GJB4 variants linked to skin disease exhibit a trafficking deficiency en route to gap junction formation that can be restored by co-expression of select connexins

• DOI: 10.3389/fcell.2023.1073805
• Publication Date: 2023-02-13T06:27:30Z
• Authors: Sergiu A. Lucaciu; Rhett Figliuzzi; Ruth Neumann; Samina Nazarali; Luigi Del Sordo; Stephanie E. Leig...; Alexandra Hauser; Qing Shao; Danielle Johnston; Donglin Bai; Dale W. Laird
• Keywords: Ectopic expression

Epidermal keratinocytes are enriched with at least nine connexins that key regulators of epidermal homeostasis. The role Cx30.3 in and health became evident when fourteen autosomal dominant mutations the Cx30.3-encoding GJB4 gene were linked to a rare incurable skin disorder called erythrokeratodermia variabilis et progressiva (EKVP). While these variants EKVP, they remain largely uncharacterized hindering therapeutic options. In this study, we characterize expression functional status three EKVP-linked mutants (G12D, T85P, F189Y) tissue-relevant differentiation-competent rat keratinocytes. We found GFP-tagged non-functional likely due their impaired trafficking primary entrapment within endoplasmic reticulum (ER). However, all failed increase BiP/GRP78 levels suggesting not inducing an unfolded protein response. FLAG-tagged also yet occasionally exhibited some capacity assemble into gap junctions. pathological impact may extend beyond deficiencies as expressing increased propidium iodide uptake absence divalent cations. Attempts rescue delivery junctions by chemical chaperone treatment ineffective. co-expression wild type greatly enhanced assembly junctions, although endogenous do appear prevent pathology patients harboring mutations. addition, spectrum connexin isoforms (Cx26, Cx30, Cx43) differential ability trans-dominantly broad range favourably interact mutants. conclude selective upregulation compatible have potential value rescuing defects invoked