Master of Science
Anatomy and Cell Biology
Dr. Dale W. Laird
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.
Summary for Lay Audience
Connexins (Cx) are a family of proteins that allow direct communication between most cells in the body. Specific mutations to the gene that makes Cx30.3 in the skin can lead to an inherited disease called erythrokeratodermia variabilis et progressive (EKVP). Some mutant connexins are incapable of reaching the surface of skin cells where they normally maintain healthy skin. Characterizing why these mutant connexins are defective will inform on possible treatment strategies for these patients, as one does not currently exist. We first found the EKVP-linked mutants were retained in the wrong compartment of the skin cells. Drugs designed to treat defective proteins did not appear to be effective for these mutants. We were excited to see skin cells that had mutant connexins mixed with other skin cell connexins were able to rescue the mutants from the wrong cellular compartment and direct them to the cell surface where they are needed. It has not been determined if these rescued connexins are functional at the cell surface, but our study suggests that treatment strategies based on these findings could lead to restored skin health in EKVP patients.
Figliuzzi, Rhett O., "Erythrokeratodermia Variabilis et Progressiva (EKVP) Linked Cx30.3 Mutants can be Selectively Rescued by Co-expression of Wildtype Keratinocyte Connexins" (2021). Electronic Thesis and Dissertation Repository. 8022.
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Available for download on Friday, August 11, 2023