Department of Anatomy and Cell Biology, University of Western Ontario, London, Canada.
Biochem J. 2010 Aug 1;429(3):473-83. doi: 10.1042/BJ20100155.
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.
尽管目前已经发现了 62 种 Cx43（连接蛋白 43）突变体可导致 ODDD（眼-齿-指发育不良），但仅有两种突变体也被报道可导致手掌足底过度角化症。为了确定 Cx43 突变体如何导致这种皮肤疾病，我们构建了表达与 ODDD 相关的 Cx43 突变体（总是与皮肤疾病相关的 fs260）、与 ODDD 相关的 Cx43 突变体（曾被报道有时会引起皮肤疾病的 fs230）、仅导致 ODDD 的 Cx43 突变体（G21R、G138R）、与 ODDD 相关的小鼠 Cx43 突变体（G60S）、与疾病无关的截短型 Cx43 突变体（被困在内质网中的 Delta244*）或全长 Cx43 的大鼠表皮角质形成细胞（REKs）。在器官型培养物中，在所研究的所有突变体中，只有表达 fs260 的 REKs 一致地表现出更薄的角质层和更低水平的 Cx43、Cx26 和板层素表达，与过表达野生型 Cx43 的 REKs 相比。表达 fs260 突变体的 REKs 在丙酮诱导损伤后也形成了更大的器官型活层，并表现出角化不全的特征。总之，我们的结果表明，携带 fs260 突变体的 ODDD 患者表现出更高的皮肤疾病负担，可能是由于突变体在表皮分化过程中产生的多种累加效应所致。
