Pathomechanisms of epidermolysis bullosa: Beyond structural proteins

Matrix Biol. 2022 Jun:110:91-105. doi: 10.1016/j.matbio.2022.04.007. Epub 2022 Apr 30.

Abstract

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-à-vis their function, associated clinical manifestations, and involvement in the pathogenesis of EB.

Keywords: Cutaneous basement membrane zone; Epidermolysis Bullosa; Mutation detection strategies; Skin fragility disorders.

Publication types

  • Review
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Adaptor Proteins, Signal Transducing / metabolism
  • Basement Membrane / metabolism
  • Epidermis / pathology
  • Epidermolysis Bullosa* / metabolism
  • Humans
  • Mutation
  • Phosphoric Diester Hydrolases / genetics
  • Skin / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • EXPH5 protein, human
  • Phosphoric Diester Hydrolases
  • USB1 protein, human