Progress in epidermolysis bullosa: Genetic classification and clinical implications

Abstract

Epidermolysis bullosa (EB), a heterogenous group of genodermatoses, is characterized by fragility and blistering of the skin associated with extracutaneous manifestations. Based on clinical severity, constellation of the phenotypic manifestations, and the level of tissue separation within the cutaneous basement membrane zone (BMZ), EB has been divided into distinct subcategories. Traditionally, these include the simplex, junctional, and dystrophic forms of EB, and recently attention has been drawn to hemidesmosomal variants demonstrating tissue separation at the level of the hemidesmosomes. Specific mutations in ten distinct genes expressed within the cutaneous BMZ have been delineated in >500 families with different variants of EB. The types of mutations, their positions along the affected genes, and their consequences at the mRNA and protein levels provide explanation for the phenotypic variability and genetic heterogeneity of this group of genodermatoses. Elucidation of mutations in different forms of EB has direct translational applications for improved diagnosis and molecularly based classification with prognostic implications as well as for genetic counseling and DNA-based prenatal testing in families with EB.

Laminin-332 coordinates mechanotransduction and growth cone bifurcation in sensory neurons

“…Laminin-332 has an extremely important role in maintaining the structural integrity of the skin as evidenced by the fact that mutations in all three subunits of laminin-332 cause junctional epidermolysis bullosa, a severe, often lethal, inherited skin blistering disease 1,3 . Little is known about the effects of laminin isoforms on neuronal function, but β2-containing isoforms such as laminin-421 (previously laminin-9) participate in the organization of neuromuscular junction via β2-mediated interactions with the calcium channel Ca V 2.2 37 , and the same interaction has been proposed to be a stop signal for sensory axon growth in the skin 38 .…”

“…Herlitz-type junctional epidermolysis bullosa is a severe blistering skin disease predominantly caused by mutations in any one of the three genes encoding the subunits of laminin-332 1,3 . Purified human laminin-111 is supportive for mechanotransduction 12 and also for the tether protein necessary for the RA-mechanosensitive current (Fig.…”

“…Mutations in all three genes coding the trimeric laminin-332 protein complex can cause epidermolysis bullosa, a severe inherited skin blistering disease 1,3 . Human keratinocytes that produce a laminin-332 free matrix have no inhibitory activity on mechanotransduction.…”

Diseases of epidermal keratins and their linker proteins

“…Mutations in different forms of EB have now been identified in each of the known genes encoding the macromolecular components of the hemidesmosomes, with the exception of BPAG1 [39,40]. Careful examination of the mutation database in these genes reveals genotypephenotype correlations which reflect the expression of the mutated genes, the types and combinations of the mutations, and their consequences at the mRNA and protein levels.…”

“…The 180-kDa bullous pemphigoid antigen (BPAG2), a transmembrane protein, also known as type XVII collagen (COL17A1), together with α6β4 integrin, extends from the intracellular compartment into the extracellular space, thus stabilizing the association of basal keratinocytes to the underlying basement membrane. Consequently, mutations resulting in abnormalities in any one of the protein components of the hemidesmosomes can give rise to different forms of EB.Mutations in different forms of EB have now been identified in each of the known genes encoding the macromolecular components of the hemidesmosomes, with the exception of BPAG1 [39,40]. Careful examination of the mutation database in these genes reveals genotypephenotype correlations which reflect the expression of the mutated genes, the types and combinations of the mutations, and their consequences at the mRNA and protein levels.…”