Additional Supporting Information may be found in the online version of this article: Figure S1. Clinical photograph of affected person and PCR genotyping. (a). Affected right hand and arm of the proband, which was characterised by episodic, self-limiting, often recurrent, local subcutaneous nonpruritic oedema. (b). Agarose gel electrophoretograms of exon 8 PCR products in affected family members, unaffected members and normal controls. Abstract: Desmosomes are highly organized intercellular junctions composed of a number of interacting proteins that provide mechanical integrity to epithelial tissues. Mutations in genes encoding desmosomal proteins, including desmoplakin (DP), are associated with human hereditary diseases affecting skin integrity. The detailed mechanism of desmosome assembly remains, despite many efforts, incompletely understood. Recently, the ubiquitinproteasome system (UPS) has been suggested to be an important regulatory system for the proper intracellular trafficking of proteins. Here, we provide evidence for a calcium-independent, but UPS-dependent, stabilization of cell-cell contacts in human keratinocytes, which might be mediated by the maintenance of DP at desmosomes.