Cx26 mutations in syndromic deafness linked to skin disease

描述(申请人提供)：连接蛋白是缝隙连接的亚单位蛋白，它允许相邻细胞之间通过细胞间通道交换离子、第二信使和小的代谢物。此外，连接蛋白还可以在非连接膜上形成功能性半管。连接蛋白基因的突变会导致多种人类疾病，包括耳聋和皮肤病。例如，连接蛋白26(Cx26或GJB2)的突变导致非综合征性耳聋，或与各种皮肤病相关的综合征性耳聋，包括掌跖角化病(PPK)、角膜炎-鱼鳞病-耳聋综合征(KID)和Vohwinkel综合征(VS)。导致皮肤病和耳聋的Cx26突变都是单一氨基酸的变化，其导致皮肤病理的机制(S)尚不清楚。由于非综合征性耳聋主要是一种功能障碍的丧失，因此，综合征性突变体可能表现出功能的改变或增加，从而导致皮肤病。在这项提议中，我们寻求准确地定义导致人类皮肤病的Cx26突变的功能后果。此外，我们寻求开发复制由连接蛋白突变引起的人类皮肤病的动物模型，并使用它们来探索潜在的治疗干预策略。我们建议首先检查导致皮肤病的显性Cx26突变的功能特性。其次，我们将建立人类皮肤病的转基因小鼠模型，并表征表皮病理的进展。第三，我们将在转基因细胞系统和转基因动物中使用药物抑制和/或反义介导的基因敲除来抑制突变的连接蛋白活性。这些研究将提供以下方面的见解：突变如何改变Cx26导致皮肤病的功能活性，这些新功能是否会改变动物模型中的表皮动态平衡，以及对突变蛋白的特定抑制是否将显示出作为潜在治疗策略的前景。 与公共卫生相关：连接蛋白基因突变导致广泛的人类健康问题。在Cx26的案例中，功能研究揭示了很多关于耳聋导致突变的信息，但对导致皮肤病的Cx26突变的功能后果知之甚少。拟议的研究将展示突变如何改变Cx26导致皮肤病的功能活性，这些新功能是否会在实验动物中导致皮肤病，以及对突变蛋白的特定抑制是否将显示出作为一种可能的治疗策略的前景。

DESCRIPTION (provided by applicant): Connexins are the subunit proteins of gap junctions, which allow the exchange of ions, second messengers and small metabolites between adjacent cells through intercellular channels. In addition, connexins can form functional hemichannels in non-junctional membranes. Mutations in connexin genes cause a variety of human diseases, including deafness and skin disorders. For example, mutations in connexin26 (Cx26, or GJB2) cause nonsyndromic deafness, or syndromic deafness associated with a variety of skin disorders including palmoplantar keratoderma (PPK), keratitis- ichthyosis-deafness syndrome (KID), and Vohwinkel syndrome (VS). The Cx26 mutations causing skin diseases and deafness are all single amino acid changes, and the mechanism(s) whereby they lead to skin pathology are unknown. Since nonsyndromic deafness is predominantly a loss of function disorder, it follows that the syndromic mutants may show an alteration, or gain, of function to cause skin disease. In this proposal, we seek to precisely define the functional consequences of Cx26 mutations that cause skin disease in humans. In addition, we seek to develop animal models that replicate human skin disorders caused by connexin mutations and use them to explore potential therapeutic intervention strategies. We propose first to examine the functional properties of dominant Cx26 mutations that cause skin disease. Second, we will generate transgenic mouse models of human skin disease and characterize the progression of epidermal pathology. Third, we will use pharmacological inhibition and/or antisense mediated knockdown in transfected cell systems and transgenic animals to inhibit mutant connexin activity. These studies will provided insights into how mutations alter the functional activity of Cx26 leading to skin disease, if these novel functions change epidermal homeostasis in animal models, and whether specific inhibition of the mutant proteins will show promise as a potential therapeutic strategy. PUBLIC HEALTH RELEVANCE: Mutations in connexin genes cause a broad spectrum of human health problems. In the case of Cx26, functional studies have revealed much about deafness causing mutations, but very little is known about the functional consequences of Cx26 mutations that cause skin disease. The proposed studies will show how mutations alter the functional activity of Cx26 leading to skin disease, whether these novel functions cause skin disease in experimental animals, and if specific inhibition of the mutant proteins will show promise as a possible therapeutic strategy.