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CCDC8
coiled-coil domain containing 8 subunit of 3M complex
CCDC8 is located on the long (q) arm of chromosome 19, at band 19q13.32. Arm ratio per GRCh38 - banding schematic.
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Overview
CCDC8 encodes coiled-coil domain containing 8, a subunit of the 3M complex that plays an essential role in regulating skeletal growth. This protein works alongside two other components, CUL7 and OBSL1, to form a functional complex that influences how cells respond to growth signals during development. The gene is located on chromosome 19 and encodes a 538-amino acid protein that contains specialised structural elements enabling it to interact with partner proteins.
Pathogenic changes in CCDC8 follow an autosomal recessive inheritance pattern, meaning affected individuals carry two altered copies of the gene. Loss of CCDC8 function disrupts the 3M complex, impairing growth regulation pathways and resulting in the characteristic features of 3-M syndrome. The gene is included in multiple NHS clinical panels related to growth disorders and skeletal development.
What the gene does
The CCDC8 protein functions as a structural and regulatory component within the 3M complex, an assembly that modulates cellular growth signalling pathways. This complex appears to influence how cells interpret signals from insulin-like growth factors and other developmental regulators, though the precise molecular mechanisms remain an active area of investigation. CCDC8 acts as a scaffold, bringing together the CUL7 ubiquitin ligase and OBSL1 proteins to form a functional unit.
Through its coiled-coil regions, CCDC8 mediates protein-protein interactions essential for complex stability and function. The protein contains a PxLPxI/L motif near its C-terminus that facilitates binding to ANKRA2, a factor involved in coordinating cellular responses to growth signals. By maintaining the structural integrity of the 3M complex, CCDC8 helps ensure proper regulation of pathways controlling skeletal development during foetal growth and early childhood. Disruption of these interactions impairs the cell's ability to coordinate growth programmes, particularly affecting bone and cartilage development.
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Chromosome location
CCDC8 is located on the long arm of chromosome 19 at position 19q13.32. This chromosomal region contains numerous genes involved in diverse cellular processes, and the specific location places CCDC8 in a gene-dense area near the telomere. The gene spans multiple exons that are transcribed and processed to produce the mature messenger RNA template for protein synthesis.
Protein structure
The CCDC8 protein comprises 538 amino acids organised into distinct functional regions. The structure includes two extended disordered regions spanning amino acids 58-128 and 213-473, which provide flexibility for protein-protein interactions and may undergo conformational changes upon binding to partner molecules. Two coiled-coil domains are present: one located at amino acids 349-366 and another near the C-terminus at amino acids 514-535. These coiled-coil structures enable CCDC8 to interact with other 3M complex components and form stable multi-protein assemblies. A PxLPxI/L motif at amino acids 500-506 mediates specific interaction with ANKRA2, contributing to the regulatory functions of the complex. The extensive disordered regions and strategically positioned coiled-coil domains together allow CCDC8 to serve as a flexible scaffold within the 3M complex.
Key variants
Pathogenic variants in CCDC8 typically result in loss of protein function, either through premature termination of translation, disruption of critical structural domains, or altered protein stability. Because 3-M syndrome follows autosomal recessive inheritance, affected individuals carry pathogenic variants on both gene copies. The variant spectrum includes nonsense mutations, frameshift deletions or insertions, and splice-site changes that prevent normal protein production.
Sample of pathogenic variants
2 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.980del | p.Gln327fs | Pathogenic/Likely pathogenic | ★★☆☆ | 3M syndrome 3 |
c.84dup | p.Lys29Ter | Pathogenic | - | 3M syndrome 3 |
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
Pathogenic variants in CCDC8 cause 3-M syndrome, a rare inherited disorder characterised by severe prenatal and postnatal growth restriction. Affected individuals typically present with distinctive facial features including a triangular face, prominent forehead, and fleshy nose, alongside pronounced short stature that becomes evident before birth. The condition affects skeletal development systemically, with individuals achieving adult heights well below typical population ranges. Intelligence is generally normal in 3-M syndrome, distinguishing it from some other growth disorders. The syndrome is named after the initials of the three researchers who first described the condition in detail.
Inheritance pattern
Conditions caused by pathogenic CCDC8 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
CCDC8 is included on several NHS Genomic Medicine Service gene panels, reflecting its clinical significance in diagnosing growth and skeletal disorders. The gene appears with green classification (indicating high evidence) on the DDG2P panel, the Fetal anomalies panel (R21), the IUGR and IGF abnormalities panel, the Monogenic short stature panel (R453), and the Skeletal dysplasia panel (R104). This broad panel representation reflects the gene's importance in differential diagnosis of severe short stature and skeletal abnormalities identified through prenatal screening or postnatal clinical evaluation.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the 3M complex and why is it important?
The 3M complex is a cellular assembly comprising three proteins - CCDC8, CUL7, and OBSL1 - that work together to regulate skeletal growth during development. This complex modulates how cells respond to growth signals, and disruption of any component can impair normal bone and cartilage development, resulting in severe short stature.
How is 3-M syndrome inherited?
3-M syndrome follows autosomal recessive inheritance, meaning an affected individual must inherit a pathogenic variant from both parents. Parents who each carry one altered copy typically show no symptoms themselves but have a 25% chance with each pregnancy of having an affected child.
Can genetic testing identify CCDC8 variants before birth?
Yes, prenatal genetic testing can identify CCDC8 variants, particularly when severe growth restriction is detected on ultrasound or when parents are known carriers. Testing is typically offered through NHS genetics services when clinical features raise suspicion of an inherited growth disorder.