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ABSTRACT

  • Epidermolysis bullosa (EB) is a group of genodermatoses that manifest with skin fragility as the unifying diagnostic feature, in association with a number of extracutaneous manifestations. The inheritance can be either autosomal dominant or autosomal recessive. The clinical severity of different variants of EB is highly variable, and in some severe cases, the disease can lead to early demise during the postnatal period. EB has been classified, on the basis of the level of tissue separation within the dermal-epidermal basement membrane zone (BMZ), to four broad categories: the simplex, hemidesmosomal, junctional, and dystrophic variants.

  • Tissue separation in various forms of EB occurs within the cutaneous BMZ, which consists of several attachment complexes forming an intricate network necessary for stable association of the epidermis to the underlying dermis. A defect in this network structure can result in fragility of skin and manifest clinically as a form of EB.

  • Hemidesmosome-anchoring filament complexes are attachment structures at the dermal-epidermal junction extending from the intracellular milieu of basal keratinocytes to the extracellular matrix of the dermal-epidermal basement membrane. Hemidesmosomes (HD) contribute to the stable association of the lower part of epidermis to the underlying basement membrane. At least four distinct proteins, plectin, BP230, BP180, and the α6β4 integrin, which represent five different gene products, are critical components of the HDs.

  • Laminins 5, 6, and 7 of the laminin family of proteins are critical components of the cutaneous BMZ. The major component, laminin 5, consists of three polypeptide subunits (α3, β3, and γ2), which are all necessary for the stable assembly of this trimeric molecule traversing the lamina lucida-lamina densa interface.

  • Type VII collagen is the major, if not the exclusive, component of the anchoring fibrils, attachment structures extending from the lower part of the lamina densa to the underlying dermis. Type VII collagen polypeptides, the α1(VII) chains, are encoded by a complex gene, COL7A1, which consists of 118 distinct exons, the largest number in any gene characterized thus far. The individual α1(VII) collagen polypeptides consist of a central collagenous domain flanked by a large (≈145-kDa) amino-terminal noncollagenous (NC-1) domain and a smaller (≈18-kDa) carboxy-terminal non-collagenous (NC-2) domain. In the extracellular space, the individual type VII collagen molecules align into anti-parallel dimers with overlapping C-terminal ends, and these dimer molecules laterally assemble into functional anchoring fibrils.

  • Cloning of the genes expressed in the cutaneous BMZ has led to development of strategies to screen genome for mutations in different variants of EB. In addition to direct sequencing of PCR-amplified cDNA and genomic sequences, novel screening technologies have been adopted, including heteroduplex scanning of PCR products for sequence variants by conformation-sensitive gel electrophoresis and the protein truncation test, which has been applied to find mutations causing premature termination codon (PTC) for translation.

  • The dystrophic forms of EB (dystrophic epidermolysis bullosa (DEB)), characterized by sublamina densa tissue separation and abnormalities in the anchoring fibrils, result from mutations in the type VII collagen gene (COL7A1). In the severely scarring ...

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