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FOXC2
forkhead box C2
The FOXC2 gene provides instructions for a protein critical in the formation of various organs and tissues during development, particularly impacting lymphatic and vascular systems. FOXC2, or forkhead box C2, codes for a transcription factor essential for embryonic development.
FOXC2 is located on the long (q) arm of chromosome 16, at band 16q24.1. Arm ratio per GRCh38 - banding schematic.
Explore chromosome 16 in the library →Overview
The FOXC2 gene produces a protein that acts as a transcription factor, meaning it helps regulate the activity of other genes. This regulatory role is vital during foetal development for the proper formation of numerous organs and tissues. Research indicates its involvement in the development of the lymphatic vessels, veins, lungs, eyes, kidneys, urinary tract, and the cardiovascular system.
What the gene does
The protein encoded by the FOXC2 gene is a transcription factor, which binds to specific regions of DNA to control the expression of other genes. This function is fundamental to various developmental processes before birth. For example, it plays a key part in the formation of the lymphatic system, which transports immune cells and fluids, and in the development of veins. Its activity influences the proper development of multiple organ systems, including the lungs, eyes, kidneys, and the cardiovascular system.
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Chromosome location
The FOXC2 gene is located on chromosome 16 at position 16q24.1. This specific genomic address helps pinpoint the gene's position within the human genome.
Protein structure
The FOXC2 protein is 501 amino acids long and contains several distinct regions. A key functional area is the Fork-head (DNA binding) domain, located between amino acids 71 and 162, which enables the protein to bind to DNA. Additionally, there are three Disordered (Region) segments found at amino acids 167-208, 232-268, and 383-420, which may contribute to protein flexibility and interactions.
Key variants
Variants in the FOXC2 gene can lead to changes in the structure or function of the encoded protein. These genetic alterations can impact the protein's ability to bind DNA effectively or may result in a prematurely truncated protein. Such changes can disrupt developmental processes where the FOXC2 protein is essential.
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.297C>G | p.Tyr99Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Distichiasis-lymphedema syndrome |
c.298C>T | p.Gln100Ter | Pathogenic | ★★☆☆ | Distichiasis-lymphedema syndrome |
c.361C>T | p.Arg121Cys | Pathogenic/Likely pathogenic | ★★☆☆ | Distichiasis-lymphedema syndrome |
c.595dup | p.His199fs | Pathogenic | ★★☆☆ | Distichiasis-lymphedema syndrome |
c.914_921del | p.Tyr305fs | Pathogenic | ★★☆☆ | FOXC2-related disorders |
c.930_936dup | p.Tyr313fs | Pathogenic | ★★☆☆ | not provided |
c.130del | p.His44fs | Pathogenic | ★☆☆☆ | not provided |
c.227_230dup | p.Tyr77Ter | Pathogenic | ★☆☆☆ | not provided |
c.311_315del | p.Asp104fs | Pathogenic | ★☆☆☆ | not provided |
c.362G>A | p.Arg121His | Pathogenic | ★☆☆☆ | Distichiasis-lymphedema syndrome |
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 FOXC2 gene are associated with inherited conditions, most notably lymphoedema-distichiasis. This condition follows an autosomal dominant inheritance pattern. These variants can impair the FOXC2 protein's normal function, leading to developmental abnormalities, particularly affecting the lymphatic system.
Inheritance pattern
Conditions caused by pathogenic FOXC2 variants typically follow autosomal dominant inheritance.
Each child has a 50% chance of inheriting the pathogenic variant, regardless of sex.
UK clinical status
In the UK, the FOXC2 gene is included in several NHS National Genomic Test Directory panels, indicating its clinical significance. It is part of the panels for Clefting, DDG2P, Foetal anomalies (R21), Foetal hydrops, Primary lymphoedema (R136), and Vascular skin disorders (R326), all listed as 'green' status on PanelApp, signifying their clinical utility.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What does the FOXC2 gene do?
The FOXC2 gene provides instructions for making a transcription factor protein that helps regulate the activity of other genes. This protein is crucial for the proper development of various organs and tissues before birth, especially the lymphatic and vascular systems.
What condition is associated with the FOXC2 gene?
Variants in the FOXC2 gene are primarily associated with lymphoedema-distichiasis. This is an inherited condition that mainly affects the lymphatic system, often leading to swelling caused by fluid accumulation, and can also involve extra eyelashes.
How is lymphoedema-distichiasis inherited?
Lymphoedema-distichiasis, linked to FOXC2 gene variants, is inherited in an autosomal dominant pattern. This means that an individual only needs one copy of the altered gene in each cell to develop the condition.
References
- Mellor RH, Brice G, Stanton AW. Mutations in FOXC2 are strongly associated with primary valve failure in veins of the lower limb. Circulation. 2007. PMID: 17372167
- Berry FB, Tamimi Y, Carle MV. The establishment of a predictive mutational model of the forkhead domain through the analyses of FOXC2 missense mutations identified in patients with hereditary lymphedema with distichiasis. Human molecular genetics. 2005. PMID: 16081467
- Brice G, Mansour S, Bell R. Analysis of the phenotypic abnormalities in lymphoedema-distichiasis syndrome in 74 patients with FOXC2 mutations or linkage to 16q24. Journal of medical genetics. 2002. PMID: 12114478
- Traboulsi EI, Al-Khayer K, Matsumoto M. Lymphedema-distichiasis syndrome and FOXC2 gene mutation. American journal of ophthalmology. 2002. PMID: 12383817
- Erickson RP, Dagenais SL, Caulder MS. Clinical heterogeneity in lymphoedema-distichiasis with FOXC2 truncating mutations. Journal of medical genetics. 2001. PMID: 11694548
- Fang J, Dagenais SL, Erickson RP. Mutations in FOXC2 (MFH-1), a forkhead family transcription factor, are responsible for the hereditary lymphedema-distichiasis syndrome. American journal of human genetics. 2000. PMID: 11078474