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 Hallopeau-Siemens variant of recessively inherited DEB (HS-RDEB) (MIM 226600), a characteristic genetic lesion is premature termination codon mutations in both COL7A1 alleles. In the milder scarring, mitis-type of RDEB (mitis variant of recessive dystrophic epidermolysis bullosa (M-RDEB)), a frequent mutation is a missense mutation or in-frame deletion in either one or both alleles. A characteristic lesion in dominantly inherited DEB (dominant dystrophic epidermolysis bullosa (DDEB); MIM 131750 and 131850) is a glycine substitution mutation in the collagenous domain of type VII collagen, which causes EB phenotype through dominant negative interference. However, not all glycine substitution mutations are dominant, and some of them can be recessive resulting in a clinical phenotype only when homozygous or compound heterozygote with a PTC. Collectively, the combination of mutations and their positions along the type VII collagen polypeptide result in abnormalities in anchoring fibrils with variable degrees of severity within the spectrum of DEB.

Mutations in the laminin 5 genes, LAMA3, LAMB3, and LAMC2, encoding the subunit polypeptides of α3, β3, and γ2, respectively, have been demonstrated in the Herlitz variant of junctional EB (H-JEB) (MIM 226700). These genetic lesions are invariably PTC mutations. Although PTCs in any of the three genes can lead to similar phenotype, most (≈80 percent) of these mutations reside in LAMB3, which is explained in part by the presence of two recurrent “hotspot” mutations, R635X and R42X. Missense mutations in the laminin 5 genes have been disclosed in cases with milder, nonlethal junctional epidermolysis bullosa (JEB).

A novel category, the hemidesmosomal variants of EB (HD-EB), was recently established. In these patients, tissue separation occurs at the basal cell/lamina lucida interface at the level of hemidesmosomes. Three clinical variants are recognized, and distinct mutations in the respective hemidesmosomal genes have been encountered. Specifically, generalized atrophic benign EB (GABEB) (MIM 226650) is due to mutations in the gene encoding the 180-kDa bullous pemphigoid antigen (BP180), a transmembrane collagen designated as type XVII collagen (BPAG2/COL17A1). Epidermolysis bullosa with congenital pyloric atresia (EB-PA) (MIM 226730) is due to mutations in the α6β4 integrin genes, ITGA6 and ITGB4, respectively. EB associated with late-onset muscular dystrophy (EB-MD, MIM 226670) results from mutations in the plectin gene (PLEC1), a multifunctional adhesion protein expressed both in the epidermis and the sarcolemma of the muscle.

Examination of the repertoire of mutations disclosed in ten distinct genes in different variants of EB adds to our understanding of the complexity of the cutaneous BMZ. The information of the nature of the genetic lesions also explains the phenotypic variability of different subtypes of EB.

The impact of molecular genetics of EB on patient care is already evident in terms of improved genetic counseling and refined classification with prognostic implications. The knowledge of candidate protein/gene systems and identification of specific mutations in such genes has paved the way to establish DNA-based prenatal testing for severe forms of EB. This information is also critical for development of emerging technologies, such as pre-implantation genetic diagnosis (PGD) and gene therapy, for EB.