The potency of the fs260 connexin43 mutant to impair keratinocyte differentiation is distinct from other disease-linked connexin43 mutants.
Although there are currently 62 mutants of Cx43 (connexin43) that can cause ODDD (oculodentodigital dysplasia), only two mutants have also been reported to cause palmar plantar hyperkeratosis. To determine how mutants of Cx43 can lead to this skin disease, REKs (rat epidermal keratinocytes) were engineered to express an ODDD-associated Cx43 mutant always linked to skin disease (fs260), an ODDD-linked Cx43 mutant which has been reported to sometimes cause skin disease (fs230), Cx43 mutants which cause ODDD only (G21R, G138R), a mouse Cx43 mutant linked to ODDD (G60S), a non-disease-linked truncated Cx43 mutant that is trapped in the endoplasmic reticulum (Delta244*) or full-length Cx43. When grown in organotypic cultures, of all the mutants investigated, only the fs260-expressing REKs consistently developed a thinner stratum corneum and expressed lower levels of Cx43, Cx26 and loricrin in comparison with REKs overexpressing wild-type Cx43. REKs expressing the fs260 mutant also developed a larger organotypic vital layer after acetone-induced injury and exhibited characteristics of parakeratosis. Collectively, our results suggest that the increased skin disease burden exhibited in ODDD patients harbouring the fs260 mutant is probably due to multiple additive effects cause by the mutant during epidermal differentiation.
Churko
Jared M
JM
Department of Anatomy and Cell Biology, University of Western Ontario, London, Canada.
Langlois
Stephanie
S
Pan
Xinyue
X
Shao
Qing
Q
Laird
Dale W
DW
D000818:Animals; D001483:Base Sequence; D002454:Cell Differentiation / Q000235:genetics*; D002478:Cells, Cultured; D000072259:Connexin 26; D018031:Connexin 43 / Q000235:genetics / Q000502:physiology*; D017630:Connexins / Q000378:metabolism; D017931:DNA Primers; D005455:Fluorescent Antibody Technique; D015603:Keratinocytes / Q000166:cytology*; D008565:Membrane Proteins / Q000378:metabolism; D016297:Mutagenesis, Site-Directed; D010766:Phosphorylation; D051381:Rats; D012871:Skin Diseases / Q000235:genetics* / Q000473:pathology
D018031:Connexin 43; D017630:Connexins; D017931:DNA Primers; C000607044:Gjb2 protein, rat; D008565:Membrane Proteins; C064554:loricrin; D000072259:Connexin 26