Connexin channels in congenital skin disorders.
Connexin channels in congenital skin disorders.
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DOI：
10.1016/j.semcdb.2015.11.018
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发表时间：
2016-02
影响因子：
7.3
通讯作者：
White TW
中科院分区：
文献类型：
--
作者：
Lilly E;Sellitto C;Milstone LM;White TW
缝隙连接和半通道组成的连接蛋白影响表皮细胞的增殖和分化。通过研究连接蛋白突变引起的疾病，我们对连接蛋白在皮肤中的功能作用的理解取得了重大进展。11种临床定义的皮肤疾病与重叠的表型谱是由5种不同的连接蛋白基因突变引起的，这突出表明必须通过了解连接蛋白功能如何受到影响来解读疾病的表现。越来越多的证据表明，由连接蛋白突变引起的皮肤病是由功能的显性增益引起的。在伴耳聋的掌跖角化病中，连接蛋白26突变可显性改变野生型连接蛋白43的功能并产生渗漏的异聚半通道。在角膜炎-鱼鳞病-耳聋综合征中，不同的连接蛋白26突变可以形成具有改变的钙调节或增加的钙渗透性的显性半通道，导致该综合征的临床亚型。只有详细了解这些细微的功能差异，我们才有希望为连接蛋白皮肤疾病创造成功的病理生理学驱动疗法。
Gap junctions and hemichannels comprised of connexins influence epidermal proliferation and differentiation. Significant advances in our understanding of the functional role of connexins in the skin have been made by studying the diseases caused by connexin mutations. Eleven clinically defined cutaneous disorders with an overlapping spectrum of phenotypes are caused by mutations in five different connexin genes, highlighting that disease presentation must be deciphered with an understanding of how connexin functions are affected. Increasing evidence suggests that the skin diseases produced by connexin mutations result from dominant gains of function. In palmoplantar keratoderma with deafness, the connexin 26 mutations transdominantly alter the function of wild-type connexin 43 and create leaky heteromeric hemichannels. In keratitis-ichthyosis-deafness syndrome, different connexin 26 mutations can either form dominant hemichannels with altered calcium regulation or increased calcium permeability, leading to clinical subtypes of this syndrome. It is only with detailed understanding of these subtle functional differences that we can hope to create successful pathophysiology driven therapies for the connexin skin disorders.