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 .

Diseases
Validation

Diseases presenting "hearing loss" symptom

22q11.2 deletion syndrome

achondroplasia

adrenomyeloneuropathy

alexander disease

benign recurrent intrahepatic cholestasis

canavan disease

cohen syndrome

congenital toxoplasmosis

dentinogenesis imperfecta

fabry disease

familial mediterranean fever

heparin-induced thrombocytopenia

hirschsprung disease

holt-oram syndrome

homocystinuria without methylmalonic aciduria

hydrocephalus with stenosis of the aqueduct of sylvius

kabuki syndrome

kallmann syndrome

neonatal adrenoleukodystrophy

pendred syndrome

von hippel-lindau disease

wolf-hirschhorn syndrome

This symptom has already been validated