Salicylate restores transport function and anion exchanger activity of missense pendrin mutations.

[pendred syndrome]

The SLC 26 A 4 gene encodes the transmembrane protein pendrin , which is involved in the homeostasis of the ion concentration of the endolymph of the inner ear , most likely by acting as a chloride /bicarbonate transporter . Mutations in the SLC 26 A 4 gene cause sensorineuronal hearing loss . However , the mechanisms responsible for such loss have remained unknown . Therefore , in this study , we focused on the function of ten missense pendrin mutations (p .P 123 S (Pendred syndrome ), p .M 147 V (NSEVA ), p .K 369 E (NSEVA ), p .A 372 V (Pendred syndrome /NSEVA ), p .N 392 Y (Pendred syndrome ), p .C 5 65 Y (NSEVA ), p .S 657 N (NSEVA ), p .S 666 F (NSEVA ), p .T 721 M (NSEVA ) and p .H 723 R (Pendred syndrome /NSEVA )) reported in Japanese patients , and analyzed their cellular localization and anion exchanger activity using HEK 293 cells transfected with each mutant gene . Immunofluorescent staining of the cellular localization of the pendrin mutants revealed that p .K 369 E and p .C 5 65 Y , as well as wild-type pendrin , were transported to the plasma membrane , while 8 other mutants were retained in the cytoplasm . Furthermore , we analyzed whether salicylate , as a pharmacological chaperone , restores normal plasma membrane localization of 8 pendrin mutants retained in the cytoplasm to the plasma membrane . Incubation with 10 mM of salicylate of the cells transfected with the mutants induced the transport of 4 pendrin mutants (p .P 123 S , p .M 147 V , p .S 657 Y and p .H 723 R ) from the cytoplasm to the plasma membrane and restored the anion exchanger activity . These findings suggest that salicylate might contribute to development of a new method of medical treatment for sensorineuronal hearing loss caused by the mutation of the deafness -related proteins , including pendrin .