Collagen, type VII, alpha 1 explained

Collagen alpha-1(VII) chain is a protein that in humans is encoded by the COL7A1 gene.^[1] It is composed of a triple helical, collagenous domain flanked by two non-collagenous domains, and functions as an anchoring fibril between the dermal-epidermal junction in the basement membrane.^[2] Mutations in COL7A1 cause all types of dystrophic epidermolysis bullosa, and the exact mutations vary based on the specific type or subtype.^[3] It has been shown that interactions between the NC-1 domain of collagen VII and several other proteins, including laminin-5 and collagen IV, contribute greatly to the overall stability of the basement membrane.^[4]

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.^[5] 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.^[6]

Type VII collagen is also found in the retina; its function in this organ is unknown.^[7]

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.^{[8] [9]} COL7A1 is transcribed into an mRNA of 9,287 bases.^[10] 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.^[11] 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.^[12] 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.^[13]

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.^{[14] [15]}

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^[16] and fibronectin, as well as collagen IV, by binding these proteins in the NC-1 domain.^{[17] [18]} The stability of the basement membrane and dermal-epidermal junction is thought to be due to these interactions.^[19]

See also

• Collagen

Further reading

• Mecklenbeck S, Hammami-Hauasli N, Höpfner B, Schumann H, Kramer A, Küster W, Bruckner-Tuderman L . Clustering of COL7A1 mutations in exon 73: implications for mutation analysis in dystrophic epidermolysis bullosa . The Journal of Investigative Dermatology . 112 . 3 . 398–400 . March 1999 . 10084325 . 10.1046/j.1523-1747.1999.00518.x . free .
• Dang N, Klingberg S, Marr P, Murrell DF . Review of collagen VII sequence variants found in Australasian patients with dystrophic epidermolysis bullosa reveals nine novel COL7A1 variants . Journal of Dermatological Science . 46 . 3 . 169–178 . June 2007 . 17425959 . 10.1016/j.jdermsci.2007.02.006 .
• Christiano AM, Rosenbaum LM, Chung-Honet LC, Parente MG, Woodley DT, Pan TC, Zhang RZ, Chu ML, Burgeson RE, Uitto J . 6 . The large non-collagenous domain (NC-1) of type VII collagen is amino-terminal and chimeric. Homology to cartilage matrix protein, the type III domains of fibronectin and the A domains of von Willebrand factor . Human Molecular Genetics . 1 . 7 . 475–481 . October 1992 . 1307247 . 10.1093/hmg/1.7.475 .
• Gammon WR, Abernethy ML, Padilla KM, Prisayanh PS, Cook ME, Wright J, Briggaman RA, Hunt SW . 6 . Noncollagenous (NC1) domain of collagen VII resembles multidomain adhesion proteins involved in tissue-specific organization of extracellular matrix . The Journal of Investigative Dermatology . 99 . 6 . 691–696 . December 1992 . 1469284 . 10.1111/1523-1747.ep12614080 . free .
• Tanaka T, Takahashi K, Furukawa F, Imamura S . Molecular cloning and characterization of type VII collagen cDNA . Biochemical and Biophysical Research Communications . 183 . 3 . 958–963 . March 1992 . 1567409 . 10.1016/S0006-291X(05)80283-9 .
• Seltzer JL, Eisen AZ, Bauer EA, Morris NP, Glanville RW, Burgeson RE . Cleavage of type VII collagen by interstitial collagenase and type IV collagenase (gelatinase) derived from human skin . The Journal of Biological Chemistry . 264 . 7 . 3822–3826 . March 1989 . 2537292 . 10.1016/S0021-9258(19)84924-4 . free .
• Fine JD, Johnson L, Wright T . Epidermolysis bullosa simplex superficialis. A new variant of epidermolysis bullosa characterized by subcorneal skin cleavage mimicking peeling skin syndrome . Archives of Dermatology . 125 . 5 . 633–638 . May 1989 . 2653224 . 10.1001/archderm.125.5.633 .
• Bart BJ, Gorlin RJ, Anderson VE, Lynch FW . Congenital localized absence of skin and associated abnormalities resembling epidermolysis bullosa. A new syndrome . Archives of Dermatology . 93 . 3 . 296–304 . March 1966 . 5910871 . 10.1001/archderm.93.3.296 .
• Tanaka T, Furukawa F, Imamura S . Epitope mapping for epidermolysis bullosa acquisita autoantibody by molecularly cloned cDNA for type VII collagen . The Journal of Investigative Dermatology . 102 . 5 . 706–709 . May 1994 . 7513737 . 10.1111/1523-1747.ep12374333 . free .
• Christiano AM, Morricone A, Paradisi M, Angelo C, Mazzanti C, Cavalieri R, Uitto J . A glycine-to-arginine substitution in the triple-helical domain of type VII collagen in a family with dominant dystrophic epidermolysis bullosa . The Journal of Investigative Dermatology . 104 . 3 . 438–440 . March 1995 . 7861014 . 10.1111/1523-1747.ep12666033 . free .
• Christiano AM, Suga Y, Greenspan DS, Ogawa H, Uitto J . Premature termination codons on both alleles of the type VII collagen gene (COL7A1) in three brothers with recessive dystrophic epidermolysis bullosa . The Journal of Clinical Investigation . 95 . 3 . 1328–1334 . March 1995 . 7883979 . 441472 . 10.1172/JCI117783 .
• Christiano AM, Greenspan DS, Lee S, Uitto J . Cloning of human type VII collagen. Complete primary sequence of the alpha 1(VII) chain and identification of intragenic polymorphisms . The Journal of Biological Chemistry . 269 . 32 . 20256–20262 . August 1994 . 8051117 . 10.1016/S0021-9258(17)31984-1 . free .
• Christiano AM, Ryynänen M, Uitto J . Dominant dystrophic epidermolysis bullosa: identification of a Gly→Ser substitution in the triple-helical domain of type VII collagen . Proceedings of the National Academy of Sciences of the United States of America . 91 . 9 . 3549–3553 . April 1994 . 8170945 . 43617 . 10.1073/pnas.91.9.3549 . 1994PNAS...91.3549C . free .
• Greenspan DS, Byers MG, Eddy RL, Hoffman GG, Shows TB . Localization of the human collagen gene COL7A1 to 3p21.3 by fluorescence in situ hybridization . Cytogenetics and Cell Genetics . 62 . 1 . 35–36 . 1993 . 8422754 . 10.1159/000133440 .
• Greenspan DS . The carboxyl-terminal half of type VII collagen, including the non-collagenous NC-2 domain and intron/exon organization of the corresponding region of the COL7A1 gene . Human Molecular Genetics . 2 . 3 . 273–278 . March 1993 . 8499916 . 10.1093/hmg/2.3.273 .
• Christiano AM, Greenspan DS, Hoffman GG, Zhang X, Tamai Y, Lin AN, Dietz HC, Hovnanian A, Uitto J . 6 . A missense mutation in type VII collagen in two affected siblings with recessive dystrophic epidermolysis bullosa . Nature Genetics . 4 . 1 . 62–66 . May 1993 . 8513326 . 10.1038/ng0593-62 . 9099319 .
• Christiano AM, Lee JY, Chen WJ, LaForgia S, Uitto J . Pretibial epidermolysis bullosa: genetic linkage to COL7A1 and identification of a glycine-to-cysteine substitution in the triple-helical domain of type VII collagen . Human Molecular Genetics . 4 . 9 . 1579–1583 . September 1995 . 8541842 . 10.1093/hmg/4.9.1579 .

External links

• GeneReviews/NCBI/NIH/UW entry on Dystrophic Epidermolysis Bullosa

Notes and References

1. Parente MG, Chung LC, Ryynänen J, Woodley DT, Wynn KC, Bauer EA, Mattei MG, Chu ML, Uitto J . 6 . 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 . 88 . 16 . 6931–6935 . August 1991 . 1871109 . 52207 . 10.1073/pnas.88.16.6931 . free . 1991PNAS...88.6931P .
2. Watanabe M, Natsuga K, Shinkuma S, Shimizu H . Epidermal aspects of type VII collagen: Implications for dystrophic epidermolysis bullosa and epidermolysis bullosa acquisita . The Journal of Dermatology . 45 . 5 . 515–521 . May 2018 . 29352483 . 10.1111/1346-8138.14222 . 19256089 .
3. Shinkuma S . Dystrophic epidermolysis bullosa: a review . English . Clinical, Cosmetic and Investigational Dermatology . 8 . 275–284 . May 2015 . 26064063 . 4451851 . 10.2147/CCID.S54681 . free .
4. Has C, Nyström A, Saeidian AH, Bruckner-Tuderman L, Uitto J . Epidermolysis bullosa: Molecular pathology of connective tissue components in the cutaneous basement membrane zone . Matrix Biology . 71-72 . 313–329 . October 2018 . 29627521 . 10.1016/j.matbio.2018.04.001 . 4718012 .
5. Bardhan A, Bruckner-Tuderman L, Chapple IL, Fine JD, Harper N, Has C, Magin TM, Marinkovich MP, Marshall JF, McGrath JA, Mellerio JE, Polson R, Heagerty AH . 6 . Epidermolysis bullosa . Nature Reviews. Disease Primers . 6 . 1 . 78 . September 2020 . 32973163 . 10.1038/s41572-020-0210-0 . 221861310 .
6. Web site: COL7A1 collagen, type VII, alpha 1 (epidermolysis bullosa, dystrophic, dominant and recessive). NCBI Entrez Gene database.
7. Ponsioen TL, van Luyn MJ, van der Worp RJ, van Meurs JC, Hooymans JM, Los LI . Collagen distribution in the human vitreoretinal interface . Investigative Ophthalmology & Visual Science . 49 . 9 . 4089–4095 . September 2008 . 18450587 . 10.1167/iovs.07-1456 . free .
8. Christiano AM, Hoffman GG, Chung-Honet LC, Lee S, Cheng W, Uitto J, Greenspan DS . Structural organization of the human type VII collagen gene (COL7A1), composed of more exons than any previously characterized gene . Genomics . 21 . 1 . 169–179 . May 1994 . 8088784 . 10.1006/geno.1994.1239 .
9. COL7A1 genomic sequence. NCBI Entrez Nucleotide Database. 2004-05-17.
10. COL7A1 mRNA sequence. NCBI Entrez Nucleotide Database . 1995-09-15 .
11. Dang N, Murrell DF . Mutation analysis and characterization of COL7A1 mutations in dystrophic epidermolysis bullosa . Experimental Dermatology . 17 . 7 . 553–568 . July 2008 . 18558993 . 10.1111/j.1600-0625.2008.00723.x . 32600295 . free .
12. Has C, Bauer JW, Bodemer C, Bolling MC, Bruckner-Tuderman L, Diem A, Fine JD, Heagerty A, Hovnanian A, Marinkovich MP, Martinez AE, McGrath JA, Moss C, Murrell DF, Palisson F, Schwieger-Briel A, Sprecher E, Tamai K, Uitto J, Woodley DT, Zambruno G, Mellerio JE . 6 . Consensus reclassification of inherited epidermolysis bullosa and other disorders with skin fragility . The British Journal of Dermatology . 183 . 4 . 614–627 . October 2020 . 32017015 . 10.1111/bjd.18921 . 211022921 . free .
13. Book: Chapel H, Haeney M, Misbah S . Essentials of clinical immunology. 25 June 2010. 2006. Wiley-Blackwell. 978-1-4051-2761-5. 207–.
14. FDA Approves First Topical Gene Therapy for Treatment of Wounds in Patients with Dystrophic Epidermolysis Bullosa . U.S. Food and Drug Administration (FDA) . 19 May 2023 . 28 May 2023.
15. Web site: Vyjuvek . U.S. Food and Drug Administration (FDA) . 19 May 2023 . 30 May 2023 . 125774 .
16. Rousselle P, Keene DR, Ruggiero F, Champliaud MF, Rest M, Burgeson RE . Laminin 5 binds the NC-1 domain of type VII collagen . The Journal of Cell Biology . 138 . 3 . 719–728 . August 1997 . 9245798 . 2141627 . 10.1083/jcb.138.3.719 .
17. Lapiere JC, Chen JD, Iwasaki T, Hu L, Uitto J, Woodley DT . Type VII collagen specifically binds fibronectin via a unique subdomain within the collagenous triple helix . The Journal of Investigative Dermatology . 103 . 5 . 637–641 . November 1994 . 7963647 . 10.1111/1523-1747.ep12398270 . free .
18. Chen M, Marinkovich MP, Veis A, Cai X, Rao CN, O'Toole EA, Woodley DT . 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 . 272 . 23 . 14516–14522 . June 1997 . 9169408 . 10.1074/jbc.272.23.14516 . free .
19. Gatseva A, Sin YY, Brezzo G, Van Agtmael T . Basement membrane collagens and disease mechanisms . Essays in Biochemistry . 63 . 3 . 297–312 . September 2019 . 31387942 . 6744580 . 10.1042/EBC20180071 .