Function and structure of pendrin in thyroid cells

描述（由申请人提供）：彭德雷德综合征是一种常染色体隐性遗传病，由先天性耳聋、甲状腺肿和甲状腺碘化组织受损定义。它是由PDS（彭德雷德综合征）基因突变引起的。该基因的突变可能是先天性耳聋最常见的遗传原因之一，因为它们不仅与Pendred综合征有关，而且还构成了两种形式的非综合征性耳聋的分子基础。PDS基因编码pdrin，这是一种属于溶质载体家族26A （SCL26A4）的阴离子转运蛋白。Pendrin主要在甲状腺、肾脏和内耳中表达。爪蟾卵母细胞的功能研究表明，penddrin能够运输氯化物和碘化物。在甲状腺滤泡细胞中，pendrin在顶膜表达，表明它可能参与碘离子进入滤泡腔的运输。在肾脏中，pendin存在于皮质集管的β -嵌层细胞中，被认为具有氯离子/碱交换剂的功能。pendrin在内耳中的确切作用尚不清楚。我们的初步数据支持pendrin是一个根尖碘转运体的概念。对pendrin阴离子运输特性的详细描述对于了解其在甲状腺细胞碘离子运输和甲状腺激素合成中的作用至关重要。目前，还没有关于pendrin介导的碘离子转运及其调控的动力学性质的数据。pendrin的膜拓扑结构和二次修饰是未知的，PDS基因表达的决定因素也没有被表征。本提案的目标集中在解决pendrin的功能和结构的研究。特异目的1的研究旨在进一步表征pendrin的碘离子输运性质。具体目标2中概述的实验旨在表征膜拓扑结构和pendrin的二次修饰，从而有助于阐明结构-功能关系。在Specific Aim 3中的实验将确定pendin启动子的细胞特异性并研究其调控。这些研究将为这种在甲状腺、肾脏和内耳中具有重要功能的新型阴离子转运体的（病理）生理学提供基本见解。

DESCRIPTION (provided by applicant): Pendred's syndrome is an autosomal recessive disorder defined by congenital deafness, goiter and an impaired thyroidal iodide organification. It is caused by mutations in the PDS (Pendred's syndrome) gene. Mutations in this gene may be among the most frequent genetic causes of congenital deafness since they are not only associated with Pendred's syndrome, but they also form the molecular basis of two forms of non-syndromic deafness. The PDS gene encodes pendrin, an anion transporter belonging to the Solute Carrier Family 26A (SCL26A4). Pendrin is predominantly expressed in the thyroid, the kidney and the inner ear. Functional studies in Xenopus oocytes revealed that pendrin is able to transport chloride and iodide. In thyroid follicular cells, pendrin is expressed at the apical membrane suggesting that it could be involved in the transport of iodide into the follicular lumen. In the kidney, pendrin is found in beta-intercalated cells of the cortical collecting duct and is thought to function as a chloride/base exchanger. The exact role of pendrin in the inner ear remains unknown. Our preliminary data support the concept that pendrin is an apical iodide transporter. A detailed characterization of the anion transport properties of pendrin is essential for the understanding of its role in iodide transport in thyrocytes and the synthesis of thyroid hormones. At this point, there are no data on the kinetic properties of pendrin-mediated iodide transport, and its regulation. The membrane topology and secondary modifications of pendrin are unknown, and the determinants for PDS gene expression have not been characterized. The goals of this proposal are focused on studies addressing the function and structure of pendrin. The studies in Specific Aim 1 aim at further characterizing the iodide transport properties of pendrin. The experiments outlined in Specific Aim 2 seek to characterize the membrane topology and secondary modifications of pendrin and will thus contribute to the elucidation of structure-function relationships. The experiments in Specific Aim 3 will determine the cell specificity of the pendrin promoter and study its regulation. These studies will provide fundamental insights into the (patho) physiology of this novel anion transporter that has important functions in the thyroid, the kidney and the inner ear.