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首页> 美国卫生研究院文献>other >Connexin26 mutations causing palmoplantar keratoderma and deafness interact with connexin43 modifying gap junction and hemichannel properties
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Connexin26 mutations causing palmoplantar keratoderma and deafness interact with connexin43 modifying gap junction and hemichannel properties

机译：连接蛋白26突变导致掌plant角化病和耳聋与连接蛋白43相互作用改变缝隙连接和半通道特性

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Mutations in GJB2 (Cx26) cause either deafness, or deafness associated with skin diseases. That different disorders can be caused by distinct mutations within the same gene suggests that unique channel activities are influenced by each class of mutation. We have examined the functional characteristics of two human mutations, Cx26-H73R and Cx26-S183F, causing palmoplantar keratoderma (PPK) and deafness. Both failed to form gap junction channels or hemichannels when expressed alone. Co-expression of the mutants with wild-type Cx43 showed a trans-dominant inhibition of Cx43 gap junction channels, without reductions in Cx43 protein synthesis. In addition, the presence of mutant Cx26 shifted Cx43 channel gating and kinetics towards a more Cx26-like behavior. Co-immunoprecipitation showed Cx43 being pulled down more efficiently with mutant Cx26, than wild-type, confirming the enhanced formation of heteromeric connexons. Finally, the formation of heteromeric connexons resulted in significantly increased Cx43 hemichannel activity in the presence of Cx26 mutants. These findings suggest a common mechanism whereby Cx26 mutations causing PPK and deafness trans-dominantly influence multiple functions of wild-type Cx43. They also implicate a role for aberrant hemichannel activity in the pathogenesis of PPK, and further highlight an emerging role for Cx43 in genetic skin diseases.
机译：GJB2（Cx26）突变会引起耳聋或与皮肤疾病有关的耳聋。同一基因内不同的突变可能导致不同的疾病，这表明独特的通道活性受每一类突变的影响。我们已经检查了两个人类突变Cx26-H73R和Cx26-S183F的功能特征，它们引起掌足角化病（PPK）和耳聋。当单独表达时，两者均未形成间隙连接通道或半通道。突变体与野生型Cx43的共表达显示出对Cx43间隙连接通道的反式抑制，而Cx43蛋白合成没有减少。此外，突变体Cx26的存在将Cx43通道门控和动力学转移到更像Cx26的行为上。免疫共沉淀显示，与野生型相比，突变型Cx26能够更有效地将Cx43下拉，这证实了异源连接体形成的增强。最后，在Cx26突变体存在下，异聚体连接子的形成导致Cx43半通道活性显着增加。这些发现提示一种共同的机制，其中引起PPK和耳聋的Cx26突变主要影响野生型Cx43的多种功能。它们还暗示了异常的半通道活性在PPK的发病机理中的作用，并进一步突显了Cx43在遗传性皮肤病中的新兴作用。

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