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Editorial |

Genotypic Heterogeneity and the Mode of Inheritance in Epidermolysis Bullosa

Jouni Uitto, MD, PhD1; Hassan Vahidnezhad, MSc1,2; Leila Youssefian, MSc1
[+] Author Affiliations
1Department of Dermatology and Cutaneous Biology, The Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, Pennsylvania
2Department of Molecular Medicine, Biotechnology Research Center, Pasteur Institute of Iran, Tehran, Iran
JAMA Dermatol. 2016;152(5):517-520. doi:10.1001/jamadermatol.2015.5237.
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Epidermolysis bullosa (EB) comprises a clinically heterogeneous group of disorders characterized by fragility of skin, leading to formation of blisters, erosions, and chronic ulcers. The cutaneous manifestations, together with extracutaneous complications, cause considerable morbidity and in some cases premature death.1,2 Epidermolysis bullosa is an orphan disease (defined in the United States as a diagnosis with < 200 000 affected individuals), yet there are up to 40 000 affected individuals in the United States and as many 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 a major burden for global health care, and the cost of the treatment of a severely affected patient in the United States can approach $300 000 per year (email communication; November 24, 2015; Brett Kopelan, executive director of the dystrophic epidermolysis bullosa research association [DEBRA] of America).

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Figure.
Structural Complexity of the Cutaneous Basement Membrane Zone and Schematic Representation of the Consequences of ITGB4 Mutations in Junctional Epidermolysis Bullosa

A, In normal skin, integrin polypeptides α6 and β4 dimerize to form integrin-α6β4 receptor which interacts with laminin 332. This complex forms the core component of hemidesmosomes, critical attachment structures within the cutaneous basement membrane zone. B, In case of loss-of-function mutations in both alleles of the ITGB4 gene, no functional β4 polypeptides are synthesized leading to absence of integrin-α6β4 and causing severe blistering as a result of minor trauma. C, The presence of an autosomal recessive loss-of-function mutation in 1 ITGB4 allele in a heterozygous carrier allows synthesis of reduced numbers of functional α6β4 integrin, but 50% is sufficient to maintain the integrity of the dermo-epidermal attachment. D, Dominant negative mutations in ITGB4 allow the synthesis and normal localization of full-length β4 polypeptides, which, however, interfere with the assembly of functional α6β4 integrin receptors, perturbing their interactions with laminin 332, and the synthesis of functional hemidesmosomes. This results in blister formation induced by trauma even in heterozygous carriers of the mutation.

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