Junctional Epidermolysis Bullosa: Allelic Heterogeneity and Mutation Stratification for Precision Medicine

Abstract

Junctional epidermolysis bullosa (JEB) is a hereditary blistering disease caused by reduced dermal-epidermal adhesion due to deficiencies of one of the proteins, laminin-332, type XVII collagen, integrin α6β4 or integrin α3. Significant progress has been achieved in the development of therapies for EB, such as bone-marrow transplantation, local or systemic injections with fibroblasts or mesenchymal stromal cells, readthrough of premature termination codons, or exon skipping. These were tailored in particular for dystrophic EB, which is caused by type VII collagen deficiency and have not yet reached broad clinical practice. Recently, pioneering combined gene and stem cell therapy was successful in treating one boy with junctional EB. Beside these exclusive approaches, no specific therapy to amend the major clinical features, skin and mucosal blistering and non-healing wounds is available to date. Here we extend the mutational spectrum of junctional EB, provide a stratification of COL17A1 mutations and discuss potential molecular therapeutic approaches.

Consensus reclassification of inherited epidermolysis bullosa and other disorders with skin fragility

“…Pathogenic variants leading to absence of laminin 332 or integrin α6β4 are associated with early lethality, whereas most COL17A1 pathogenic variants result in absence of collagen XVII but are associated with less severe phenotypes . Missense or splicing mutations allowing expression of a residual protein lead to milder phenotypes.…”

“…antisense oligonucleotides for exon skipping 93 ) or modulation of protein misfolding, 94 may be applied for different genes/ proteins, under the premise of knowledge of individual mutations and their consequences. Therefore, subclassification of EB and SF disorders on the basis of the molecular defect, and stratification of mutations for precision medicine 44 is a tempting challenge for the future.…”

Multiple Skin Squamous Cell Carcinomas in Junctional Epidermolysis Bullosa Due to Altered Laminin-332 Function

“…In addition, JEB-related non-blistering conditions with specific tissue manifestations result from dominant haploinsufficiency or from partial loss-of-function that spares the amount and coiled coil domain of the heterotrimer [3,[11][12][13]. JEB-GI can also be due to genetic defects in COL17A1 encoding collagen XVII [14].…”

Basement membrane collagens and disease mechanisms

“…COL17A1 mutations cause junctional epidermolysis bullosa (OMIM # 226650), which can also be caused by mutations in the laminin genes LAMA3, LAMB3, LAMC2 and integrin genes ITGA3, ITGA6 and ITGB4 [7,96,97], and is characterised by dermal–epidermal separation leading to skin blistering, and epithelial recurrent erosion dystrophy, alopecia and nail dystrophy [96]. The majority of mutations are nonsense mutations but some glycine missense mutations occur, which cause intracellular retention and thermal instability of the protein [98], indicating protein misfolding.…”

“…Here, we will provide a brief overview of recent progress in mechanisms of disease caused by mutations in BM collagens, and development of therapeutic strategies. For more in depth reviews on collagens and their diseases we refer the reader to the following: collagen IV [3–5], collagen VI [6], collagen VII and XVII [7,8], collagen XV and XVIII [9].…”