CCDC40 is a coiled-coil structural component of the axoneme of motile cilia. Together with CCDC39, it forms part of the longitudinal scaffold organizing the 96-nm repeat and the positioning of inner dynein arms and associated regulatory structures. Human respiratory-cell studies link loss of CCDC40 to disrupted axonemal periodicity, defective inner dynein arms and ineffective ciliary beating, while the outer dynein-arm repeat can remain intact. CCDC40-dependent organization also supports recruitment or retention of other axonemal proteins. Its ciliary role contributes to mucociliary transport and embryonic left-right patterning. Biallelic loss-of-function variants cause primary ciliary dyskinesia, frequently with laterality abnormalities; the functions of its individual alternative products are not separately established.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0001947 heart looping | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Ciliary structure contributes to heart laterality rather than a separate cardiac activity. Reason: The PAINT assertion is biologically compatible with the conserved motile-cilium role and the zebrafish heart-looping perturbation/rescue experiments in PMID:21131974. The target in the descendant evidence is legitimate, not circular. Retain this developmental outcome as non-core; the actual IBD placement and alignment were not inspected. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: PANTHER:PTN002701912 UNRESOLVED The source node is recorded exactly; its IBD placement and alignment were not inspected. Independent biological evidence supports the target assertion. |
| GO:0001947 heart looping | IMP PMID:22693285 Delineation of CCDC39/CCDC40 mutation spectrum and associate... | KEEP AS NON CORE | Summary: Retain the curated heart-looping involvement as a developmental consequence. Reason: PMID:22693285 is a human CCDC39/CCDC40 clinical cohort, but its full organ-level data were inaccessible. Independent CCDC40 evidence in PMID:21131974 includes zebrafish heart-looping randomization and rescue with ccdc40 mRNA, alongside human laterality disease. This supports the broad conserved involvement and curator deference, without claiming a human cardiomyocyte assay or a distinct morphogenetic activity. |
| GO:0003341 cilium movement | IMP PMID:22499950 High prevalence of respiratory ciliary dysfunction in congen... | ACCEPT | Summary: CCDC40 supports effective movement of motile cilia. Reason: The canonical PMID:22499950 abstract identifies CCDC39/CCDC40-mutant PCD controls in a study of nasal ciliary motion, but does not expose their individual motility measurements. Independent human CCDC40 nasal-brushing and organoid studies in PMID:21131974, PMID:23255504 and PMID:37258679 establish defective beating. Retain the curated movement assertion with this independent support, without attributing every heterotaxy-cohort defect to CCDC40. The separately inspected selected Results are identified in the notes by their public article URL; patient-level supplementary movies and tables remain uninspected. |
| GO:0003351 epithelial cilium movement involved in extracellular fluid movement | IMP PMID:21131974 The coiled-coil domain containing protein CCDC40 is essentia... | ACCEPT | Summary: Axonemal organization enables epithelial ciliary fluid transport. Reason: PMID:21131974 reports human CCDC40-mutant respiratory cilia with rigid, ineffective motion and defective inner dynein-arm/regulatory-complex organization. CCDC40 supplies the structural machinery on which beating depends; it is not merely cargo transported by that beating. The extracellular fluid is the process output and does not locate CCDC40 outside the cell. |
| GO:0003356 regulation of cilium beat frequency | IMP PMID:21131974 The coiled-coil domain containing protein CCDC40 is essentia... | KEEP AS NON CORE | Summary: Retain the measured beat-frequency involvement as a non-core consequence of axonemal organization. Reason: PMID:21131974 establishes abnormal human ciliary waveform and amplitude; the frequency-specific involvement is independently supported by actual CCDC40 patient measurements in PMID:23255504. GO:0003356 allows modulation of cilium movement frequency and does not require a kinase or motor activity. Retain the curated process annotation, but classify it as non-core: the inspected experiments link the frequency phenotype to disruption of axonemal architecture without separating a distinct frequency-setting operation performed by CCDC40. The structural scaffold and cilium-movement core capture the established mechanism. |
| GO:0003356 regulation of cilium beat frequency | IMP PMID:23255504 Mutations in CCDC39 and CCDC40 are the major cause of primar... | KEEP AS NON CORE | Summary: Human CCDC40 deficiency alters measured ciliary beat frequency. Reason: PMID:23255504 reports a mean 37-degree C CCDC40 patient ciliary beat frequency of 9.2 Hz against a normal range of 11–16 Hz, with substantial variation and immotile patches. This is a measured human frequency phenotype, not an inference from waveform alone. Preserve the experimental annotation as non-core while the core describes CCDC40's structural contribution to axonemal organization and movement. These measurements do not isolate a separate frequency-setting operation; they also do not refute the broad regulation term or establish that a structural protein cannot influence frequency. Supporting Evidence: PMID:23255504 9.2Hz in CCDC40 patients |
| GO:0003674 molecular_function | ND GO_REF:0000015 | MODIFY | Summary: Replace the unknown molecular function with a supported cytoskeletal structural role. Reason: GO:0005200 describes contribution to the structural integrity of a cytoskeletal structure. Human cryo-EM and patient-derived epithelial studies in PMID:37258679 place the CCDC39–CCDC40 coiled coil in the axonemal repeat and show selective loss of 96-nm organization in CCDC40-deficient axonemes. This is positive structural participation, beyond knockout necessity alone. Human models combine density with predicted structures and algal guidance, so individual human contact interfaces are not all independently demonstrated. Refine this existing ND row instead of adding a duplicate NEW MF; preserve the historical ND source fields. Proposed replacements: structural constituent of cytoskeleton Supporting Evidence: PMID:37258679 Mutations in CCDC39 and CCDC40 cause complete loss of the 96-nm repeat |
| GO:0005576 extracellular region | IEA GO_REF:0000120 | REMOVE | Summary: The process-to-location inference does not establish an extracellular CCDC40 pool. Reason: This electronic row cites epithelial ciliary fluid movement and left-right ciliary movement as its source terms. GO:0005576 denotes space outside the plasma membrane. The ciliary axoneme is intracellular, and human structural evidence places CCDC40 in that axonemal scaffold. Movement of extracellular fluid does not entail extracellular localization of the participating protein. Reject this specific inference, not the source processes and not every hypothetical release of CCDC40. GO_REF:0000120 identifies combined IEA methods; the exact historical execution trace was not recovered. Propagation Review Root cause: PROPAGATION BAD Failure modes: COMPARTMENT OR COMPLEX MISMATCH Sources checked: GO:0003351 SUPPORTS SOURCE BUT NOT TARGET The ciliary process is supported, but movement of extracellular fluid does not locate the axonemal protein outside the plasma membrane. GO:0060287 SUPPORTS SOURCE BUT NOT TARGET The ciliary process is supported, but movement of extracellular fluid does not locate the axonemal protein outside the plasma membrane. |
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Retain a broad cytoplasmic pool without making it the structural core location. Reason: PMID:21131974 describes mouse Ccdc40 in the apical cytoplasm and motile cilia, using a mutant specificity control. This is compatible with a conserved cytoplasmic pool. The PAINT node itself remains uninspected; target self-evidence is legitimate. Retain the broad compartment as non-core, while the demonstrated axonemal structural activity is localized more precisely. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: PANTHER:PTN000780552 UNRESOLVED The source node is recorded exactly; its IBD placement and alignment were not inspected. Independent biological evidence supports the target assertion. |
| GO:0005737 cytoplasm | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: The UniProt cytoplasm mapping is compatible with the observed broad compartment. Reason: The source is the Swiss-Prot subcellular-location vocabulary SL-0086, not a new localization experiment. Mouse cytoplasmic localization in PMID:21131974 supports the biological plausibility of this broad mapping, but does not establish a separate human cytosolic molecular activity. Retain as non-core and do not replace cytoplasm with the narrower cytosol. |
| GO:0005737 cytoplasm | ISS GO_REF:0000024 | KEEP AS NON CORE | Summary: The mouse ortholog supports a broad cytoplasmic localization transfer. Reason: The exact source is mouse Ccdc40 Q8BI79. PMID:21131974 directly reports mouse localization in apical cytoplasm and tracheal cilia with lnks-mutant controls. This supports the conserved broad compartment; it is not a direct human antibody experiment or evidence for an independent cytoplasmic core. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: UniProtKB:Q8BI79 · mouse Ccdc40 SUPPORTS TRANSFER Actual mouse localization or partner-recruitment evidence was read; the target claim is also consistent with human CCDC40 biology. |
| GO:0005929 cilium | IBA GO_REF:0000033 | ACCEPT | Summary: Ciliary localization is integral to the conserved structural function. Reason: The PAINT assertion agrees with direct human axonemal structural placement in PMID:37258679 and mouse ciliary localization in PMID:21131974. Retain the inherited ciliary location; no claim is made that the actual ancestral placement was independently inspected. The target in the donor list is not circular evidence. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN002701912 UNRESOLVED The source node is recorded exactly; its IBD placement and alignment were not inspected. Independent biological evidence supports the target assertion. |
| GO:0005929 cilium | IDA PMID:27120127 Mutations in GAS8, a Gene Encoding a Nexin-Dynein Regulatory... | ACCEPT | Summary: Retain the human ciliary localization detected in the GAS8 study. Reason: The complete PMID:27120127 abstract explicitly describes respiratory-cilia immunofluorescence and preserved CCDC39/CCDC40 expression in GAS8-mutant patients. Its title foregrounding GAS8 does not exclude CCDC40 assays. Full target panels and antibody controls were not accessible; curator deference is reinforced by independent human axonemal placement in PMID:37258679. Supporting Evidence: PMID:27120127 Immunofluorescence studies performed on patients' respiratory cilia revealed that GAS8 is not required for the proper expression of CCDC39 and CCDC40. |
| GO:0005929 cilium | IEA GO_REF:0000044 | ACCEPT | Summary: The UniProt cilium mapping matches the demonstrated site of structural action. Reason: SL-0066 is a subcellular-location mapping, not an independent experiment. It agrees with the human axonemal structural study in PMID:37258679 and the primary mouse ciliary localization in PMID:21131974. No extension to all primary sensory cilia or all five alternative products is inferred. |
| GO:0005929 cilium | ISS GO_REF:0000024 | ACCEPT | Summary: Mouse Ccdc40 supports conserved ciliary localization. Reason: The source Q8BI79 was experimentally localized to mouse tracheal motile cilia in PMID:21131974. This is not inferred merely from a paralog name. Human structural placement in PMID:37258679 independently supports the target location while leaving species-specific antibody details distinct. Propagation Review Root cause: NO FAILURE CORE Sources checked: UniProtKB:Q8BI79 · mouse Ccdc40 SUPPORTS TRANSFER Actual mouse localization or partner-recruitment evidence was read; the target claim is also consistent with human CCDC40 biology. |
| GO:0005930 axoneme | IDA PMID:23255504 Mutations in CCDC39 and CCDC40 are the major cause of primar... | ACCEPT | Summary: Retain the axonemal location with independent direct human structural support. Reason: PMID:23255504 studies human CCDC40-mutant cilia, but the selected localization panels read use antibodies against CCDC39 and radial-spoke proteins rather than proving a CCDC40-specific antibody result. This access boundary does not justify rejecting the curator assignment. PMID:37258679 independently places CCDC40 in the human axonemal coiled-coil scaffold. |
| GO:0005930 axoneme | TAS PMID:26387594 Loss-of-Function GAS8 Mutations Cause Primary Ciliary Dyskin... | ACCEPT | Summary: The axoneme is the relevant structural compartment. Reason: PMID:26387594 discusses CCDC39/CCDC40 as ruler proteins and directly tests loss of GAS8 localization in Ccdc40-mutant mouse trachea. Those observations are distinct from direct CCDC40 localization imaging. Retain its TAS axoneme assertion, corroborated by the human CCDC40 structural study. |
| GO:0030317 flagellated sperm motility | IMP PMID:23255504 Mutations in CCDC39 and CCDC40 are the major cause of primar... | KEEP AS NON CORE | Summary: Retain the reported human sperm-motility phenotype with its limited presentation. Reason: PMID:23255504 explicitly reports sperm dysmotility in one CCDC40 patient, alongside three CCDC39 patients, but states that the data are not shown. Retain the existing experimental assertion as a reproductive context of the axonemal role. Do not present it as a purified flagellar mechanism, an isoform assignment or a fully inspected sperm dataset. Supporting Evidence: PMID:23255504 sperm dysmotility was also recorded (data not shown) |
| GO:0030324 lung development | IMP PMID:22693285 Delineation of CCDC39/CCDC40 mutation spectrum and associate... | UNDECIDED | Summary: The specific lung-development assertion remains unresolved. Reason: PMID:22693285 is available only as a complete abstract. Its human clinical cohort establishes CCDC39/CCDC40-associated PCD but does not expose the target-specific observation underlying lung development. Chronic respiratory disease and laterality defects alone do not distinguish morphogenesis from consequences of impaired clearance. Preserve the experimental row as undecided pending the full organ-level evidence, not as a wrong-gene citation. |
| GO:0031514 motile cilium | IDA PMID:26387594 Loss-of-Function GAS8 Mutations Cause Primary Ciliary Dyskin... | ACCEPT | Summary: Retain motile-cilium localization of the structural component. Reason: The available PMID:26387594 body includes the Ccdc40 lnks mouse tracheal experiment and summarizes human CCDC40-dependent axonemal recruitment. The inspected source passage measures GAS8 rather than a direct CCDC40 antibody signal. Independent human axonemal structures in PMID:37258679 support the established motile-cilium location, so the original IDA is retained with this explicit source-access boundary. |
| GO:0035082 axoneme assembly | IBA GO_REF:0000033 | ACCEPT | Summary: The inherited axoneme-assembly role is supported by direct target biology. Reason: Human CCDC40 loss disrupts inner-arm and regulatory architecture, and the human structural study resolves the CCDC39–CCDC40 component of the 96-nm scaffold. This supports assembly and organization of the axoneme as defined by GO:0035082. The actual PTN002701912 placement was not inspected; no donor-count or self-reference objection is warranted. Propagation Review Root cause: NO FAILURE CORE Sources checked: PANTHER:PTN002701912 UNRESOLVED The source node is recorded exactly; its IBD placement and alignment were not inspected. Independent biological evidence supports the target assertion. |
| GO:0035082 axoneme assembly | IEA GO_REF:0000002 | ACCEPT | Summary: The InterPro family inference agrees with experimentally established axoneme organization. Reason: IPR037386 is the CCDC40 family source in this row. The inference is independently grounded by human CCDC40 loss-of-function ultrastructure and direct structural placement in PMID:21131974 and PMID:37258679. It does not imply that CCDC40 polymerizes tubulin or supplies a motor ATPase. |
| GO:0035469 determination of pancreatic left/right asymmetry | IMP PMID:22693285 Delineation of CCDC39/CCDC40 mutation spectrum and associate... | KEEP AS NON CORE | Summary: Retain conserved pancreatic laterality involvement as a non-core developmental consequence. Reason: Independent CCDC40 evidence in PMID:21131974 scores heart, liver and pancreas situs in the same zebrafish experiment. Two splice-blocking morpholinos disturb organ laterality, and ccdc40 mRNA rescues the laterality phenotype. The actual pancreatic position readout supports the corresponding left/right-asymmetry term, consistent with the conserved ciliary mechanism and human CCDC40 laterality disease. Retain the existing curator-supported human assertion as non-core on that combined evidence, using the same standard as heart looping. This does not verify the original patient-level pancreatic observation in the inaccessible full PMID:22693285 report or turn the fish assay into a human organ-specific experiment. Supporting Evidence: PMID:21131974 pancreas on the right side of the midline |
| GO:0036159 inner dynein arm assembly | IMP PMID:23255504 Mutations in CCDC39 and CCDC40 are the major cause of primar... | ACCEPT | Summary: CCDC40 structurally supports inner dynein-arm assembly. Reason: PMID:23255504 documents loss of inner arms in human CCDC40-mutant cross-sections while outer arms are retained. Together with direct human ruler placement in PMID:37258679, this supports CCDC40 participation through structural docking and organization, not only a generic requirement for the phenotype. This does not assign dynein motor catalysis to CCDC40. Supporting Evidence: PMID:23255504 90% (CCDC40) of cilia cross sections |
| GO:0044458 motile cilium assembly | IMP PMID:23255504 Mutations in CCDC39 and CCDC40 are the major cause of primar... | ACCEPT | Summary: CCDC40 contributes to assembly of a functional motile axoneme. Reason: PMID:23255504 shows defective axonemal organization and inner-arm assembly in existing patient cilia. GO:0044458 includes assembly of the motile ciliary structure; it does not require complete absence of cilia after depletion. Human structural placement supplies the positive component role. Retain the broad process without claiming a basal-body amplification or membrane-biogenesis activity. |
| GO:0044782 cilium organization | IC PMID:26387594 Loss-of-Function GAS8 Mutations Cause Primary Ciliary Dyskin... | ACCEPT | Summary: Recruitment and positioning of axonemal components is cilium organization. Reason: The IC source explicitly derives from protein localization to cilium. PMID:26387594 provides the Ccdc40 mouse GAS8-localization experiment, while human CCDC40 structures show organization of the 96-nm repeat. The inferred organization term fits this physical scaffold role rather than an unrelated organ phenotype. |
| GO:0060287 epithelial cilium movement involved in determination of left/right asymmetry | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Ciliary function contributes to left-right patterning as a developmental context. Reason: The inherited assertion is supported by CCDC40-dependent motility and the mouse/zebrafish laterality experiments in PMID:21131974, together with human situs phenotypes. Preserve this considered PAINT assertion without claiming that the IBD placement was inspected or that CCDC40 is a dedicated laterality signaling factor. Propagation Review Root cause: NO FAILURE NON CORE Sources checked: PANTHER:PTN002701912 UNRESOLVED The source node is recorded exactly; its IBD placement and alignment were not inspected. Independent biological evidence supports the target assertion. |
| GO:0060287 epithelial cilium movement involved in determination of left/right asymmetry | IMP PMID:21131974 The coiled-coil domain containing protein CCDC40 is essentia... | KEEP AS NON CORE | Summary: Motile-cilium defects explain the conserved left-right patterning involvement. Reason: PMID:21131974 combines human CCDC40-associated situs phenotypes with mouse and zebrafish functional experiments. Retain the original process as a developmental consequence of the structural ciliary machinery. The zebrafish rescue uses ccdc40 mRNA; it is not a human embryo experiment or evidence for direct specification of each internal organ. |
| GO:0061512 protein localization to cilium | ISO GO_REF:0000008 | ACCEPT | Summary: The mouse ortholog transfer supports localization of axonemal partners. Reason: The exact ISO donor is PR:Q8BI79, mouse Ccdc40. The lnks tracheal experiment in PMID:26387594 shows loss of GAS8 axonemal localization; PMID:21131974 independently shows CCDC39 recruitment defects in human CCDC40-mutant cilia. This supports transfer of the partner-localization function without equating recruitment or retention with active transport by CCDC40. Propagation Review Root cause: NO FAILURE CORE Sources checked: PR:Q8BI79 · mouse Ccdc40 SUPPORTS TRANSFER Actual mouse localization or partner-recruitment evidence was read; the target claim is also consistent with human CCDC40 biology. Supporting Evidence: PMID:26387594 Absent localization of GAS8 was confirmed in tracheal sections of mice |
| GO:0061512 protein localization to cilium | TAS PMID:26387594 Loss-of-Function GAS8 Mutations Cause Primary Ciliary Dyskin... | ACCEPT | Summary: CCDC40 organizes the axonemal localization of other proteins. Reason: PMID:26387594 links CCDC40 to proper GAS8 positioning, including an actual mouse lnks experiment, and summarizes the earlier human findings. PMID:21131974 directly documents human CCDC39 loss from the cilium and enrichment at its base. The annotation describes structural recruitment or retention, not an untested motor or cargo-transport activity. Supporting Evidence: PMID:21131974 CCDC40 appears to be responsible for axonemal recruitment of CCDC39 |
| GO:0070286 axonemal dynein complex assembly | IMP PMID:21131974 The coiled-coil domain containing protein CCDC40 is essentia... | ACCEPT | Summary: The broad dynein-complex assembly term is supported through inner-arm organization. Reason: PMID:21131974 demonstrates defective inner dynein-arm and regulatory-complex organization in CCDC40-mutant human cilia with retained outer-arm markers. CCDC40 contributes a structural platform; the broad parent term does not imply equal necessity for outer dynein-arm assembly, which the human 2023 study also distinguishes. |
| GO:0071907 determination of digestive tract left/right asymmetry | IMP PMID:22693285 Delineation of CCDC39/CCDC40 mutation spectrum and associate... | UNDECIDED | Summary: The digestive-tract laterality assertion awaits the target-specific clinical evidence. Reason: The complete abstract of PMID:22693285 does not identify the CCDC40 patient or digestive-tract observation underlying this IMP. General human situs abnormalities and vertebrate laterality experiments make it plausible, but do not verify this precise original mapping. Preserve the row as undecided pending full text and relevant clinical data. |
| GO:0071910 determination of liver left/right asymmetry | IMP PMID:22693285 Delineation of CCDC39/CCDC40 mutation spectrum and associate... | KEEP AS NON CORE | Summary: Retain conserved liver laterality involvement as a non-core developmental consequence. Reason: Independent CCDC40 evidence in PMID:21131974 scores heart, liver and pancreas situs in the same zebrafish experiment. Two splice-blocking morpholinos disturb organ laterality, and ccdc40 mRNA rescues the laterality phenotype. The actual liver position readout supports the corresponding left/right-asymmetry term, consistent with the conserved ciliary mechanism and human CCDC40 laterality disease. Retain the existing curator-supported human assertion as non-core on that combined evidence, using the same standard as heart looping. This does not verify the original patient-level liver observation in the inaccessible full PMID:22693285 report or turn the fish assay into a human organ-specific experiment. Supporting Evidence: PMID:21131974 liver on the left |
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Download this section (compressed HTML)Q: Which patient-level observations in the full PMID:22693285 report support CCDC40-specific lung development and digestive-tract laterality? The original human heart, pancreas and liver mappings also remain uninspected even though conserved involvement is retained from independent laterality evidence.
Q: How do the five human CCDC40 alternative products differ in expression, axonemal incorporation and partner recruitment? Existing evidence does not resolve these products separately.
Q: Does the observed cytoplasmic CCDC40 pool perform a defined preassembly or trafficking step, or mainly supply the axonemal scaffold? Partner localization defects alone do not establish active transport.
Q: Which historical IBD placements support the five PAINT rows, and which rule execution produced the process-to-extracellular-location inference? The accepted biology does not depend on assuming those uninspected details.
Experiment: Compare endogenous, isoform-resolved human CCDC40 localization and rescue in patient-derived airway epithelia, measuring 96-nm organization, partner retention, ciliary frequency and waveform together. Distinguish axonemal assembly from cytoplasmic preassembly with temporally controlled rescue.
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