Affinage

CCDC40

Coiled-coil domain-containing protein 40 · UniProt Q4G0X9

Length
1142 aa
Mass
130.1 kDa
Annotated
2026-04-28
17 papers in source corpus 7 papers cited in narrative 8 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

CCDC40 is a structural component of motile cilia and sperm flagella that, together with CCDC39, forms a molecular ruler complex maintaining the 96 nm axonemal repeat unit. CCDC40 is required for axonemal recruitment of CCDC39 and for correct assembly of inner dynein arm heavy chains (DNAH1, DNAH2, DNAH6, DNAH7), dynein regulatory complexes, and the central pair of microtubules; its loss produces a rigid/stiff ciliary beating pattern (PMID:21131974, PMID:39056782, PMID:35449766). Biallelic loss-of-function mutations in CCDC40 cause primary ciliary dyskinesia (PCD) with randomized left-right body axis patterning—mediated by impaired nodal fluid flow and disrupted Nodal signaling—recurrent respiratory infections, and male infertility due to multiple morphological abnormalities of sperm flagella (PMID:21131974, PMID:28182636, PMID:36873931, PMID:23255504). All identified disease-causing CCDC40 variants are protein-truncating, indicating that complete protein function is essential (PMID:23255504).

Mechanistic history

Synthesis pass · year-by-year structured walk · 6 steps
  1. 2010 High

    The foundational discovery that CCDC40 localizes to motile cilia, recruits CCDC39 to the axoneme, and is required for inner dynein arm and dynein regulatory complex assembly established CCDC40 as a core axonemal organizer and identified it as a PCD disease gene.

    Evidence Immunofluorescence, TEM ultrastructure, and genetic loss-of-function in mouse, zebrafish, and human PCD patients

    PMID:21131974

    Open questions at the time
    • Direct biochemical interaction between CCDC39 and CCDC40 not demonstrated
    • Mechanism by which CCDC40 recruits specific IDA heavy chains not defined
    • No structural model of CCDC40 or the CCDC39–CCDC40 complex
  2. 2013 Medium

    Comprehensive mutation screening across 54 PCD families revealed that all pathogenic CCDC40 alleles are protein-truncating, demonstrating that partial protein function cannot sustain axonemal organization and identifying a mutational hotspot (c.248delC).

    Evidence Sequencing of CCDC39/CCDC40 in 54 families with co-segregation analysis

    PMID:23255504

    Open questions at the time
    • Genotype–phenotype correlations with specific truncation positions not resolved
    • No residual protein or partial function characterized for any variant
  3. 2017 Medium

    Genetic epistasis experiments placed CCDC40 upstream of the Nodal signaling cascade, showing that defective cilia motility impairs nodal flow to delay and randomize asymmetric gene expression, mechanistically linking ciliary dysfunction to laterality defects.

    Evidence Double-mutant analysis (Ccdc40; Nodal heterozygote) with in situ hybridization for Lefty1/2, Nodal, Cerl2 in mouse embryos

    PMID:28182636

    Open questions at the time
    • Quantitative relationship between residual cilia motility and flow-dependent Nodal threshold not defined
    • Single lab; epistasis not confirmed with independent laterality pathway components
  4. 2022 Low

    Extension of the IDA assembly defect to DNAH2 and direct demonstration of a stiff/rigid ciliary beating pattern in CCDC40-mutant cilia refined the motility phenotype, while a minigene assay confirmed that a splice-site variant produces a truncated protein.

    Evidence High-speed video microscopy, immunofluorescence for DNAH2 in patient cilia/sperm; minigene splicing assay

    PMID:35449766 PMID:36245716

    Open questions at the time
    • DNAH2 loss shown in a single patient—awaits replication in larger cohorts
    • Minigene assay for one variant only; endogenous splicing not confirmed
    • Quantitative contribution of DNAH2 loss to the stiff beating phenotype unclear
  5. 2023 Medium

    Direct demonstration that CCDC39 protein is absent from sperm flagella in CCDC40-mutant patients extended the CCDC39–CCDC40 co-dependency from respiratory cilia to flagella and established CCDC40 loss as a cause of male infertility via multiple morphological abnormalities of sperm flagella.

    Evidence Immunofluorescence and TEM on sperm flagella from CCDC40-mutant patients; semen analysis

    PMID:36873931

    Open questions at the time
    • Whether CCDC40 loss produces flagellar defects independent of CCDC39 loss not tested
    • Rescue of sperm motility not attempted
  6. 2024 Medium

    A large patient cohort study defined the full repertoire of IDA heavy chains (DNAH1, DNAH6, DNAH7) lost from the axoneme in CCDC39/CCDC40-mutant cilia, consolidating the molecular ruler model.

    Evidence Immunofluorescence for multiple IDA components in respiratory cilia from 51 patients with CCDC39/CCDC40 variants

    PMID:39056782

    Open questions at the time
    • Whether CCDC40 directly contacts these IDA heavy chains or acts indirectly is unknown
    • No structural or cross-linking data for the molecular ruler complex
    • Contribution of individual IDA subtypes to motility phenotype not dissected

Open questions

Synthesis pass · forward-looking unresolved questions
  • The structural basis of the CCDC39–CCDC40 molecular ruler, the mechanism by which it templates 96 nm repeat periodicity, and the direct versus indirect nature of its interaction with specific IDA heavy chains remain unresolved.
  • No high-resolution structure of the CCDC39–CCDC40 complex
  • No in vitro reconstitution of ruler function
  • Mechanism of 96 nm periodicity establishment not defined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0005198 structural molecule activity 2
Localization
GO:0005929 cilium 5
Pathway
R-HSA-1266738 Developmental Biology 2 R-HSA-1852241 Organelle biogenesis and maintenance 2
Partners
CCDC39DNAH1DNAH2DNAH6DNAH7GAS8
Complex memberships
CCDC39–CCDC40 molecular ruler complex

Evidence

Reading pass · 8 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2010 CCDC40 localizes to motile cilia and the apical cytoplasm, and is required for axonemal recruitment of CCDC39; loss of CCDC40 results in misplacement of the central pair of microtubules and defective assembly of inner dynein arms (IDAs) and dynein regulatory complexes in human respiratory cilia. Immunofluorescence localization, genetic loss-of-function in mouse, zebrafish, and human patients with ultrastructural analysis by TEM Nature genetics High 21131974
2010 CCDC40 is required for correct left-right axis patterning; Ccdc40 mutant mice and zebrafish display cilia with reduced ranges of motility, leading to randomized laterality. Genetic loss-of-function (mouse and zebrafish mutants), high-speed video microscopy of cilia motility Nature genetics High 21131974
2017 In Ccdc40 mutant mouse embryos, defective motile cilia impair fluid flow across the node, causing delayed and randomized asymmetric Cerl2 and Nodal expression, which underlies left isomerism; reducing Nodal gene dosage in Ccdc40 mutants shifts the phenotype to predominant right isomerism, placing CCDC40 upstream of the Nodal signaling cascade. Genetic epistasis (double mutant Ccdc40lnks/lnks; NodalLacZ/+), in situ hybridization for Lefty1, Lefty2, Nodal, Cerl2 PloS one Medium 28182636
2013 All disease-causing mutations in CCDC40 identified across 54 PCD families are nonsense, splice, or frameshift variants predicting complete protein loss, indicating that CCDC40 function is fully required for normal IDA assembly and axonemal organization; a major hotspot mutation CCDC40 c.248delC was identified. Sequencing of CCDC39 and CCDC40 in 54 families, co-segregation analysis, protein truncation prediction Human mutation Medium 23255504
2024 CCDC39 and CCDC40 form a molecular ruler complex maintaining the 96 nm axonemal repeat; loss of either protein causes absence of IDA heavy chains DNAH1, DNAH6, and DNAH7 (centrin2-containing IDAs) within respiratory ciliary axonemes, in addition to previously known loss of GAS8, CCDC39, and DNALI1 assembly. Immunofluorescence analysis of respiratory cilia from 51 individuals with disease-causing variants in CCDC39/CCDC40; next-generation sequencing Cells Medium 39056782
2023 CCDC39 protein is absent or severely reduced in sperm flagella of CCDC40-mutant individuals, providing direct evidence of a CCDC39–CCDC40 interaction in flagella; loss of CCDC40 also causes multiple morphological abnormalities of sperm flagella (MMAF) and male infertility. Immunofluorescence microscopy on sperm flagella from CCDC40-mutant patients; transmission electron microscopy; semen analysis Frontiers in genetics Medium 36873931
2022 Loss of CCDC40 function (compound heterozygous variants) results in loss of inner dynein arm protein DNAH2 in both respiratory cilia and sperm flagella, and produces a rigid, stiff ciliary beating pattern detectable by high-speed video microscopy. High-speed video microscopy analysis, immunofluorescence for DNAH2 in cilia and sperm, scanning electron microscopy Pharmacogenomics and personalized medicine Low 35449766
2022 A CCDC40 splice-site variant (c.2236-2delA) leads to formation of a truncated protein via splicing disruption, as demonstrated by a minigene splicing assay. Minigene assay using pcDNA3.1(+) plasmid, Sanger sequencing Frontiers in pediatrics Low 36245716

Source papers

Stage 0 corpus · 17 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2010 The coiled-coil domain containing protein CCDC40 is essential for motile cilia function and left-right axis formation. Nature genetics 258 21131974
2013 Mutations in CCDC39 and CCDC40 are the major cause of primary ciliary dyskinesia with axonemal disorganization and absent inner dynein arms. Human mutation 158 23255504
2012 Delineation of CCDC39/CCDC40 mutation spectrum and associated phenotypes in primary ciliary dyskinesia. Journal of medical genetics 78 22693285
2023 Pathogenic gene variants in CCDC39, CCDC40, RSPH1, RSPH9, HYDIN, and SPEF2 cause defects of sperm flagella composition and male infertility. Frontiers in genetics 24 36873931
2015 CCDC40 mutation as a cause of primary ciliary dyskinesia: a case report and review of literature. The clinical respiratory journal 22 25619595
2022 Novel Compound Heterozygous Variants in CCDC40 Associated with Primary Ciliary Dyskinesia and Multiple Morphological Abnormalities of the Sperm Flagella. Pharmacogenomics and personalized medicine 12 35449766
2021 CCDC40 mutation as a cause of infertility in a Chinese family with primary ciliary dyskinesia. Medicine 11 34941110
2024 Primary Ciliary Dyskinesia Associated Disease-Causing Variants in CCDC39 and CCDC40 Cause Axonemal Absence of Inner Dynein Arm Heavy Chains DNAH1, DNAH6, and DNAH7. Cells 8 39056782
2018 Generation of the induced pluripotent stem cell line UHOMi001-A from a patient with mutations in CCDC40 gene causing Primary Ciliary Dyskinesia (PCD). Stem cell research 7 30296669
2017 Mechanism for generation of left isomerism in Ccdc40 mutant embryos. PloS one 6 28182636
2013 Identification of the first deletion-insertion involving the complete structure of GAA gene and part of CCDC40 gene mediated by an Alu element. Gene 6 23402890
2018 Severe disease due to CCDC40 gene variants and the perils of late diagnosis in primary ciliary dyskinesia. BMJ case reports 5 30209139
2022 Pulmonary Hypertension in a Patient With Kartagener's Syndrome and a Novel Homozygous Nonsense Mutation in CCDC40 Gene: A Case Report. Frontiers in medicine 4 35433722
2024 Identification of a Homozygous Mutation of CCDC40 in a Chinese Infertile Man with MMAF and PCD-like Phenotypes. Genetic testing and molecular biomarkers 3 38837151
2022 Novel compound heterozygous CCDC40 mutations in a familial case of primary ciliary dyskinesia. Frontiers in pediatrics 3 36245716
2025 Genomic Complexity of ccdc40 in Xenopus : Implications for CRISPR Targeting and Disease Modeling. microPublication biology 0 40415903
2024 Novel rare variation of CCDC40 plays a role in the development of idiopathic scoliosis possibly via dysfunction of cilia motility. The spine journal : official journal of the North American Spine Society 0 39662682