Differential Pathomechanisms of Desmoglein 1 Transmembrane Domain Mutations in Skin Disease.

• Type of Material: Article
• Authors: Stephanie E Zimmer, The Pennsylvania State University; Takuya Takeichi, Nagoya University; Daniel E Conway, Virginia Commonwealth University; Akiharu Kubo, Division of Dermatology, Department of Internal Related, Kobe University Graduate School of Medicine, Kobe, Japan.; Yasushi Suga, Kobe University; Masashi Akiyama, Nagoya University; Andrew Kowalczyk, Emory University
• Language: English
• Date: 2022-02
• Publisher: Emory University Libraries
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2021 The Authors. Published by Elsevier, Inc. on behalf of the Society for Investigative Dermatology.
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.jid.2021.07.154
• Title of Journal or Parent Work: J Invest Dermatol
• Volume: 142
• Issue: 2
• Start Page: 323
• End Page: 332.e8
• Keywords: Desmosomal Cadherins; Desmoglein 1; Keratoderma, Palmoplantar; Membrane Microdomains; Epidermis; Humans; Mutation, Missense; Cell Line, Tumor; Desmosomes; Loss of Function Mutation; Cell Adhesion; Protein Domains; Protein Stability

Abstract

Dominant and recessive mutations in the desmosomal cadherin, desmoglein (DSG) 1, cause the skin diseases palmoplantar keratoderma (PPK) and severe dermatitis, multiple allergies, and metabolic wasting (SAM) syndrome, respectively. In this study, we compare two dominant missense mutations in the DSG1 transmembrane domain (TMD), G557R and G562R, causing PPK (DSG1PPK-TMD) and SAM syndrome (DSG1SAM-TMD), respectively, to determine the differing pathomechanisms of these mutants. Expressing the DSG1TMD mutants in a DSG-null background, we use cellular and biochemical assays to reveal the differences in the mechanistic behavior of each mutant. Super-resolution microscopy and functional assays showed a failure by both mutants to assemble desmosomes due to reduced membrane trafficking and lipid raft targeting. DSG1SAM-TMD maintained normal expression levels and turnover relative to wildtype DSG1, but DSG1PPK-TMD lacked stability, leading to increased turnover through lysosomal and proteasomal pathways and reduced expression levels. These results differentiate the underlying pathomechanisms of these disorders, suggesting that DSG1SAM-TMD acts dominant negatively, whereas DSG1PPK-TMD is a loss-of-function mutation causing the milder PPK disease phenotype. These mutants portray the importance of the DSG TMD in desmosome function and suggest that a greater understanding of the desmosomal cadherin TMDs will further our understanding of the role that desmosomes play in epidermal pathophysiology.