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CCDC39
coiled-coil domain 39 molecular ruler complex subunit
CCDC39 is located on the long (q) arm of chromosome 3, at band 3q26.33. Arm ratio per GRCh38 - banding schematic.
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Overview
CCDC39 (coiled-coil domain 39 molecular ruler complex subunit) is located on chromosome 3 and encodes a 941-amino-acid protein essential for the proper assembly of motile cilia. The protein belongs to a family characterised by extended coiled-coil domains that enable protein-protein interactions within the ciliary axoneme, the structural core of cilia.
Motile cilia project from the surface of cells lining the airways, brain ventricles, and reproductive tract. Their rhythmic beating clears mucus and debris from the lungs, circulates cerebrospinal fluid, and establishes left-right body asymmetry during development. CCDC39 contributes to the structural scaffold that organises inner dynein arms, molecular motors responsible for generating ciliary movement. Loss of CCDC39 function results in abnormal ciliary architecture and impaired or absent beating, affecting multiple organ systems.
What the gene does
The CCDC39 protein functions as a component of the axonemal ruler complex, a molecular assembly that controls the length and spacing of inner dynein arm structures along the ciliary axoneme. This ruler complex ensures that dynein motor proteins are positioned at precise intervals, enabling coordinated ciliary beating.
Within the axoneme, CCDC39 localises to the doublet microtubules that form the cylindrical framework of each cilium. The protein's extended coiled-coil architecture allows it to span substantial distances along the microtubule surface, acting as a measuring device during cilia assembly. This spatial organisation is critical for the attachment of regulatory and motor complexes that drive ciliary movement.
When CCDC39 is absent or non-functional, the axoneme exhibits disorganised inner dynein arms and often displays structural defects visible by electron microscopy. The resulting cilia may be immotile or beat with severely reduced amplitude and frequency, impairing mucociliary clearance and other ciliary functions throughout the body.
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Chromosome location
CCDC39 is located on the long arm of chromosome 3 at position 3q26.33. The gene spans a genomic region that includes multiple exons encoding the full-length protein. This chromosomal region contains several other genes involved in diverse cellular processes, though CCDC39 itself shows highly specific expression in ciliated tissues.
Protein structure
The CCDC39 protein comprises 941 amino acids with a domain organisation dominated by coiled-coil structures. Four distinct coiled-coil regions span amino acids 16-122, 164-273, 306-605, and 665-825. These coiled-coil domains mediate interactions with other ruler complex components and axonemal proteins, forming stable multi-protein assemblies within the ciliary structure.
The C-terminal region (amino acids 868-941) is disordered, lacking a fixed three-dimensional structure. Disordered regions often serve regulatory or flexible linker functions, potentially enabling dynamic interactions during ciliary assembly or responding to cellular signals that modulate cilia behaviour.
Key variants
Pathogenic variants in CCDC39 are typically loss-of-function changes, including nonsense mutations, frameshift deletions or insertions, and splice-site alterations that disrupt normal protein production. Missense variants affecting the coiled-coil domains can also impair protein stability or interaction with binding partners. Because CCDC39-related disease follows an autosomal recessive inheritance pattern, affected individuals carry pathogenic variants in both gene copies.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.1018_1019insG | p.His340fs | Pathogenic/Likely pathogenic | ★★☆☆ | Primary ciliary dyskinesia 14 |
c.1356C>A | p.Tyr452Ter | Pathogenic | ★★☆☆ | Respiratory ciliopathies including non-CF bronchiectasis |
c.1417_1420del | p.Asn473fs | Pathogenic | ★★☆☆ | Primary ciliary dyskinesia |
c.1540_1544del | p.Phe514fs | Pathogenic/Likely pathogenic | ★★☆☆ | Primary ciliary dyskinesia |
c.1625_1632del | p.Arg542fs | Pathogenic | ★★☆☆ | Primary ciliary dyskinesia |
c.1876_1877dup | p.Glu627fs | Pathogenic/Likely pathogenic | ★★☆☆ | Primary ciliary dyskinesia |
c.210+2T>C | - | Pathogenic | ★★☆☆ | Primary ciliary dyskinesia 14 |
c.216_217del | p.Cys73fs | Pathogenic | ★★☆☆ | Primary ciliary dyskinesia |
c.74del | p.Lys25fs | Pathogenic/Likely pathogenic | ★★☆☆ | Primary ciliary dyskinesia |
c.931-1G>T | - | Pathogenic | ★★☆☆ | Primary ciliary dyskinesia |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Biallelic pathogenic variants in CCDC39 cause primary ciliary dyskinesia, a genetically heterogeneous disorder characterised by chronic respiratory infections, persistent wet cough, and bronchiectasis due to impaired mucociliary clearance. Many affected individuals also experience situs abnormalities (randomised or reversed organ positioning) because motile cilia are essential for establishing left-right asymmetry during embryonic development. Male infertility is common due to abnormal sperm flagella, which share structural features with motile cilia. Chronic middle-ear infections and hearing loss may occur. The clinical severity and specific features vary among individuals, even within families sharing the same variants.
- Primary ciliary dyskinesia Dedicated page coming soon
Inheritance pattern
Conditions caused by pathogenic CCDC39 variants typically follow autosomal recessive inheritance.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
UK clinical status
CCDC39 is included on multiple NHS Genomic Medicine Service gene panels relevant to respiratory and developmental conditions. It appears on the Primary ciliary disorders panel, the Respiratory ciliopathies including non-CF bronchiectasis panel (R189), and the Laterality disorders and isomerism panel (R139), all with green classifications indicating strong evidence for clinical validity. The gene is also listed on the Fetal anomalies panel (green, R21) and the DDG2P resource, reflecting its role in developmental phenotypes detectable prenatally or in early childhood.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the inheritance pattern for CCDC39-related conditions?
CCDC39-related primary ciliary dyskinesia follows an autosomal recessive inheritance pattern. An individual must inherit a pathogenic variant from both parents to develop the condition. Carriers, who have one pathogenic variant and one typical copy, generally do not show symptoms.
How does CCDC39 affect respiratory health?
CCDC39 is essential for building functional motile cilia in the airways. When the protein is absent or defective, cilia cannot beat effectively to clear mucus and trapped bacteria, leading to chronic respiratory infections, persistent cough, and progressive lung damage including bronchiectasis.
Are all individuals with CCDC39 variants affected in the same way?
No. While chronic respiratory symptoms are nearly universal, the presence and severity of situs abnormalities, hearing loss, and fertility issues vary among affected individuals. Environmental factors, genetic background, and specific variants all influence the clinical presentation.