Inherited blistering skin diseases: underlying molecular mechanisms and emerging therapies

Figures & data

Figure 1. Histology of normal human skin (haematoxylin and eosin; scale bar = 25 μm).

Figure 2. Light microscopic appearances of inherited skin fragility at either the dermal-epidermal junction (A) or within the lower epidermis (B). Asterisk indicates the blister formation (Richardson's stain; scale bar = 50 μm).

Figure 3. Stylized diagram depicting the important components in the skin that provide the keratinocyte, cell-cell, and cell-extracellular matrix integrity along with the protein components that are mutated in inherited skin fragility diseases.

Figure 4. Clinical illustrations of different genetic disorders showing varying degrees of skin fragility. In each case the mutated skin protein is shown.

Table I. Summary of the gene and protein targets and disease phenotypes in the inherited skin fragility disorders.

Target protein	Target gene	Disease
Established EB disorders:
Keratins 5 and 14	KRT5, KRT14	EB simplex
Plectin	PLEC	EB simplex associated with muscular dystrophy
		EB simplex associated with pyloric atresia
		EB simplex associated with pyloric atresia and muscular dystrophy
		EB simplex–Ogna
α6β4 integrin	ITGA6, ITGB4	Junctional EB associated with pyloric atresia
		Non-Herlitz junctional EB
Laminin-332	LAMA3, LAMB3, LAMC2	Herlitz junctional EB
		Non-Herlitz junctional EB
		Laryngo-onycho-cutaneous syndrome (LAMA3A)
Type XVII collagen	COL17A1	Non-Herlitz junctional EB
Type VII collagen	COL7A1	Recessive dystrophic EB
		Dominant dystrophic EB
Kindlin-1	KIND1	Kindler syndrome
Plakophilin-1	PKP1	Ectodermal dysplasia–skin fragility syndrome
Desmoplakin	DSP	Striate palmoplantar keratoderma
		Woolly hair, keratoderma with or without cardiomyopathy
		Lethal acantholytic EB
Newer EB disorders:
Dystonin-epithelial isoform	DST1-e	Autosomal recessive EB simplex
α3 integrin	ITGA3	EB–congenital nephrotic syndrome–interstitial lung disease
Plakoglobin	JUP	Naxos disease
		Lethal congenital EB
Exophilin-5	EXPH5	Autosomal recessive trauma-induced skin fragility
Transglutaminase-5	TGM5	Acral peeling skin syndrome (autosomal recessive EB simplex)
Other possible EB-like disorders:
Desmocollin-3	DSC3	Hereditary hypotrichosis with skin blistering
Desmoglein -1	DSG1	Striate palmoplantar keratoderma (sometimes with skin fragility)
Corneodesmosin	CDSN	Generalised skin peeling syndrome
CD151 antigen/tetraspanin	CD151	Hereditary nephritis, skin fragility and beta-thalassemia minor
Keratins 1 and 10	KRT1, KRT10	Epidermolytic ichthyosis

Figure 5. Clinical illustration of the therapeutic challenge presented by a patient with recessive dystrophic EB and very extensive skin fragility. The various endeavours to develop new therapies that are currently at preclinical or clinical trial stages are listed.

Figure 6. Clinicopathological features of revertant mosaicism in a patient with recessive dystrophic EB and potential clinical translation for therapy. There are demarcated areas in which trauma-induced blistering does not occur on the left wrist (A) and right shin (B). Immunolabelling of the dermal-epidermal junction (C) with an antibody to type VII collagen (C7) shows bright linear staining in normal skin but a complete absence in patient skin (arrow-heads indicate dermal-epidermal junction, and asterisk denotes subepidermal blistering). In contrast, in the revertant areas there is bright linear labelling for type VII collagen (arrows) which resembles normal skin (scale bar = 50 μm). Ultrastructurally (D), the patient's blister-prone skin shows focal blistering beneath the lamina densa (asterisk), whereas in the area of revertant mosaicism there is no blistering and also evidence of new anchoring fibrils (arrows) that are completely lacking in the blistered skin (scale bar = 0.2 μm). The phenomenon of revertant mosaicism presents several opportunities for translational research and therapy (E), including culturing the reverted keratinocytes, skin grafting, and creation of inducible pluripotent stem cells.