Genotypic Heterogeneity and the Mode of Inheritance in Epidermolysis Bullosa

Abstract

Epidermolysis bullosa (EB) comprises a clinically heterogeneousgroupofdisorderscharacterizedbyfragilityof skin, leading to formation of blisters, erosions, and chronic ulcers. The cutaneousmanifestations, together with extracutaneous complications, cause considerable morbidity and in some cases premature death.1,2 Epidermolysis bullosa is anorphandisease (defined in theUnited States as adiagnosiswith <200000affected individuals), yet thereareup to40000affected individuals in theUnitedStates and asmany as half a million patients globally. The disease is characteristically diagnosed at birth or during the early postnatal period, and there is currently no effective and specific treatment beyond prevention of trauma, appropriate wound care, and prevention of infections. Thus, EB imposes amajor burden for global health care, and the cost of the treatment of a severely affected patient in the United States can approach $300000peryear (email communication;November24,2015; Brett Kopelan, executive director of the dystrophic epidermolysis bullosa research association [DEBRA] of America). The heritable forms of EB have been divided into 4 broad categories based on the level of blister formation within the dermoepidermal basement membrane zone (BMZ) as determined by immunoepitope mapping or diagnostic transmission electronmicroscopy (Table). In the classic simplex (EBS) junctional (JEB) anddystrophic (DEB) formsofEB, tissue separation is within the basal cell layer of epidermis, within the lamina lucida of the BMZ, and sublamina densa, respectively, whereas the Kindler syndrome (KS), which has been recently classified as a form of EB, can demonstrate multiple levels of blistering.Asmanyas 18different geneshavenowbeenshown to harbormutations resulting in EB phenotypes (Table).3 The tremendous clinical variability noted in patients with EB can be explained by the topographic location of expression of the mutant geneswithin the BMZ, the types and combinations of mutations in these genes, and their interactionswith environmental factors, particularly trauma, at the genome/environment interface. The mode of inheritance of EB can be variably either autosomal dominant (AD) or autosomal recessive (AR).1 Thehistorical suggestions of X-linked forms of EB have been discounted by molecular diagnostics. Specifically, EBS is AD in most cases, although approximately 25%of familiesmayhave anARmodeof inheritance.Thedystrophic formscanbeeither AD or AR, the dominant forms being usually less severe, whereas the most devastating type, recessive dystrophic EB, thegeneralized severe, is inherited in anARpattern. The junctional forms aswell asKShavebeenuniformlydescribedwith AR inheritance.4,5 In this issue, Turcan and coworkers6 report a novel heterozygousmissensemutation in the ITGB4gene,whichcosegregates with the JEB phenotype in an extended family in an apparent AD pattern. This gene encodes an integrin polypeptide (β4), which physiologically dimerizes with another integrin polypeptide (α6) to form a cell surface receptor, α6β4 integrin (Figure).Thus,bothpolypeptides,α6andβ4,are required for formation of this protein that is critical for cell-matrix interaction through their association with laminin 332.7 These proteins form hemidesmosomes, multiprotein attachment complexes stabilizing the adherence of the epidermis to the underlying basement membrane. This mutation was found only in the affected patients and was not present in unaffectedmembers of the family. The authors6 conclude that this study highlights, for the first time, the possibility of a dominant mode of inheritance in the JEB, thus expanding the genotypic heterogeneity and extending the genotype-phenotypecorrelations forEB.They6alsopostulate,butdonotprove, that the effect of thismutation is dominant negative. In other words, the mutated gene product interferes with the functionof thenormal product, thusdestabilizing the assembly of hemidesmosomes and rendering them nonfuncational (Figure). A large number ofmutations in the candidate genes have beenpreviously identified indifferent formsofEB,andthemutations in the same gene can result either in an AD or AR inheritance pattern.3 For example, most mutations in the keratin 14 gene (KRT14) result inAD inheritance, but 14 cases have been shown toharbormutations in this gene in amanner that results inARmodeof inheritance. Similarly, Turcanet al6 now demonstrate that a heterozygous missense mutation in the ITGB4 gene isAD,while all previously publishedmutations in the samegeneareAR.What then is theexplanation for themutations in the same gene giving rise to 2 different forms of inheritance? In all previously published cases of ITGB4, the mutations cause loss of function, as a result of premature termination codon of translation resulting in synthesis of truncated and nonfunctional polypeptides, for example.4 In heterozygous carriers of such mutations, half of the protein is truncated and nonfunctional whereas the normal allele results in the synthesis of functional full-length polypeptide (Figure, C). In this case, half of the physiological level of the protein is sufficient to maintain normal integrity of the BMZ, and only in complete absence of the functional protein, as a result of either homozygous or compound heterozygous Related article page 558 Opinion