inner arm heavy chain d... | ACCEPT | Summary: Homozygous DNAH1 mutations in 5 of 18 MMAF men cause severe asthenozoospermia with flagellar malformation. Reason: Direct human loss-of-function evidence for the core process. Supporting Evidence: PMID:24360805 Five unrelated subjects out of 18 (28%) carried a homozygous variant in DNAH1 |
| GO:0030317 flagellated sperm motility | IMP PMID:27798045 Whole-exome sequencing of familial cases of multiple morphol... | ACCEPT | Summary: Independent exome study identifying DNAH1 mutations in four MMAF men from two families. Reason: Independent replication of the human loss-of-function phenotype. Supporting Evidence: PMID:27798045 WES for six families with men affected by MMAF syndrome allowed the identification of DNAH1 mutations in four affected men distributed in two out of the six families |
| GO:0031514 motile cilium | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt subcellular-location mapping to motile cilium. Reason: DNAH1 is present along respiratory ciliary axonemes, and mouse knockout reduces tracheal ciliary beat frequency. Supporting Evidence: PMID:39056782 IF staining against DNAH1 demonstrated the localization along the full-length ciliary axoneme. |
| GO:0036126 sperm flagellum | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT inference at PTN002580741, seeded by mouse Dnah1 and human DNAH1. Reason: Supported by multiple direct localizations of DNAH1 along the sperm flagellum; the IBA additionally records that this is conserved in the Dnah1 clade. Supporting Evidence: PMID:24360805 In control individuals, DNAH1 antisera decorated the full length of the sperm flagellum |
| GO:0036126 sperm flagellum | IDA PMID:11371505 Disruption of an inner arm dynein heavy chain gene results i... | ACCEPT | Summary: Mdhc7 (Dnah1) knockout mouse paper; the cached record is abstract-only, and the localization data cited by the curator are presumably in the full text. Reason: The flagellar location is well established by other studies; deferring to the curator, who had the full text. Supporting Evidence: PMID:24360805 In control individuals, DNAH1 antisera decorated the full length of the sperm flagellum |
| GO:0036126 sperm flagellum | IDA PMID:24360805 Mutations in DNAH1, which encodes an inner arm heavy chain d... | ACCEPT | Summary: DNAH1 immunostaining along the full length of control human sperm flagella. Reason: Direct localization. Supporting Evidence: PMID:24360805 In control individuals, DNAH1 antisera decorated the full length of the sperm flagellum |
| GO:0036126 sperm flagellum | IDA PMID:39503742 DNAH3 deficiency causes flagellar inner dynein arm loss and ... | ACCEPT | Summary: DNAH3 study; DNAH1 was stained in control sperm flagella as an IDA marker and was reduced in DNAH3-deficient sperm. Reason: Direct localization of DNAH1 in sperm flagella used as an IDA marker. Supporting Evidence: PMID:39503742 Moreover, the absence of DNAH3 led to decreased expression of other IDA-associated proteins, including DNAH1, DNAH6 and DNALI1. |
| GO:0036126 sperm flagellum | IDA PMID:40146200 Deficiency in DNAH12 causes male infertility by impairing DN... | ACCEPT | Summary: DNAH12 study; DNAH1 is localized in control sperm flagella and fails to be recruited when DNAH12 is lost. Reason: Direct localization of DNAH1 to the sperm flagellum. Supporting Evidence: PMID:40146200 DNAH12 plays a crucial role in the proper organization of axoneme in sperm flagella, but not cilia, by recruiting DNAH1 and DNALI1 in both humans and mice. |
| GO:0036126 sperm flagellum | IEA GO_REF:0000120 | ACCEPT | Summary: Combined automated annotation (ARBA plus mouse ortholog) to sperm flagellum. Reason: Agrees with direct experimental localization. |
| GO:0036156 inner dynein arm | IDA PMID:24360805 Mutations in DNAH1, which encodes an inner arm heavy chain d... | ACCEPT | Summary: Loss of DNAH1 removes the IDA marker DNALI1 and most inner dynein arms from patient sperm. Reason: DNAH1 is an inner-arm heavy chain; PCD and sperm studies place it in the DNALI1-containing IDA d. Supporting Evidence: PMID:24360805 Fifteen outer dynein arms (ODA) and only 4 inner dynein arms (IDA) were observed, confirming the complete disorganization of the IDA. PMID:39056782 affects the encoded heavy chains DNAH1 and DNAH7 of IDAd and IDAb/e, respectively |
| GO:0036156 inner dynein arm | IEA GO_REF:0000117 | ACCEPT | Summary: ARBA prediction of inner dynein arm membership. Reason: Agrees with the experimental evidence. Supporting Evidence: PMID:39056782 affects the encoded heavy chains DNAH1 and DNAH7 of IDAd and IDAb/e, respectively |
| GO:0036159 inner dynein arm assembly | IDA PMID:24360805 Mutations in DNAH1, which encodes an inner arm heavy chain d... | ACCEPT | Summary: In DNAH1-mutant sperm the inner dynein arms, including DNALI1, are lost, showing that DNAH1 is needed for IDA assembly in the sperm flagellum. Reason: As a heavy chain, DNAH1 supplies the structural core of its arm, so its loss prevents assembly of that arm. The acts_upstream_of_or_within qualifier fits the evidence. Supporting Evidence: PMID:24360805 Fifteen outer dynein arms (ODA) and only 4 inner dynein arms (IDA) were observed, confirming the complete disorganization of the IDA. |
| GO:0036159 inner dynein arm assembly | IEA GO_REF:0000117 | ACCEPT | Summary: ARBA prediction of involvement in inner dynein arm assembly. Reason: Consistent with the human data; DNAH1 is a structural component of the arm whose loss prevents IDA assembly in sperm. Supporting Evidence: PMID:24360805 A general axonemal disorganization including mislocalization of the microtubule doublets and loss of the inner dynein arms was observed. |
| GO:0045505 dynein intermediate chain binding | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: PAINT inference at the deep dynein heavy chain node PTN000743491, seeded only by a Dictyostelium cytoplasmic dynein heavy chain. Reason: Heavy chain stems generally bind intermediate chains, so the inference is reasonable, but the node lies far from DNAH1 and no intermediate-chain partner of DNAH1 has been identified; the known partners are the light intermediate chain DNALI1 and TTC29/ZMYND12. |
| GO:0045505 dynein intermediate chain binding | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: InterPro DHC domain mapping to dynein intermediate chain binding. Reason: Generic family-level inference without a specific intermediate-chain partner for DNAH1. |
| GO:0051959 dynein light intermediate chain binding | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT inference at PTN000743491 seeded by cytoplasmic dynein-1 heavy chains (human DYNC1H1, mouse and rat). Reason: For DNAH1 this inference is matched by data: DNAH1 associates with the axonemal light intermediate chain DNALI1, co-purifies with it in TTC29/ZMYND12 pull-downs, and depends on it for flagellar localization. Supporting Evidence: PMID:36792588 As anticipated, the murine DNALI1 is localized within the entire sperm flagellum and interacts with the HDC subunit DNAH1 in the testis PMID:37934199 Thus, our data indicate that ZMYND12 interacts with DNAH1 and DNALI1, two established components of the axonemal IDA. |
| GO:0051959 dynein light intermediate chain binding | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro DHC domain mapping to dynein light intermediate chain binding. Reason: Supported for DNAH1 by its association with DNALI1. Supporting Evidence: PMID:36792588 Accordingly, we demonstrated that DNAH1 and DNAH7 were absent from the flagella lacking DNALI1 in both species. |
| GO:0060285 cilium-dependent cell motility | NAS PMID:9373155 Identification of dynein heavy chain genes expressed in huma... | MODIFY | Summary: Statement from the 1997 cloning paper that axonemal dyneins drive cilia and flagella. Reason: Correct but less specific than the evidence supports. DNAH1 drives both sperm flagellar and ciliary motility, so both specific descendants apply: flagellated sperm motility (GO:0030317), already ACCEPTed in this review on human and mouse mutant data, and cilium movement involved in cell motility (GO:0060294), supported by the roughly 50% reduction of tracheal ciliary beat frequency in Dnah1-null mice. The respiratory role is modest in humans. Proposed replacements: flagellated sperm motility cilium movement involved in cell motility Supporting Evidence: PMID:11371505 we measured the beat frequency of tracheal cilia and observed a decrease in the beat frequency of approximately 50% in MDHC7(-/-) mice |
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Download this section (compressed HTML)Q: Why does DNAH1 loss disrupt the whole axoneme (including the central pair) in human sperm but leave mouse axonemes grossly intact? Does the short Dnah1 isoform described in mice exist and compensate in human testis?
Q: Why is DNAH1 deficiency mostly confined to the sperm flagellum in humans, when the protein is present along respiratory ciliary axonemes? Is the single PCD family (CILD37, p.Lys1154Gln) a distinct allele class, or is another heavy chain compensating in respiratory cilia?
Q: What is the order of assembly among DNAH1, DNALI1, DNAH3, DNAH12, TTC29 and ZMYND12 in the sperm IDA, given that each of the others is needed for DNAH1 to reach the flagellum?
Q: The ferf1 missense allele gives motile but zona-penetration-defective sperm. Does this reflect a change in waveform (hyperactivation) rather than in basic motility?
Experiment: Cryo-ET of the 96-nm repeat in DNAH1-mutant human sperm and Dnah1-null mouse sperm, to confirm that DNAH1 is the IDA d heavy chain and to measure which other arms are lost secondarily.
Type: cryo-electron tomography
Experiment: Recombinant DNAH1 motor domain in microtubule gliding and ATPase assays, including the CILD37 p.Lys1154Gln and ferf1 variants, to test direct effects on motor activity.
Type: in vitro motility assay
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