Pendred's syndrome is an autosomal recessive disorder defined by congenital deafness, goiter and an impairedthyroidal iodide organification. It is caused by mutations in the PDS (Pendred's syndrome) gene. Mutations inthis gene may be among the most frequent genetic causes of congenital deafness since they are not onlyassociated with Pendred's syndrome, but they also form the molecular basis of two forms of non-syndromicdeafness. 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. Functionalstudies in Xenopus oocytes revealed that pendrin is able to transport chloride and iodide. In thyroid follicularcells, pendrin is expressed at the apical membrane suggesting that it could be involved in the transport ofiodide into the follicular lumen. In the kidney, pendrin is found in 13-intercalated cells of the cortical collectingduct and is thought to function as a chloride/base exchanger. The exact role of pendrin in the inner earremains unknown. Our preliminary data support the concept that pendrin is an apical iodide transporter. Adetailed characterization of the anion transport properties of pendrin is essential for the understanding of itsrole in iodide transport in thyrocytes and the synthesis of thyroid hormones. At this point, there are no data onthe kinetic properties of pendrin-mediated iodide transport, and its regulation. The membrane topology andsecondary modifications of pendrin are unknown, and the determinants for PDS gene expression have notbeen characterized. The goals of this proposal are focused on studies addressing the function and structure ofpendrin. 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 secondarymodifications of pendrin and will thus contribute to the elucidation of structure-function relationships. Theexperiments in Specific Aim 3 will determine the cell specificity of the pendrin promoter and study itsregulation. These studies will provide fundamental insights into the (patho)physiology of this novel aniontransporter that has important functions in the thyroid, the kidney and the inner ear.
|Effective start/end date||1/1/03 → 12/31/07|
- National Institute of Diabetes and Digestive and Kidney Diseases (5 R01 DK063024-05 (Rev.3/09/07))