Dystrophic epidermolysis bullosa: a review

Clinical, Cosmetic and Investigational Dermatology Dovepress open access to scientific and medical research Review Clinical, Cosmetic and Investigational Dermatology downloaded from https://www.dovepress.com/ by 5.135.15.0 on 13-Jul-2018 For personal use only. Open Access Full Text Article Dystrophic epidermolysis bullosa: a review This article was published in the following Dove Press journal: Clinical, Cosmetic and Investigational Dermatology 26 May 2015 Number of times this article has been viewed Satoru Shinkuma Department of Dermatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan Abstract: Dystrophic epidermolysis bullosa is a rare inherited blistering disorder caused by mutations in the COL7A1 gene encoding type VII collagen. The deficiency and/or dysfunction of type VII collagen leads to subepidermal blistering immediately below the lamina densa, resulting in mucocutaneous fragility and disease complications such as intractable ulcers, extensive scarring, malnutrition, and malignancy. The disease is usually diagnosed by immunofluorescence mapping and/or transmission electron microscopy and subsequently subclassified into one of 14 subtypes. This review provides practical knowledge on the disease, including new therapeutic strategies. Keywords: type VII collagen, anchoring fibril, subtypes, revertant mosaicism, treatment, gene therapy Introduction Epidermolysis bullosa (EB) is an inherited disorder characterized by mechanical stress-induced blistering of the skin and mucous membranes.1 EB is classified into four major types, namely, EB simplex (EBS), junctional EB (JEB), dystrophic EB (DEB), and Kindler syndrome, based on the distinguishing ultrastructural site of skin cleavage.2,3 Tissue separation occurs in the epidermis (EBS), in the lamina lucida (JEB), or in the sublamina densa (DEB). Kindler syndrome, a mixed type, exhibits multiple cleavage planes. Estimates of the prevalence and incidence of EB have been attempted using different sampling techniques in different regions of the world. There is some variation in the frequency of the DEB among different populations.4–8 According to several registries for EB, the overall prevalence was estimated as 8–10 per million births (for DEB: 2–6 per million births).5,6 The male:female ratio for EB and DEB cases is approximately 1:1. Most DEB patients are symptomatic at birth and until the age of 1 year. Type VII collagen and the pathogenesis of dystrophic epidermolysis bullosa Correspondence: Satoru Shinkuma Department of Dermatology, Hokkaido University Graduate School of Medicine, N15 W7, Sapporo 060-8638, Japan Tel +81 11 716 1161 Fax +81 11 706 7820 Email 275 submit your manuscript | www.dovepress.com Clinical, Cosmetic and Investigational Dermatology 2015:8 275–284 Dovepress © 2015 Shinkuma. This work is published by Dove Medical Press Limited, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License. The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. Permissions beyond the scope of the License are administered by Dove Medical Press Limited. Information on how to request permission may be found at: http://www.dovepress.com/permissions.php http://dx.doi.org/10.2147/CCID.S54681 Powered by TCPDF (www.tcpdf.org) DEB is caused by mutations in the COL7A1 gene encoding type VII collagen.9 Type VII collagen is a major component of the anchoring fibril located below the basement membrane in the upper dermis, providing stable dermal–epidermal adhesion.3 Type VII collagen is a homotrimer composed of three proα1 (VII) chains which are encoded by the 32 kb COL7A1 gene on chromosome 3p21.10 The mRNA transcript of approximately 8.9 kb is translated into a procollagen α1 (VII) chain composed of 2,944 amino Dovepress Clinical, Cosmetic and Investigational Dermatology downloaded from https://www.dovepress.com/ by 5.135.15.0 on 13-Jul-2018 For personal use only. Shinkuma acids.11 Each procollagen α1 (VII) polypeptide chain contains a central collagenous, triple-helical domain (145 kDa) flanked by both a large amino-terminal noncollagenous 1 (NC-1) domain (145 kDa) and a small carboxyl-terminal NC-2 domain (30 kDa).11,12 The triple-helical domain consists of a repeating Gly-X-Y sequence that is interrupted by 19 noncollagenous regions. In the middle of the triple-helical domain, there is a 39-amino acid noncollagenous region, known as the “hinge” region, which is susceptible to proteolytic digestion with pepsin.13 The amino-terminal NC-1 consists of submodules with homology to known adhesive proteins, including cartilage matrix protein, type III repeats of fibronectin, a von Willebrand factor type A-like motif, and short cysteine- and proline-rich domains.14 The NC-1 domain mediates the attachment of the anchoring fibrils into the principal components of the cutaneous basement membrane, such as type IV collagen and laminin-332.15,16 The carboxyl-terminal NC-2 domain contains conserved cysteines involved in the formation of disulfide bonds which enable linkage between type VII collagen homotrimers.17 Type VII collagen is synthesized both by epidermal keratinocytes and dermal fibroblasts.18 Upon synthesis of a complete procollagen α1 (VII) chain, three polypeptides associate through their carboxyl-terminal ends to form a trimer whose collagenous portion folds into the triple-helical formation.12 The triple-helical molecules are then secreted to the extracellular milieu where two type VII collagen molecules align into a tail-to-tail antiparallel dimer.19 A portion of the NC-2 domain is removed, and the association of the homotrimers is stabilized by intermolecular disulfide bond formation in the overlapping carboxyl-terminal regions. Subsequently, a large number of these antiparallel dimers aggregate laterally to form anchoring fibrils.12 Clinical features of dystrophic epidermolysis bullosa Clinical subtypes DEB has been classified according to inheritance pattern, clinical features, and expression level of type VII collagen.1 Four international consensus meetings on EB diagnosis and classification have been held since 1988.1,2,20,21 In the 25 years since the first consensus meeting, several clinical subtypes were identified, and the names of subtypes using eponyms have been eliminated and substituted with descriptive terms. In the most recent proposed classification, there are 14 subtypes of DEB (Table 1).1 DEB has two patterns of inheritance: autosomal dominant (DDEB) and autosomal recessive (RDEB). DEB has the three 276 Powered by TCPDF (www.tcpdf.org) submit your manuscript | www.dovepress.com Dovepress Table 1 Dystrophic epidermolysis bullosa clinical subtypes DEB, major All subtypes subtypes Old terms DDEB DDEB, Cockayne– Touraine and Pasini RDEB DDE (...truncated)