C39X and C44X channel proteins are trafficking defective. We show that C39X and C44X channels undergo translation reinitiation at M60 which deletes the hERG N-terminus including the first 34 residues of the Per, Arnt, and Sim (PAS) domain. In contrast to the reinitiation of Q81X channels at M124, in which the PAS domain is nearly completely deleted, reinitiation at M60 disrupts the folding of this highly structured domain, precluding the efficient folding and trafficking of the mutant channels. The RNase protection assay, western blot analysis and electrophysiology were used to characterize the LQT2 mutants at the RNA, protein, and functional level. Our findings indicate that translation reinitiation may give rise to trafficking as well as functional defects of mutant hERG channels associated with LQT2 nonsense mutations.
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