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.