Dystrophic forms of epidermolysis bullosa (DEB) are associated with mutations in the type VII collagen gene (Col7a1) which encodes the major component of anchoring

Epidermolysis bullosa (EB) is a group of heritable mechanobullous disorders characterized by fragility of the skin and mucous membranes. Traditionally, EB has been divided into three broad categories based on the level of tissue separation within the cutaneous basement membrane zone (BMZ) (Christiano and Uitto, 1996a; Fine et al., 1999; Uitto et al., 1997). One of these subsets, the dystrophic forms of EB (DEB), is inherited in either an autosomal dominant (DDEB) or autosomal recessive (RDEB) fashion. DEB is characterized by tissue separation below the lamina densa, at the dermal side of the dermal-epidermal basement membrane where anchoring fibrils are located (Christiano and Uitto, 1996b). Ultrastructurally, the non-blistered skin of patients with DEB is characterized by abnormalities in the anchoring fibrils, attachment structures extending from the lower portion of the dermal-epidermal basement membrane to the underlying dermis (Tidman and Eady, 1985). These structures can be morphologically altered, reduced in number, or entirely absent in DEB patients’ skin. Early biochemical evidence indicated that type VII collagen is the major, if not the exclusive, protein component of the anchoring fibrils (Sakai et al., 1986; Keene et al., 1987). Type VII collagen, as all collagen molecules (Kivirikko, 1993), consists of three polypeptide chains, [proα1(VII)]3. The central portion of the trimer type VII collagen molecule consists of a collagenous segment, with repeating Gly-Xaa-Yaa amino acid sequence, which is interrupted by imperfections, including a 39-amino acid ‘hinge’ region in the middle of the collagenous sequence (Christiano et al., 1994a). Thus, the triple-helical region of type VII collagen is divided into two segments, the collagenous domains 1 and 2, of approximately equal size. The collagenous domains are flanked by a large, ~145 kDa, noncollagenous amino-terminal globular domain (NC1) and a smaller, ~20 kDa, carboxy-terminal globular domain (NC2) 3641 Journal of Cell Science 112, 3641-3648 (1999) Printed in Great Britain © The Company of Biologists Limited 1999 JCS4685