Collagen, type VII, alpha 1

Structure

Type VII collagen is composed of three main domains in the following order: a non-collagenous domain, abbreviated NC-1; a collagenous domain; and a second non-collagenous domain, NC-2. The NC-1 domain has a cartilage matrix protein (CMP), nine fibronectin III (FNIII)-like subdomains, and a von Willebrand Factor A-like subdomain (VWFA1); a notable segment in the NC-2 domain is analogous to a Kunitz protease inhibitor molecule.

Function

This gene encodes the alpha chain of type VII collagen. The type VII collagen fibril, composed of three identical alpha collagen chains, is restricted to the basement zone beneath stratified squamous epithelia. It functions as an anchoring fibril between the external epithelia and the underlying stroma. Mutations in this gene are associated with all forms of dystrophic epidermolysis bullosa. In the absence of mutations, however, an autoimmune response against type VII collagen can result in an acquired form of this disease called epidermolysis bullosa acquisita.

Type VII collagen is also found in the retina; its function in this organ is unknown.

COL7A1 is located on the short arm of human chromosome 3, in the chromosomal region denoted 3p21.31. The gene is approximately 31,000 base pairs in size and is remarkable for the extreme fragmentation of its coding sequence into 118 exons. COL7A1 is transcribed into an mRNA of 9,287 bases. In the skin, the type VII collagen protein is synthesized by keratinocytes and dermal fibroblasts.

The symbol for the orthologous gene in the mouse is Col7a1.

Clinical significance

The inherited disease, dystrophic epidermolysis bullosa, is caused by recessive or dominant mutations in COL7A1. Recessive dystrophic epidermolysis bullosa, the most severe type of epidermolysis bullosa, has two subtypes, generalized intermediate and generalized severe, which have been linked to different mutations in the COL7A1 gene. Recessive dystrophic epidermolysis bullosa, generalized intermediate, is caused primarily by missense, in-frame, and splice-site mutations on one allele. The generalized severe subtype may be caused by premature termination codons in both alleles. These mutations cause little to no expression of collagen VII, which manifests primarily as generalized blistering in the skin and mucosal membranes. This blistering may also lead to several other complications, such as eye abrasions, esophageal stricture, deformity of the hands and feet, and squamous cell carcinoma, among others.

Dominant dystrophic epidermolysis bullosa is most often caused by missense mutations, especially glycine substitutions in the collagenous domain. The symptoms of dominant dystrophic epidermolysis bullosa are less severe than those of the recessive types, with mild blistering and loss of nails.

Epidermolysis bullosa acquisita involves an autoimmune reaction to this form of collagen.

Beremagene geperpavec (Vyjuvek), is a gene therapy indicated for the treatment of wounds for people with dystrophic epidermolysis bullosa with mutation(s) in the collagen type VII alpha 1 chain (COL7A1) gene.

Interactions

Collagen, type VII, alpha 1 forms a complex network with several other proteins in the basement membrane. It has been shown to interact with laminin 5 and fibronectin, as well as collagen IV, by binding these proteins in the NC-1 domain. The stability of the basement membrane and dermal-epidermal junction is thought to be due to these interactions.

References

References

1. (August 1991). "Human type VII collagen: cDNA cloning and chromosomal mapping of the gene". Proceedings of the National Academy of Sciences of the United States of America.
2. (May 2018). "Epidermal aspects of type VII collagen: Implications for dystrophic epidermolysis bullosa and epidermolysis bullosa acquisita". The Journal of Dermatology.
3. (May 2015). "Dystrophic epidermolysis bullosa: a review". Clinical, Cosmetic and Investigational Dermatology.
4. (October 2018). "Epidermolysis bullosa: Molecular pathology of connective tissue components in the cutaneous basement membrane zone". Matrix Biology.
5. (September 2020). "Epidermolysis bullosa". Nature Reviews. Disease Primers.
6. "COL7A1 collagen, type VII, alpha 1 (epidermolysis bullosa, dystrophic, dominant and recessive)". [[National Center for Biotechnology Information.
7. (September 2008). "Collagen distribution in the human vitreoretinal interface". Investigative Ophthalmology & Visual Science.
8. (May 1994). "Structural organization of the human type VII collagen gene (COL7A1), composed of more exons than any previously characterized gene". Genomics.
9. (2004-05-17). "COL7A1 genomic sequence".
10. (1995-09-15). "COL7A1 mRNA sequence".
11. {{OMIM. 120120. COL7A1
12. (July 2008). "Mutation analysis and characterization of COL7A1 mutations in dystrophic epidermolysis bullosa". Experimental Dermatology.
13. (October 2020). "Consensus reclassification of inherited epidermolysis bullosa and other disorders with skin fragility". The British Journal of Dermatology.
14. (2006). "Essentials of clinical immunology". Wiley-Blackwell.
15. (19 May 2023). "FDA Approves First Topical Gene Therapy for Treatment of Wounds in Patients with Dystrophic Epidermolysis Bullosa".
16. (19 May 2023). "Vyjuvek".
17. (August 1997). "Laminin 5 binds the NC-1 domain of type VII collagen". The Journal of Cell Biology.
18. (November 1994). "Type VII collagen specifically binds fibronectin via a unique subdomain within the collagenous triple helix". The Journal of Investigative Dermatology.
19. (June 1997). "Interactions of the amino-terminal noncollagenous (NC1) domain of type VII collagen with extracellular matrix components. A potential role in epidermal-dermal adherence in human skin". The Journal of Biological Chemistry.
20. (September 2019). "Basement membrane collagens and disease mechanisms". Essays in Biochemistry.