Erythrokeratodermia Variabilis et Progressiva (EKVP) Linked Cx30.3 Mutants can be Selectively Rescued by Co-expression of Wildtype Keratinocyte Connexins
Abstract
Connexin 30.3 (Cx30.3) is a β-connexin encoded by GJB4 that is key in epidermal homeostasis. Eleven mutations to the GJB4 are linked to an autosomal dominant skin disease called erythrokeratodermia variabilis et progressiva (EKVP). These mutations remain largely uncharacterized, limiting therapeutic options. In this study, we characterize the expression and functional status of three EKVP-linked Cx30.3 mutants, G12D, T85P and F189Y in rat epidermal keratinocytes. We found that EKVP-linked Cx30.3 mutants were not functional due to their retention in the endoplasmic reticulum (ER), but did not upregulate BiP, an indicator of ER stress. Sub-physiological incubation and chemical chaperones (such as 4-PBA, TUDCA, and glycerol) failed to rescue EKVP-linked mutants to the cell surface, however, we found that co-expression of wildtype keratinocyte connexins rescued the assembly of all three EKVP-linked mutants into gap junctions. This suggests that selective upregulation of wildtype keratinocytes may have therapeutic value.