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CCBE1
collagen and calcium binding EGF domains 1
The CCBE1 gene provides instructions for a protein crucial in the development and maintenance of the lymphatic system, a vital part of the body's immune and fluid balance systems. CCBE1 encodes a protein found in the extracellular matrix, which is involved in guiding the formation of lymphatic vessels.
CCBE1 is located on the long (q) arm of chromosome 18, at band 18q21.32. Arm ratio per GRCh38 - banding schematic.
Explore chromosome 18 in the library →Overview
The CCBE1 gene, or collagen and calcium binding EGF domains 1, is essential for the proper formation and function of the lymphatic system. This system is a network of vessels and tissues that transport lymph-a fluid containing white blood cells, nutrients, and proteins-throughout the body, playing a key role in immunity and fluid homeostasis.
The protein produced from the CCBE1 gene is located within the extracellular matrix, which is the supportive scaffold between cells. Its involvement in guiding the maturation and movement of cells that form lymphatic vessels highlights its critical developmental role.
What the gene does
The CCBE1 protein contributes to the development of the lymphatic system by supporting the differentiation and migration of lymphangioblasts, which are immature cells that eventually line lymphatic vessels. It collaborates with the ADAMTS3 protein to regulate the activity of vascular endothelial growth factor receptor 3 (VEGFR3).
VEGFR3 is a crucial protein for the formation and maintenance of the lymphatic system. By influencing VEGFR3 activity, the CCBE1 protein helps ensure the correct patterning and function of the lymphatic vessel network, underpinning its importance in preventing lymphatic disorders.
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Chromosome location
The CCBE1 gene is situated on chromosome 18, specifically at position 18q21.32. This indicates its location on the long arm (q) of chromosome 18, within region 21, band 32.
Protein structure
The CCBE1 protein has a length of 406 amino acids and features several distinct domains. It includes an EGF-like; calcium-binding domain spanning amino acids 134-175. The protein also contains two collagen-like domains: Collagen-like 1 from amino acids 245-290 and Collagen-like 2 from amino acids 300-333. Additionally, there are two disordered regions, located at amino acids 244-335 and 360-406, which suggest flexibility in these parts of the protein.
Key variants
Genetic variations within the CCBE1 gene can lead to changes in the protein it produces. Pathogenic variants are those that impair the protein's function, often resulting in conditions related to lymphatic system development. These variants can affect different parts of the gene, leading to varying impacts on protein structure and activity.
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.223T>A | p.Cys75Ser | Pathogenic | ★★☆☆ | not provided |
c.322C>T | p.Arg108Ter | Pathogenic | ★★☆☆ | Hennekam lymphangiectasia-lymphedema syndrome 1 |
c.352C>T | p.Arg118Ter | Pathogenic/Likely pathogenic | ★★☆☆ | CCBE1-related disorder |
c.683_684insT | p.Leu229fs | Pathogenic | ★★☆☆ | CCBE1-related disorder |
g.(?_57363841)_(57364574_?)del | - | Pathogenic | ★☆☆☆ | not provided |
c.262G>T | p.Glu88Ter | Pathogenic | ★☆☆☆ | not provided |
c.294T>A | p.Cys98Ter | Pathogenic | ★☆☆☆ | not provided |
c.37_58del | p.Arg13fs | Pathogenic | ★☆☆☆ | not provided |
c.3G>A | p.Met1Ile | Pathogenic | ★☆☆☆ | not provided |
c.477C>A | p.Cys159Ter | Pathogenic | ★☆☆☆ | not provided |
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 the CCBE1 gene are known to cause Hennekam syndrome, an inherited disorder characterised by abnormalities of the lymphatic system. Individuals with Hennekam syndrome frequently experience dilated lymphatic vessels (lymphangiectasias) and an accumulation of lymph, known as lymphoedema, in various tissues. This condition is inherited in an autosomal recessive pattern.
Inheritance pattern
Conditions caused by pathogenic CCBE1 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
The CCBE1 gene is included in several NHS England Genomic Medicine Service national test panels. These include panels for COVID-19 research, DDG2P, Foetal anomalies (R21), Foetal hydrops, Intellectual disability, Intestinal failure or congenital diarrhoea (R331), Primary immunodeficiency or monogenic inflammatory bowel disease (R15), Primary lymphoedema (R136), and Vascular skin disorders (R326). Its presence on these 'green' panels indicates that there is strong evidence for its association with these conditions.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the primary function of the CCBE1 gene?
The CCBE1 gene produces a protein vital for the proper development and maintenance of the lymphatic system. It helps guide the formation and movement of cells that eventually become lymphatic vessels.
What condition is associated with pathogenic variants in the CCBE1 gene?
Pathogenic variants in the CCBE1 gene are associated with Hennekam syndrome, an inherited disorder characterised by lymphatic system abnormalities such as dilated lymphatic vessels and lymphoedema.
How is Hennekam syndrome inherited?
Hennekam syndrome, caused by pathogenic variants in the CCBE1 gene, is inherited in an autosomal recessive pattern. This means an individual must inherit two copies of the pathogenic variant, one from each parent, to develop the condition.
References
- Bos FL, Caunt M, Peterson-Maduro J. CCBE1 is essential for mammalian lymphatic vascular development and enhances the lymphangiogenic effect of vascular endothelial growth factor-C in vivo. Circulation research. 2011. PMID: 21778431
- Connell F, Kalidas K, Ostergaard P. Linkage and sequence analysis indicate that CCBE1 is mutated in recessively inherited generalised lymphatic dysplasia. Human genetics. 2010. PMID: 19911200
- Alders M, Hogan BM, Gjini E. Mutations in CCBE1 cause generalized lymph vessel dysplasia in humans. Nature genetics. 2009. PMID: 19935664