Messages from Mutant Desmosomes

Abstract

Single gene disorders are ideally suited to establish robust genotype‒phenotype correlations and provide excellent opportunities to understand molecular pathomechanisms with relevance to complex disorders. The observation that patients diagnosed with the same causative mutation can present with phenotypic disease variability illustrates the significant role of disease modifiers and warns against oversimplification. In a new article in the Journal of Investigative Dermatology, Zimmer etal. (2021) analyze two mutations located in the desmoglein (DSG) 1 transmembrane domain (TMD) and find that both mutants fail to assemble into desmosomes owing to reduced membrane trafficking and lipid raft targeting. One mutation maintained normal protein expression levels and turnover relative to those of wild-type (WT) DSG1, and behaved as a dominant negative. The second mutant showed reduced stability and increased turnover compared with WT DSG1 as well as reduced desmosome size and abundance. A full understanding of the TMD of DSG1 requires cell biological approaches, underscoring the value of cell biology in biomedical research in general.