Cx26 mutations in syndromic deafness linked to skin disease

与皮肤病相关的综合征性耳聋中的 Cx26 突变

• 批准号: 8034257
• 负责人: THOMAS W WHITE
• 金额: $ 33.67万
• 依托单位: STATE UNIVERSITY NEW YORK STONY BROOK
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-04-01 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8034257
• 关键词: Alleles; Amino Acids; Animal Model; Animals; Antisense Oligonucleotides; Behavior; Biological Assay; Cell Culture Techniques; Cell Line; Cells; Connexins; Cyclic AMP; Data; Disease; Dyes; Epidermis; Exhibits; Flufenamic Acid; Gap Junctions; Gel; Genes; Health; Hearing Impaired Persons; Homeostasis; Human; In Vitro; Individual; Intervention; Ion Exchange; Keratin; Lead; Link; Mediating; Membrane; Methods; Mus; Mutation; Palmoplantar Keratosis; Pathology; Permeability; Pharmaceutical Preparations; Pluronics; Property; Proteins; Publishing; Second Messenger Systems; Senter syndrome; Skin; Skin Abnormalities; Syndrome; System; Terminator Codon; Testing; Tetanus Helper Peptide; Tetracycline Control; Therapeutic; Therapeutic Intervention; Topical application; Trans-Activators; Transgenes; Transgenic Animals; Transgenic Mice; Xenopus oocyte; deafness; disease-causing mutation; gain of function; human disease; in vivo; inhibitor/antagonist; insight; keratinocyte; loss of function; loss of function mutation; mouse model; mutant; novel; promoter; public health relevance; second messenger; skin disorder

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.

描述（由申请人提供）：连接蛋白是间隙连接的亚基蛋白，它允许离子、第二信使和小代谢物通过细胞间通道在相邻细胞之间交换。此外，连接蛋白可以在非连接膜上形成功能性的半通道。连接蛋白基因的突变导致多种人类疾病，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，或与多种皮肤疾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）。导致皮肤疾病和耳聋的Cx26突变都是单氨基酸变化，它们导致皮肤病理的机制尚不清楚。由于非综合征性耳聋主要是一种功能丧失障碍，因此，综合征性突变可能表现出功能的改变或增加，从而导致皮肤疾病。在本提案中，我们试图精确定义导致人类皮肤病的Cx26突变的功能后果。此外，我们寻求开发动物模型来复制由连接蛋白突变引起的人类皮肤疾病，并利用它们来探索潜在的治疗干预策略。我们建议首先研究导致皮肤疾病的显性Cx26突变的功能特性。其次，我们将产生人类皮肤病转基因小鼠模型，并表征表皮病理的进展。第三，我们将在转染的细胞系统和转基因动物中使用药理学抑制和/或反义介导的敲低来抑制突变的连接蛋白活性。这些研究将深入了解突变如何改变导致皮肤病的Cx26的功能活性，这些新功能是否会改变动物模型中的表皮稳态，以及特异性抑制突变蛋白是否有望成为一种潜在的治疗策略。