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Molecular Heterogeneity of Blistering Disorders View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Elsevier - Publisher Connector GENETICS OF STRUCTURAL SKIN DISORDERS Molecular Heterogeneity of Blistering Disorders: The Paradigm of Epidermolysis Bullosa Leena Bruckner-Tuderman1,2 and Cristina Has1 1Department of Dermatology, University Medical Center Freiburg, Freiburg, Germany and 2Freiburg Institute for Advanced Studies, School of Life Sciences – LifeNet, Freiburg, Germany Correspondence: Leena Bruckner-Tuderman, E-mail: [email protected] doi:10.1038/skinbio.2012.2 INTRODUCTION Koebner more than 120 years ago recombinant protein expression sys- Inherited epidermolysis bullosa (EB) (Koebner, 1886). It has remained in tems facilitated the isolation and mole- represents a clinically and genetically use until today, although this group of cular characterization of the proteins of heterogeneous group of genodermatoses disorders now encompasses the entire the dermal–epidermal basement mem- characterized by skin fragility, i.e., spectrum of known skin fragility dis- brane zone or their functional domains. blisters and erosions of skin and mucous orders, a concept sometimes difficult to Using molecular tools, combined membranes in response to minor friction comprehend by the patients and some with immunoelectron microscopy, or mechanical trauma (Figure 1a–e). EB clinicians as well. In the first half of the such pivotal adhesion proteins as lami- comprises a broad spectrum of pheno- 20th century, the major achievements nin-332 (previously kalinin, laminin 5) types, ranging from severe cutaneous in the EB field consisted of defining and collagen VII were identified as and extracutaneous involvement caused clinical entities and distinguishing bet- structural components of the hemides- by severely compromised dermal–epi- ween inherited and acquired forms of mosomes and the anchoring fibrils dermal or intra-epidermal adhesion to bullous diseases. In the 1960s, ultra- (Sakai et al., 1986; Bruckner-Tuderman discrete traits caused by subtle molecu- structural studies led to the classifica- et al., 1987, 1988; Marinkovich et al., lar defects. On the basis of our current tion of EB into three major types— 1992, 1993; Urban, 2012). All the knowledge, mutations in 17 different simplex, junctional, and dystrophic— new knowledge and diagnostic ad- genes account for the genetic and allelic based on the precise level of tissue vances acquired during this decade heterogeneity of EB (Figure 1). The EB- separation (Pearson, 1962; Hashimoto were reflected in the revised clinical associated genes code for intracellular, et al., 1975; Rodeck et al., 1980; first and laboratory criteria for EB, pub- transmembrane, or extracellular proteins milestone). In the 1970s and 1980s, a lished in 1991, which split EB into involved in cytoskeleton, cell–cell or plethora of clinically distinct EB sub- numerous clinical subtypes (Fine et al., cell–matrix adhesion (Figure 1f). The types were defined, often designated by 1991). main adhesive structures in the skin, eponyms. In particular, the monograph The 1990s were marked by rapid i.e., desmosomes, hemidesmosomes, published in 1971 by Tobias Gedde- progress in genetics, which was based basement membrane, and anchoring Dahl included meticulously collected on the development of molecular fibrils represent supramolecular protein data on more than 100 patients with EB genetic methods, including gene clon- complexes and networks that not only (Gedde-Dahl, 1971). ing, linkage analyses for gene mapping, assure the integrity and mechanical In the 80s, development of immuno- and efficient DNA sequencing. In stability of the integument, but also fluorescence techniques and genera- 1991, KRT14 mutations were found to regulate cellular functions by transmit- tion of polyclonal and monoclonal cause EB simplex, the most common ting signals between the cells and their antibodies resulted in the identification EB type (Coulombe et al., 1991). extracellular milieu. Therefore, the of the first molecules causally involved Thereafter, in rapid succession, map- heterogeneity and the partial overlap in EB and the establishment of first ping and discovery of the genetic between clinical and molecular EB molecular criteria for diagnosis using defects underlying several different EB subtypes are not surprising if one con- immunofluorescence mapping of the subtypes were reported (Ryynanen siders the high density of molecules and dermal–epidermal junction ((Hintner et al., 1991a, 1991b, 1992; Hovnanian their complex interactions in cell–cell et al., 1981), reviewed in (Fine, et al., 1992; Christiano et al., 1993; and cell–matrix adhesions. 1987)). This was the second milestone Hilal et al., 1993; McGrath et al., 1995; in our pathogenetic understanding of Li and Uitto, 2012). Molecular genetic HISTORICAL PERSPECTIVE this group of disorders. diagnostics became available, but The term EB (implying involvement In parallel, rapid improvements were still labor-intensive, expensive, limited to epidermis) was coined by in protein biochemical methods and and dependent on pre-screening. In E2 NOVEMBER 2012 MILESTONES | CUTANEOUS BIOLOGY Figure 1. Clinical and molecular heterogeneity of epidermolysis bullosa (EB). (a) Residual superficial erosions after blistering on the heel of a boy with acral peeling syndrome and transglutaminase 5 mutations, p.[G113C];[L214CfsX15]. (b) Grouped blisters and crusts on the foot of a girl with EB simplex Dowling-Meara caused by the keratin 14 mutation, p.R125C. (c) The right hand of a woman with junctional EB–other and collagen XVII mutations, p.[M1T];[R1226X], showing blisters, erosions, crusts, hypopigmentation, and nail loss. (d) Feet of a boy with dystrophic EB with COL7A1 mutations (c.[425A4G];[3276G4A]) demonstrate crusts, extensive scarring, webbing of the toes, and nail loss. (e) The left hand of a young man with Kindler syndrome homozygous for the frameshift mutation in the FERMT1 gene p.[D153RfsX3];[D153RfsX3], demonstrates pronounced skin atrophy, incipient webbing of the finders, and nail dystrophy. (f) The left panel shows immunofluorescence staining of normal human skin with antibodies to desmoplakin (red) and collagen IV (green); nuclei are in blue. The levels of skin cleavage, which correspond to the main EB types and subtypes, and the defective proteins are indicated on the right side of the figure. parallel to the elucidation of new CLINICAL CLASSIFICATION stantial advances in understanding the genetic defects and different kinds In the beginning of the 21st century, molecular basis of many old and new of mutations in the known genes, a rich body of molecular genetic data EB forms led to the tendency to avoid researchers started to explore the on EB was already available. Muta- splitting of the disease into too many molecular mechanisms underlying tion databases (http://www.interfil.org, sub-entities and to reduce the use of keratinocyte fragility in EB simplex eponyms. However, this is in part https://portal.biobase-international.com/ and dermal–epidermal destabilization counteracted by continuous progress hgmd/) and patient registries (https:// in junctional and dystrophic EB. In relating to discovery of new genes in grenada.lumc.nl/LOVD2, http://www. 1997, revertant mosaicism, i.e., genetic rare EB subtypes. deb-central.org/molgenis.do, http://www. reversion of inherited mutations was recognized clinically in patients with col7.info) facilitated both the study of junctional EB and demonstrated genotype–phenotype correlations and CLINICAL AND GENETIC FEATURES on molecular genetic level (Jonkman the genetic counselling. Together with OF EB SUBTYPES et al., 1997). For many years, this the knowledge acquired on biochem- The most extensive changes have con- phenomenon of natural healing was ical and cell biological disease mechan- cerned EB simplex. Although the vast considered rare and described only in isms, these data served as prerequisite majority of EB simplex cases is caused isolated cases. Recently, however, it for rational disease classifications. Dur- by keratin 5/14 mutations (Figure 1b), has become clear that revertant mosai- ing the first decade of the 21st century, several new causative genes have been cism occurs in most, if not all EB types, two revisions of the EB classification identified. BPAG1e (dystonin isoform and is more widespread than expected were needed to reflect the complexity 4) and plectin mutations can cause (Lai-Cheong et al., 2011; Kiritsi et al., and significant developments in the cytolysis of basal keratinocytes and 2012; McLean and Irvine, 2012). field (Fine et al., 2000, 2008). Sub- mild blistering, and may account for MILESTONES | CUTANEOUS BIOLOGY NOVEMBER 2012 E3 at least some of the molecularly un- encoding collagen VII, the main com- mentation of novel biologically valid solved EB simplex cases (Rezniczek ponent of the anchoring fibrils. The therapies must take into account the et al., 2010; Liu et al., 2012). Further- clinical presentations vary from severe balance between the gain and risk. No more, the spectrum of EB simplex has generalized blistering and scarring unique solution will be available for all extended to include subtypes with (Figure 1d) to sole nail dystrophy patients, but the success will rather cleavage in the suprabasal epidermal without skin blistering. Although more come with personalized therapies layers, e.g., the plakophilin deficiency than 600 COL7A1 gene mutations are adapted to the individual molecular and the lethal
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