Pendred syndrome, manifested by sensorineural hearing loss and goiter is the result of mutations in the PDS gene. PDS encodes a protein labeled pendrin that functions as a chloride, formate and iodide transporter and is expressed in the thyroid, inner ear and kidney. Pendrin's function is similar to a previously described chloride/formate exchanger that plays an important role in NaCl transport across epithelial cells, suggesting that pendrin might perform a similar role in the inner ear. Recent evidence suggests that some individuals with mutations in the PDS gene do not develop thyroid abnormalities but instead have non-syndromic deafness with dilated vestibular aqueducts (DFNB4).
The aims of this proposal are to characterize pendrin in terms of its function, location and regulation and determine how different PDS mutations affect pendrin. The following approach will be taken to achieve these aims: Polyclonal anti-pendrin antibodies (already generated by the Principal Investigator) will be used to identify the cell types in which pendrin is expressed. Pendrin function will be analyzed by determining substrate specificity, inhibitor profile, kinetics of transport and regulation, and chloride/bicarbonate exchange. The effect of different mutations in PDS on protein production, processing, regulation and transport properties will be examined. A knock out mouse model will be used to study the mechanisms of ion transport in cells where pendrin is normally expressed but rendered inactive. This work is a first step towards understanding the physiologic role of pendrin and determining how defects in pendrin lead to the clinical manifestations of Pendred syndrome.
| Karniski, Lawrence P (2004) Functional expression and cellular distribution of diastrophic dysplasia sulfate transporter (DTDST) gene mutations in HEK cells. Hum Mol Genet 13:2165-71 |
