Integrin mutations in blistering skin diseases and related genetically engineered mouse models

Abstract

As major receptors for cellular adhesion, integrins in the epidermis are critical to maintain skin integrity. Integrins α6β4 and α3β1 are among the most highly and widely expressed integrins in the skin. Perhaps not surprisingly, mutation in subunits associated with these integrins cause variations of a blistering skin disease called junctional epidermolysis bullosa (JEB), which is characterized by blisters that form between the epidermis and dermis of the skin. This review highlights how the differences in structural roles and functions for these epidermal integrins lead to distinct JEB phenotypes resulting from their absence. Additionally, much has been learned by using genetically engineered mouse models, which are featured throughout the review, as they closely resemble the disorders of human patients that harbor analogous mutations.

Keywords: Epidermolysis bullosa; Integrin; Mouse models; Mutation; Skin disease.

Figure 1.

The integrin family of cell adhesion receptors and their ligand-binding specificities. There are 18 α subunits and eight β subunits that can dimerize in different but limited combinations to form 24 distinct integrins with different ligand-binding specificities. A classical categorization of integrins is shown [3]. Epidermal integrins include laminin receptors, α6β4 and α3β1, collagen receptor α2β1, RGD-binding receptors α5β1, αvβ5, and αvβ6, as well as integrin α9β1. Note that while classically categorized as a leukocyte receptor due to its presence on leukocytes, integrin α9β1 in the skin binds to several ligands of the skin ECM including tenascin-C, fibronectin, and osteopontin [11]. This figure was adapted from earlier work [3] and created using BioRender.