Long QT syndrome (LQTS) is a disorder characterized by delayed cardiac repolarization and an increased risk of arrhythmias and sudden death. Long QT syndrome type 2 (LQT2) is caused by mutations in the human ether-a-go-go-related gene (hERG). hERG encodes the pore-forming subunit of the rapidly activating delayed rectifier potassium channel in the heart. LQT2 is the second most prevalent form of LQTS, accounting for 35% to 40% of genotyped cases of LQTS. LQT2 mutations can cause hERG channel dysfunction by a variety of mechanisms. In the previous funding period, we have shown that nonsense-mediated mRNA decay and splicing defects are important mechanisms of hERG channel dysfunction in LQT2. We have also shown that generation of hERG C-terminal isoforms is determined by competition between alternative splicing and polyadenylation of hERG intron 9 and that the relative expression of hERG C-terminal isoforms plays an important role in regulation of hERG channel function. In the present application, we will use full-length hERG gene constructs to study mechanisms that underlie the regulation of hERG C-terminal isoform expression, characterize two new mechanisms of hERG channel dysfunction in LQT2, and develop a novel approach to modulate the relative expression of hERG C-terminal isoforms. In addition, we will use patient-specific induced pluripotent stem (iPS) cell-derived cardiomyocytes as a model to study pathophysiology of LQT2.
The specific aims of this application are:
Aim 1) To study a newly identified LQT2 splice site mutation that disrupts the 3'splice site of intron 9 and alters the relative expression of hERG C-terminal isoforms.
Aim 2) To develop an antisense approach to increase hERG current by inducing a shift in hERG C-terminal isoform expression from the nonfunctional isoform to the functional isoform.
Aim 3) To characterize a new mechanism of LQT2 in which premature termination followed by the reinitiation of translation results in the generation of N-terminally truncated hERG channels with altered gating properties.
Aim 4) To create LQT2 patient-specific iPS cell lines and characterize LQT2 mutations in iPS cell-derived cardiomyocytes. This study will increase our knowledge of how LQT2 mutations lead to hERG channel dysfunction at the posttranscriptional and translational level. We believe that this work will have a sustained and significant impact on our understanding and treatment of long QT syndrome.

Public Health Relevance

Long QT syndrome is a disease associated with delayed cardiac repolarization and prolonged QT intervals on the electrocardiogram, which can lead to ventricular arrhythmias and sudden death. The goal of present proposal is to elucidate how disease-causing mutations lead to hERG channel dysfunction and develop a novel approach to increase hERG channel function. The knowledge gained from this study will strengthen our understanding of the pathogenesis of hERG mutations in long QT syndrome and provide information directed towards the development of new therapeutic strategies for long QT syndrome.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Electrical Signaling, Ion Transport, and Arrhythmias Study Section (ESTA)
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Wang, Lan-Hsiang
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Oregon Health and Science University
Internal Medicine/Medicine
Schools of Medicine
United States
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Gong, Qiuming; Stump, Matthew R; Zhou, Zhengfeng (2014) Upregulation of functional Kv11.1 isoform expression by inhibition of intronic polyadenylation with antisense morpholino oligonucleotides. J Mol Cell Cardiol 76:26-32
Gong, Qiuming; Stump, Matthew R; Zhou, Zhengfeng (2014) Position of premature termination codons determines susceptibility of hERG mutations to nonsense-mediated mRNA decay in long QT syndrome. Gene 539:190-7
Gong, Qiuming; Stump, Matthew R; Deng, Vivianne et al. (2014) Identification of Kv11.1 isoform switch as a novel pathogenic mechanism of long-QT syndrome. Circ Cardiovasc Genet 7:482-90
Stump, Matthew R; Gong, Qiuming; Zhou, Zhengfeng (2013) LQT2 nonsense mutations generate trafficking defective NH2-terminally truncated channels by the reinitiation of translation. Am J Physiol Heart Circ Physiol 305:H1397-404
Zarraga, Ignatius Gerardo; Zhang, Li; Stump, Matthew R et al. (2011) Nonsense-mediated mRNA decay caused by a frameshift mutation in a large kindred of type 2 long QT syndrome. Heart Rhythm 8:1200-6
Gong, Qiuming; Stump, Matthew R; Zhou, Zhengfeng (2011) Inhibition of nonsense-mediated mRNA decay by antisense morpholino oligonucleotides restores functional expression of hERG nonsense and frameshift mutations in long-QT syndrome. J Mol Cell Cardiol 50:223-9
Stump, Matthew R; Gong, Qiuming; Zhou, Zhengfeng (2011) Multiple splicing defects caused by hERG splice site mutation 2592+1G>A associated with long QT syndrome. Am J Physiol Heart Circ Physiol 300:H312-8
Gong, Qiuming; Stump, Matthew R; Dunn, A Russell et al. (2010) Alternative splicing and polyadenylation contribute to the generation of hERG1 C-terminal isoforms. J Biol Chem 285:32233-41
Hou, Luqia; Deo, Makarand; Furspan, Philip et al. (2010) A major role for HERG in determining frequency of reentry in neonatal rat ventricular myocyte monolayer. Circ Res 107:1503-11
Bhuiyan, Zahurul A; Momenah, Tarek S; Gong, Qiuming et al. (2008) Recurrent intrauterine fetal loss due to near absence of HERG: clinical and functional characterization of a homozygous nonsense HERG Q1070X mutation. Heart Rhythm 5:553-61

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