The Cx26-G45E mutation displays increased hemichannel activity in a mouse model of the lethal form of keratitis-ichthyosis-deafness syndrome.
The Cx26-G45E mutation displays increased hemichannel activity in a mouse model of the lethal form of keratitis-ichthyosis-deafness syndrome.
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DOI：
10.1091/mbc.e11-09-0778
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发表时间：
2011-12
影响因子：
3.3
通讯作者：
White TW
中科院分区：
文献类型：
--
作者：
Mese G;Sellitto C;Li L;Wang HZ;Valiunas V;Richard G;Brink PR;White TW
导致角膜炎-鱼鳞病-耳聋综合征（KIDS）的显性Cx26突变显示半通道活性增加。这些突变的转基因表达在小鼠身上重现了人类皮肤病。过量的半通道活性持续存在于转基因小鼠的病变表皮中。因此，半通道活性可能是治疗KIDS的一个新的治疗靶点。GJB2基因（Cx26）的突变导致人类耳聋。大多数是功能丧失突变，引起非综合征性耳聋。一些突变产生功能增益，并引起与皮肤疾病相关的综合征性耳聋，如角膜炎-鱼鳞病-耳聋综合征（KIDS）。Cx26-G45E是一种与KIDS相关的致命突变，它形成了构成性活性连接蛋白半通道。突变的Cx26半通道干扰正常表皮角化的病理机制尚不清楚。我们通过在角质形成细胞中诱导表达Cx26-G45E的转基因小鼠，建立了KIDS的动物模型。Cx26-G45E小鼠表现出活力降低、角化过度、结垢、皮肤褶皱和脱发。组织病理学包括增生、棘层增生、乳头状瘤病、细胞增大和骨堵塞。这些异常与人类KIDS病理相关，并与转基因角质形成细胞中增加的半通道电流相关。这些结果证实了G45E突变的致病性质，并为研究异常连接蛋白半通道在表皮分化和遗传性连接蛋白疾病中的作用提供了新的模型。
Dominant Cx26 mutations that cause keratitis-ichthyosis-deafness syndrome (KIDS) show increased hemichannel activity. Transgenic expression of these mutations recapitulates human skin disease in mice. Excess hemichannel activity persists in diseased epidermis from the transgenic mice. Thus hemichannel activity may be a novel therapeutic target in the treatment of KIDS. Mutations in the GJB2 gene (Cx26) cause deafness in humans. Most are loss-of-function mutations and cause nonsyndromic deafness. Some mutations produce a gain of function and cause syndromic deafness associated with skin disorders, such as keratitis-ichthyosis-deafness syndrome (KIDS). Cx26-G45E is a lethal mutation linked to KIDS that forms constitutively active connexin hemichannels. The pathomechanism(s) by which mutant Cx26 hemichannels perturb normal epidermal cornification are poorly understood. We created an animal model for KIDS by generating an inducible transgenic mouse expressing Cx26-G45E in keratinocytes. Cx26-G45E mice displayed reduced viability, hyperkeratosis, scaling, skin folds, and hair loss. Histopathology included hyperplasia, acanthosis, papillomatosis, increased cell size, and osteal plugging. These abnormalities correlated with human KIDS pathology and were associated with increased hemichannel currents in transgenic keratinocytes. These results confirm the pathogenic nature of the G45E mutation and provide a new model for studying the role of aberrant connexin hemichannels in epidermal differentiation and inherited connexin disorders.