Epidermolysis Bullosa: The Expanding Mutation Database

Abstract

Epidermolysis bullosa (EB) is a group of heritable mechanobullous disorders characterized by fragility of the skin within the cutaneous basement membrane zone (BMZ) (Fine et al, 2000). The severity of skin manifestations can be highly variable, so that in one end of the spectrum the skin findings may be relatively minor blistering tendency primarily on the hands and feet, whereas at the other end of the spectrum the compromised integrity of skin can result in early postnatal demise of the affected individual. Prior to identification of the gene/protein systems harboring mutations in different variants of EB, this phenotypic variability was quite puzzling, compounded by the fact that there are a number of extracutaneous manifestations associated with the skin findings. This phenotypic complexity, coupled with classifications riddled with eponyms, has led to a suggestion that there are 30 different subtypes of EB (Anton-Lamprecht and Gedde-Dahl, 2002). Traditionally, EB has been divided into three broad categories: (a) the simplex forms demonstrate tissue separation within the basal keratinocytes; (b) the junctional forms depict tissue separation within the lamina lucida of the dermal–epidermal basement membrane; and (c) the dystrophic forms show tissue cleavage below the lamina densa within the upper papillary dermis (Fig 1). We have recently proposed a fourth subtype, the hemidesmosomal variants of EB, in which the tissue separation is at the basal cell/lamina lucida interface at the level of hemidesmosomes (Fig 1) (Pulkkinen and Uitto, 1998). In fact, the hemidesmosomal variants include the following clinical entities: (a) Generalized atrophic benign EB (GABEB) that has been previously included in the category of non-Herlitz junctional EB (JEB); (b) EB with pyloric atresia where tissue separation is either just outside of the plasma membrane of the basal cells or in the low intracellular compartment and has occasionally been referred as ‘‘pseudo-junctional’’ EB; (c) EB with muscular dystrophy which shows low intracellular cytolysis occasionally suggested to belong to the simplex category of EB (Pulkkinen and Uitto, 1998). With the advent of molecular genetics in general and essential completion of the human genome project, specific mutations have now been identified in ten distinct genes expressed within the cutaneous BMZ (Table I) (Uitto et al, 2002). The compartmentalized expression of these genes within the cutaneous BMZ, the types and combinations of the mutations, and their consequences at the mRNA and protein levels, when superimposed on the individuals’ genetic background and combined with environmental factors, explain the spectrum of severity in EB. Considerable clinical and molecular heterogeneity is recognized particularly in the JEB, which has been traditionally divided into Herlitz (lethal) and non-Herlitz variants depending on the severity and outcome of the disease. Specifically, most children with the Herlitz variant die within the first year of life, whereas non-Herlitz patients have life-long blistering but their lifespan is not significantly compromised. The Herlitz JEB is due to absence of laminin 5, and mutations have been identified in three genes (LAMA3, LAMB3, and LAMC2), which encode the subunit polypeptides a3, b3, and g2 of laminin 5, respectively. Most of these mutations result in premature termination codon for translation (PTC) (Nakano et al, 2000). In non-Herlitz variants, missense mutations have been identified also in the laminin 5 genes, but in addition, mutations can reside in the 180 kDa bullous pemphigoid antigen/type XVII collagen gene, BPAG2/ COL17A1 (Nakano et al, 2002). In this issue, Posteraro et al (2004) have analyzed an Italian cohort of 19 patients with JEB, 11 being affected with the severe Herlitz type and eight with milder non-Herlitz type. The authors concentrated their analysis on LAMA3, LAMB3, and LAMC2 and identified 18 mutations, seven of which were previously unpublished. In accordance with previous observations, PTC mutations in both alleles of the laminin 5 genes were predominant in Herlitz JEB patients, whereas splicing or missense mutations resulting in reduced synthesis of partially functional laminin 5 were predominantly found in non-Herlitz variants. The authors also disclosed a number of recurrent mutations, including R635X in the LAMB3 gene, a mutation frequent in Caucasian Herlitz JEB patients, particularly in Northern European