CCDC40 contributes structure to the motile-cilium axoneme. The most informative synthesis is one CCDC39–CCDC40 structural unit that organizes the 96-nm repeat and the recruitment or retention of inner dynein-arm and regulatory components. It is not a dynein ATPase, a demonstrated active cargo transporter, or an extracellular protein merely because cilia move extracellular fluid. Human structural evidence supports refining the existing unknown molecular-function row to structural constituent of cytoskeleton, GO:0005200. No NEW annotation is proposed.
The normal seed contains 33 assertions and five alternative products for human CCDC40, Q4G0X9, HGNC:26090, NCBI Gene 55036. The canonical UniProt sequence is 1,142 amino acids, sequence version 2, CRC64 B18A5808B0BEC212. All source fields, product objects, qualifiers and source identifiers remain exact. No source row is isoform-specific or negated. The five products are not assumed to share independently demonstrated activities; no product-specific mechanism was inferred from the canonical sequence.
The frozen project association remains autosomal recessive primary ciliary dyskinesia 15, Definitive. The clinical annotation review does not alter that disease-validity assessment. Thirteen seeded references are retained and assessed; the already canonical human structural study PMID:37258679(https://pubmed.ncbi.nlm.nih.gov/37258679/) is added. All canonical source bytes remain protected. The original automated family files remain TMP evidence, not authored source caches.
The original CCDC40 study, PMID:21131974, combines human patient genetics and respiratory-cell phenotypes with mouse and zebrafish experiments. The complete cached scientific prose and Methods were read. Human mutant cilia show defective inner-arm/regulatory organization and ineffective motion; outer-arm markers are retained. Direct Ccdc40 antibody localization to tracheal cilia and apical cytoplasm is mouse evidence, supported by the lnks mutant control. The human localization experiment in Figure 5 detects CCDC39 recruitment, not CCDC40 itself. Zebrafish depletion/rescue supports heart and visceral laterality; this is not a human embryo or human cardiomyocyte assay. The paper's earlier structural-scaffold hypothesis is now reinforced by direct human structural data. Its alternative preassembly/transport suggestions do not independently establish motor activity. No figure pixels, movies or complete supplements were inspected.
PMID:37258679(https://pubmed.ncbi.nlm.nih.gov/37258679/) provides the critical direct human structural evidence. Selected complete human Results, captions and Methods were read, alongside the complete abstract. Patient ID03 has a homozygous CCDC40 exon 1–3 deletion; ID04 is the separate CCDC39 mutant. Patient-derived epithelial/organoid axonemes lose the 96-nm repeat, including its coiled coil, while outer-arm docking and the 24-nm repeat remain. Radial spokes can enter the axoneme but fail to attach periodically. This supports a structural contribution to organization rather than merely an indirect requirement for healthy cilia. The human models integrate cryo-EM density, structure prediction and algal structural guidance; not every contact is a directly demonstrated human interface. The earlier algal FAP59/FAP172 findings are contextual, not substituted for the human CCDC40 experiment. Complete figure pixels and supplements were not inspected.
PMID:23255504(https://doi.org/10.1002/humu.22261) was read at selected complete human Results, relevant Methods and localization passages. CCDC40-mutant cross-sections lose inner arms while retaining outer arms. The report gives CCDC40-specific frequency measurements, not just altered waveforms. It also reports sperm dysmotility in one CCDC40 patient but does not display those data. That supports retaining the existing sperm-motility assertion as non-core with its presentation limit. CCDC39 and radial-spoke staining in CCDC40-mutant cells must not be relabeled as direct CCDC40 antibody localization. Preserved radial-spoke staining does not establish normal periodic attachment or function.
PMID:26387594(https://pubmed.ncbi.nlm.nih.gov/26387594/) centers on GAS8 but includes an actual Ccdc40 lnks mouse tracheal experiment showing loss of GAS8 localization, as well as discussion of the earlier human CCDC40 findings. Selected complete target Results/Discussion were read from the canonical full HTML cache. The mouse experiment and the human cited experiment are kept distinct. Supplementary Figure S4 pixels were not inspected. It supports partner positioning without proving that CCDC40 itself transports cargo.
| Source | Canonical access | Actual additional reading and limit |
|---|---|---|
| PMID:21131974 | Full XML | Complete cached scientific prose/Methods; no full supplements or image audit. |
| PMID:22499950 | Abstract only | Separately authenticated normal XML in TMP supplied selected complete CCDC40 Results/Discussion. Patient 1401 carries variants in trans; patient 564 is not silently treated as a proven biallelic case. Supplementary target movies/tables remain uninspected. The canonical abstract cache is unchanged. |
| PMID:22693285 | Abstract only | Complete abstract and official source identity verified; publisher access failed. Specific organ-level observations remain unresolved. |
| PMID:23255504 | Full XML | Selected complete target Results, Methods and relevant localization passages, not a blanket full-paper/supplement claim. |
| PMID:26387594 | Full HTML | Selected target Results/Discussion, with mouse experiment versus cited human evidence distinguished. |
| PMID:27120127 | Abstract only | Complete abstract explicitly includes respiratory-cilia CCDC39/CCDC40 immunofluorescence context. Full target panels and antibody controls remain unavailable. |
| PMID:37258679 | Full XML | Complete abstract and selected human structure, genetic, epithelial, analysis and modeling Methods/Results/captions. Integrative models and uninspected images/supplements remain explicit. |
The cilium/axoneme IDA assertions are retained where independent direct human structure establishes the same location, while the original target-panel access limit remains stated. A paper foregrounding GAS8 or a CCDC39 antibody does not prove a curator misattribution. Four original PMID:22693285 claims—lung development, pancreatic laterality, digestive-tract laterality and liver laterality—remain UNDECIDED because the source-specific human clinical evidence was not available. Broad heart-looping involvement is retained as non-core with independently established conserved laterality biology and curator deference; no direct human cardiac mechanism is claimed.
The current official GO:0005200 definition describes a contribution to cytoskeletal structural integrity. Its structural-molecule parent and cytoskeleton organization relationship fit the axonemal scaffold. A generic protein-complex scaffold term was considered, but the demonstrated cytoskeletal context supports this existing specific structural term. Refining the existing ND row avoids a duplicate NEW molecular function. Existing assembly and localization annotations already cover the demonstrated processes; no gap was inferred from absent comparator rows and no NEW process was manufactured.
The current official extracellular-region definition concerns space outside the plasma membrane. The supplied GO:0003351 and GO:0060287 terms describe ciliary movement and fluid/laterality outcomes, not the protein's extracellular residence. The related ontology chain through extracellular transport explains the possible geography leakage, but the actual CCDC40 source remains GO_REF:0000120, combined IEA methods. A related CCDC39 inference uses a different GO reference; that history was not substituted here. Removal is limited to this unsupported electronic localization route. It does not deny the underlying ciliary processes or every hypothetical extracellular release event.
GO:0035082 covers axoneme assembly and organization, so intact but disorganized cilia do not refute it. GO:0003356 concerns beat frequency; the actual human frequency measurements support retention without a new biochemical regulator claim. Broad cytoplasm is not the narrower cytosol. Mouse localization supports broad cytoplasmic non-core retention, while the structural core is localized to the axoneme and motile cilium.
All five PAINT rows preserve their exact PTN nodes. The IBD placements and alignments were not inspected, and are marked unresolved at the source-entity level. Their target functions are independently supported; neither donor count nor the target's appearance in the source list is used to allege circularity. The ISS/ISO mouse donor remains Q8BI79/PR:Q8BI79, supported by the actual mouse experiments. GO_REF:0000044 rows are vocabulary mappings, and GO_REF:0000002 is InterPro inference; neither is mislabeled as an independent assay.
The 33 decisions are 19 ACCEPT, eight KEEP_AS_NON_CORE, four UNDECIDED, one MODIFY and one REMOVE. One structural core unifies axonemal assembly/organization, partner positioning, ciliary movement and beat-frequency support. Developmental laterality and the limited sperm observation remain non-core. The four clinical uncertainties, product-specific functions and any distinct cytoplasmic preassembly role remain explicit questions.
Eight short canonical verbatim anchors are embedded in the review and core. Notes add no new quotations. A mechanical audit counts repeated uses separately and requires at most 25 aggregate quoted words per source. No artifact-only wording is represented as canonical supporting text.
Normal validation, status checking and rendering returned zero. Validation reports eight missing per-row quotation advisories for retained experimental assertions; the underlying reasons and independent source support are explicit. A target antibody panel that was not read is not supplied with an invented quotation, and short repeated fragments are not added merely to suppress a warning. The candidate remains DRAFT under normal status computation, with four biological uncertainties preserved.
ROOT's normal deep-research command failed before obtaining a provider report because the offline environment could not resolve deep-research-client[cyberian] version 0.2.7rc1 (native b858bf). A separate established isolated Falcon attempt with the configured perplexity-lite fallback also failed with connection errors, returned 1 and produced no report (native 7660bd/227a37; receipt in the TMP isolated attempt directory). These are distinct failed attempts, not successful research. This document is manually authored research notes; no provider-named report or missing primary text was fabricated. The annotation-reviewer and core-function-synthesizer workflows were applied manually, with read-only primary research and exact source preservation. Final validation/status/render receipts and the independent peer must accompany application; ROOT alone executes any canonical change or history creation.
This entry supersedes the initial action counts and the earlier four-organ uncertainty summary. The current follow-up retains all 33 source assertions, five alternative products, 14 reference identities and the original source bytes. It makes four action changes: the two beat-frequency assertions become KEEP_AS_NON_CORE, and the pancreatic and liver laterality assertions become KEEP_AS_NON_CORE. The 33 decisions are now 17 ACCEPT, 12 KEEP_AS_NON_CORE, two UNDECIDED, one MODIFY and one REMOVE, with no NEW annotation.
The actual PMID:21131974 Results score heart, liver and pancreas situs together at 48 hours after fertilization, using two different splice-blocking morpholinos and ccdc40-mRNA rescue. The Methods describe RNA in situ analysis of organ laterality. The official pancreatic and liver terms concern the asymmetric organ position, which this readout measures. The same conserved-evidence standard therefore supports all three existing organ laterality assertions as non-core. It does not identify the original human patient-level findings in PMID:22693285. The lung-development and digestive-tract rows remain UNDECIDED: the inspected situs experiment does not supply those missing endpoints, and respiratory disease alone does not settle lung morphogenesis.
The current GO:0003356 definition and parent allow frequency modulation; they do not restrict it to kinases, signaling enzymes or motors. The human frequency measurements in PMID:23255504 remain positive evidence for the existing annotations. The narrower synthesis decision is to retain those measured consequences as non-core and omit the frequency process from the structural core, because the inspected patient and structural experiments do not separate an additional frequency-setting operation from loss of axonemal organization. This is not a claim that the annotation is biologically false or that a structural contribution could never regulate frequency.
The assembly core now selects inner dynein arm assembly rather than also listing its broader axoneme-assembly context. The official GO:0036159 hierarchy places it under axonemal dynein complex assembly and within axoneme assembly. The existing broader assembly annotations remain ACCEPT: they describe the same core structural biology at broader granularity and need not each occupy a redundant core slot. Protein localization to cilium and cilium movement remain in the synthesis; no new molecular activity or process was added.
The cilium-movement rationale no longer relies on patient identifiers or phasing details. The canonical PMID:22499950 abstract explicitly includes CCDC39/CCDC40 PCD controls, and the movement conclusion is independently established by the cached human CCDC40 studies. The separately read richer XML corresponds to the public PMC3770728 article and published paper. Its selected Results section, Sequencing Analysis of 14 Known PCD Genes, states that patient 1401 had a second CCDC40 variant confirmed in trans and compatible ultrastructural abnormalities. That statement is retained here solely as explicit external-body reading provenance; supplementary patient movies and tables were not inspected. A fresh direct PMC open encountered a browser challenge. The canonical abstract-only cache and its access flag are unchanged, and no external-only passage is used as canonical supporting_text. The reference remains VERIFIED within this stated identity and target-relevance scope, rather than implying complete verification of all assays.
The existing PMID:27120127 anchor is expanded to include the respiratory-cilia immunofluorescence context, including its GAS8-negative result. Full target panels and antibody controls remain inaccessible, so the localization judgment still combines curator deference with independent human structural evidence. Two short PMID:21131974 organ-position anchors were added. All other existing quotes remain exact. Notes add no verbatim scientific quotation; the mechanical audit counts every candidate anchor occurrence separately and preserves the 25-word-per-source ceiling.
No inference was made that UNDECIDED necessarily controls the normal DRAFT status. No missing full text was replaced with fabricated text, and no experimental annotation was removed from a title, abstract omission or paralog comparison. The original notes above remain as an append-only record; the present entry records the revised final judgments.
Normal follow-up validation, status checking and rendering returned zero. Seven unchanged per-row quotation advisories remain for other accepted experimental assertions; no extra quote was added merely to suppress them. Status remains DRAFT with two unresolved biological assertions. After adding this actual check summary to notes, only rendering was repeated so that the delivered HTML includes the final append.