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 13-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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK063024-05
Application #
7169850
Study Section
Endocrinology Study Section (END)
Program Officer
Malozowski, Saul N
Project Start
2003-01-01
Project End
2007-12-31
Budget Start
2007-01-01
Budget End
2007-12-31
Support Year
5
Fiscal Year
2007
Total Cost
$246,409
Indirect Cost
Name
Northwestern University at Chicago
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
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