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COL7A1
collagen type VII alpha 1 chain
The COL7A1 gene encodes the alpha 1 chain of Type VII collagen, a crucial protein for the structural integrity and stability of the skin. COL7A1 provides the blueprint for a protein integral to Type VII collagen, which forms anchoring fibrils that bind the layers of the skin together.
COL7A1 is located on the short (p) arm of chromosome 3, at band 3p21.31. Arm ratio per GRCh38 - banding schematic.
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Overview
The COL7A1 gene is responsible for producing a component of Type VII collagen, a protein vital for strengthening and stabilising connective tissues throughout the body, particularly the skin. Type VII collagen is the primary constituent of anchoring fibrils, which are specialised structures that connect the epidermis (outer skin layer) to the dermis (inner skin layer). This connection is essential for maintaining skin integrity and preventing blistering.
Mutations in the COL7A1 gene can impair the production or function of Type VII collagen, leading to fragile skin that is highly susceptible to blistering and trauma. This gene is associated with inherited conditions primarily affecting skin structure.
What the gene does
The COL7A1 gene provides instructions for the pro-alpha1(VII) chain, which assembles into Type VII collagen. This collagen is a key structural protein that forms anchoring fibrils within the epidermal basement membrane zone, the area between the epidermis and dermis. These fibrils act like anchors, securing the two skin layers together and providing mechanical strength.
Initially, three pro-alpha1(VII) chains twist to form a triple-stranded molecule called procollagen. After secretion from cells, enzymes process these molecules by cleaving extra protein segments. The processed molecules then assemble into long, thin bundles of mature Type VII collagen. This mature collagen is critical for reinforcing the skin's stability and preventing its layers from separating under stress.
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Chromosome location
The COL7A1 gene is situated on chromosome 3, specifically located at position 3p21.31. This genomic location refers to the short (p) arm of chromosome 3, within band 21.31.
Protein structure
The COL7A1 gene encodes the collagen type VII alpha 1 chain, a protein approximately 2944 amino acids long. Key regions and domains include a large Nonhelical region (NC1) spanning amino acids 17-1253. Within this region are two VWFA domains, VWFA 1 (amino acids 38-211) and VWFA 2 (amino acids 1054-1229). Multiple Fibronectin type-III domains are also present: Fibronectin type-III 1 (amino acids 234-329), Fibronectin type-III 2 (amino acids 330-416), Fibronectin type-III 3 (amino acids 417-507), Fibronectin type-III 4 (amino acids 510-597), Fibronectin type-III 5 (amino acids 600-687), Fibronectin type-III 6 (amino acids 688-775), Fibronectin type-III 7 (amino acids 778-866), Fibronectin type-III 8 (amino acids 869-957), and Fibronectin type-III 9 (amino acids 958-1051). A Cell attachment site motif is found at amino acids 1170-1172. Additionally, two Disordered regions are identified at amino acids 632-651 and 1239-1941.
Key variants
Variants within the COL7A1 gene can influence the structure, function, or production of Type VII collagen. Over 700 distinct variants have been identified that are associated with inherited conditions. These genetic changes can range from single-nucleotide alterations to larger deletions or insertions, and they can lead to an abnormal or absent Type VII collagen protein, impacting skin integrity.
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.1294del | p.Leu432fs | Pathogenic/Likely pathogenic | ★★☆☆ | Nonsyndromic congenital nail disorder 8 |
c.266+1G>A | - | Pathogenic/Likely pathogenic | ★★☆☆ | Nonsyndromic congenital nail disorder 8 |
c.2858_2859del | - | Pathogenic | ★★☆☆ | Recessive dystrophic epidermolysis bullosa |
c.4439G>A | p.Gly1480Asp | Pathogenic/Likely pathogenic | ★★☆☆ | Recessive dystrophic epidermolysis bullosa |
c.4943del | p.Pro1648fs | Pathogenic/Likely pathogenic | ★★☆☆ | Epidermolysis bullosa dystrophica |
c.5774G>A | p.Gly1925Asp | Pathogenic/Likely pathogenic | ★★☆☆ | COL7A1-related disorder |
c.6989G>A | p.Gly2330Asp | Pathogenic/Likely pathogenic | ★★☆☆ | Nonsyndromic congenital nail disorder 8 |
c.7505G>A | p.Gly2502Glu | Pathogenic/Likely pathogenic | ★★☆☆ | Generalized dominant dystrophic epidermolysis bullosa |
c.8093del | p.Gly2698fs | Pathogenic | ★★☆☆ | Nonsyndromic congenital nail disorder 8 |
c.8219_8226+1delinsAC | - | Pathogenic | ★★☆☆ | Epidermolysis bullosa dystrophica |
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 COL7A1 gene are primarily associated with Epidermolysis bullosa (dystrophic, recessive), a group of inherited skin disorders characterised by extremely fragile skin that blisters easily. These variants can also cause a rare condition known as epidermolysis bullosa with congenital localised absence of skin (Bart syndrome), where individuals are born with patches of missing skin, typically on the legs, in addition to general skin fragility.
Inheritance pattern
Conditions caused by pathogenic COL7A1 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 COL7A1 gene is recognised in the UK's National Genomic Test Directory. It is listed on the green (approved) panels for 'Epidermolysis bullosa' and 'Epidermolysis bullosa and congenital skin fragility' (R164). Additionally, it is found on the 'Primary immunodeficiency or monogenic inflammatory bowel disease' (R15) panel.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the main function of the COL7A1 gene?
The COL7A1 gene provides instructions for creating a component of Type VII collagen, which forms anchoring fibrils. These fibrils are crucial for connecting the outer and inner layers of the skin, providing stability and strength.
What conditions are associated with COL7A1 gene variants?
Variants in the COL7A1 gene are primarily associated with Dystrophic Epidermolysis Bullosa, a condition causing very fragile skin and easy blistering. They can also lead to epidermolysis bullosa with congenital localised absence of skin, characterised by patches of missing skin at birth.
How does Type VII collagen contribute to skin health?
Type VII collagen is the main component of anchoring fibrils located in the epidermal basement membrane zone. These fibrils act to firmly attach the epidermis to the dermis, preventing skin layers from separating and forming blisters, thereby maintaining overall skin integrity.
References
- Han YM, Lee N, Byun SY. Bart's Syndrome with Novel Frameshift Mutations in the COL7A1 Gene. Fetal and pediatric pathology. 2019. PMID: 30523708
- Chen Z, Bu W, Feng S. Bart's syndrome in a family affected three consecutive generations with mutation c.6007G>A in COL7A1. The Journal of dermatology. 2018. PMID: 29722429
- Almaani N, Liu L, Dopping-Hepenstal PJ. Identical glycine substitution mutations in type VII collagen may underlie both dominant and recessive forms of dystrophic epidermolysis bullosa. Acta dermato-venereologica. 2011. PMID: 21448560
- Varki R, Sadowski S, Uitto J. Epidermolysis bullosa. II. Type VII collagen mutations and phenotype-genotype correlations in the dystrophic subtypes. Journal of medical genetics. 2007. PMID: 16971478
- Dang N, Klingberg S, Marr P. Review of collagen VII sequence variants found in Australasian patients with dystrophic epidermolysis bullosa reveals nine novel COL7A1 variants. Journal of dermatological science. 2007. PMID: 17425959
- Pourreyron C, Cox G, Mao X. Patients with recessive dystrophic epidermolysis bullosa develop squamous-cell carcinoma regardless of type VII collagen expression. The Journal of investigative dermatology. 2007. PMID: 17495952
- Kern JS, Kohlhase J, Bruckner-Tuderman L. Expanding the COL7A1 mutation database: novel and recurrent mutations and unusual genotype-phenotype constellations in 41 patients with dystrophic epidermolysis bullosa. The Journal of investigative dermatology. 2006. PMID: 16484981
- Ortiz-Urda S, Garcia J, Green CL. Type VII collagen is required for Ras-driven human epidermal tumorigenesis. Science (New York, N.Y.). 2005. PMID: 15774758
- Sawamura D, Goto M, Yasukawa K. Genetic studies of 20 Japanese families of dystrophic epidermolysis bullosa. Journal of human genetics. 2005. PMID: 16189623
- Gardella R, Castiglia D, Posteraro P. Genotype-phenotype correlation in italian patients with dystrophic epidermolysis bullosa. The Journal of investigative dermatology. 2002. PMID: 12485454
- Bruckner-Tuderman L, Höpfner B, Hammami-Hauasli N. Biology of anchoring fibrils: lessons from dystrophic epidermolysis bullosa. Matrix biology : journal of the International Society for Matrix Biology. 1999. PMID: 10367730
- Järvikallio A, Pulkkinen L, Uitto J. Molecular basis of dystrophic epidermolysis bullosa: mutations in the type VII collagen gene (COL7A1). Human mutation. 1997. PMID: 9375848
- Adam MP, Bick S, Mirzaa GM. Dystrophic Epidermolysis Bullosa. 1993. PMID: 20301481