Pathomechanisms of epidermolysis bullosa: Beyond structural proteins

Epidermolysis bullosa (EB), a phenotypically and genetically heterogeneous disorder, has been linked to mutations in the genes encoding structural proteins that reinforce skin integrity via dermal-epidermal adhesion. Breakdowns in these adhesion mechanisms result in four different subtypes of EB classified on the basis of the level of tissue separation within the cutaneous basement membrane zone (BMZ). Mutations in as many as 17 distinct genes that encode structural proteins in the BMZ have been linked to EB. Despite the clinical and histopathological confirmation of EB, many cases remain genetically unsolved. Technical advancements in next-generation sequencing have paved the way for the identification of genes involved in the pathophysiology of EB. Structural proteins have long been identified as the candidate molecules altered in EB, however, recently non-structural proteins, encoded for example by PLOD3, USB1, EXPH5, and KLHL24, involved in enzymatic modification or migration of structural proteins have been implicated. In this overview, we discuss recent work regarding these proteins vis-a-vis their function, associated clinical manifestations, and involvement in the pathogenesis of EB. (C) 2022 Elsevier B.V. All rights reserved.

Automated summary

Epidermolysis bullosa (EB) is a phenotypically and genetically heterogeneous disorder caused by mutations in genes encoding structural proteins that reinforce skin integrity. Breakdowns in these proteins lead to the disruption of skin adhesion mechanisms. Despite clinical and histopathological confirmation, there are still many genetically unsolved cases of EB. Recent advancements have implicated non-structural proteins in the pathophysiology of EB.