LQT2 Nonsense Mutations Generate Trafficking Defective NH2-Terminally Truncated Channels by the Reinitiation of Translation

Document Type

Article

Publication Date

11-1-2013

Abstract

LQT2 nonsense mutations generate trafficking defective NH2-terminally truncated channels by the reinitiation of translation. Am J Physiol Heart Circ Physiol 305: H1397–H1404, 2013. First published August 30, 2013; doi:10.1152/ajpheart.00304.2013.—The human ether-a-go-go-related gene (hERG) encodes a voltage-activated Kr channel that contributes to the repolarization of the cardiac action potential. Long QT syndrome type 2 (LQT2) is an autosomal dominant disorder caused by mutations in hERG, and patients with LQT2 are susceptible to severe ventricular arrhythmias. We have previously shown that nonsense and frameshift LQT2 mutations caused a decrease in mutant mRNA by the nonsense-mediated mRNA decay (NMD) pathway. The Q81X nonsense mutation was recently found to be resistant to NMD. Translation of Q81X is reinitiated at Met124, resulting in the generation of NH2-terminally truncated hERG channels with altered gating properties. In the present study, we identified two additional NMD-resistant LQT2 nonsense mutations, C39X and C44X, in which translation is reinitiated at Met60. Deletion of the first 59 residues of the channel truncated nearly one-third of the highly structured Per-Arnt-Sim domain and resulted in the generation of trafficking-defective proteins and a complete loss of hERG current. Partial deletion of the Per-Arnt-Sim domain also resulted in the accelerated degradation of the mutant channel proteins. The coexpression of mutant and wild-type channels did not significantly disrupt the function and trafficking properties of wild-type hERG. Our present findings indicate that translation reinitiation may generate traffickingdefective as well as dysfunctional channels in patients with LQT2 premature termination codon mutations that occur early in the coding sequence.

Comments

Originally published in American journal of physiology. Heart and circulatory physiology. 2013; 305(9).

https://doi.org/10.1152/ajpheart.00304.2013

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