Long QT syndrome is a disorder characterized by delayed cardiac repolarization and an increased risk of arrhythmias and sudden death. Both congenital and acquired (such as drug-induced) forms of long QT syndrome have been identified. Long QT syndrome type 2 (LQT2) is caused by mutations in the KCNH2 gene (also known as hERG1 or hERG). KCNH2 encodes the Kv11.1 K+ channel that conducts the rapidly activating delayed rectifier K+ current (IKr) in the heart. The Kv11.1 channel plays an important role in congenital and drug-induced forms of long QT syndrome. LQT2 is the second most prevalent form of congenital long QT syndrome accounting for 35 to 40% of genotyped cases of long QT syndrome. Many drugs cause drug- induced long QT syndrome by inhibition of Kv11.1 channel function. Kv11.1 channel dysfunction results in the delay in action potential repolarization, leading to QT prolongation and cardiac arrhythmias. In the previous funding period, we have identified isoform switch as a novel mechanism of Kv11.1 channel dysfunction in LQT2. We also showed that the relative expression of Kv11.1 C-terminal isoforms plays an important role in the regulation of Kv11.1 channel function, and developed an antisense approach to increase the functional Kv11.1 isoform expression. In the present application, we will study the mechanisms underling the developmental and tissue-specific regulation of Kv11.1 isoform expression and demonstrate the modulation of Kv11.1 isoform expression as a novel mechanism of drug-induced suppression of Kv11.1 channel function. In addition, we will test the antisense-induced upregulation of Kv11.1 channel function in induced pluripotent stem cell-derived cardiomyocytes and a knock-in mouse model.
The specific aims of this application are:
Aim 1) To study the mechanisms underlying the tissue-specific and developmental regulation of Kv11.1 isoform expression.
Aim 2) To identify the modulation of the relative expression Kv11.1 isoforms as a novel mechanism of drug-induced suppression of Kv11.1 channel function.
Aim 3) To study the antisense-induced upregulation of functional Kv11.1 isoform expression in LQT2 patient-specific induced pluripotent stem cell-derived cardiomyocytes that carry different KCNH2 mutations.
Aim 4) To study the antisense-induced upregulation of functional Kv11.1 isoform expression in a knock-in mouse model. The knowledge gained from this study will strengthen our understanding of the molecular mechanisms of long QT syndrome and provide information directed towards the development of novel therapeutic strategies for 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 the underlying mechanisms of Kv11.1 channel dysfunction in congenital and drug-induced long QT syndrome and test the antisense-induced upregulation of Kv11.1 channel function in induced pluripotent stem cell-derived cardiomyocytes and a knock-in mouse model. The knowledge gained from this study will strengthen our understanding of the molecular mechanisms of long QT syndrome and provide information directed towards the development of novel therapeutic strategies for long QT syndrome.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL068854-14
Application #
8961627
Study Section
Electrical Signaling, Ion Transport, and Arrhythmias Study Section (ESTA)
Program Officer
Lathrop, David A
Project Start
2001-12-05
Project End
2019-03-31
Budget Start
2015-07-01
Budget End
2016-03-31
Support Year
14
Fiscal Year
2015
Total Cost
Indirect Cost
Name
Oregon Health and Science University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
096997515
City
Portland
State
OR
Country
United States
Zip Code
97239
Gong, Qiuming; Zhou, Zhengfeng (2018) Nonsense-Mediated mRNA Decay of hERG Mutations in Long QT Syndrome. Methods Mol Biol 1684:37-49
Gong, Qiuming; Stump, Matthew R; Zhou, Zhengfeng (2018) Upregulation of functional Kv11.1a isoform expression by modified U1 small nuclear RNA. Gene 641:220-225
Gong, Qiuming; Stump, Matthew R; Zhou, Zhengfeng (2018) Regulation of Kv11.1 potassium channel C-terminal isoform expression by the RNA-binding proteins HuR and HuD. J Biol Chem 293:19624-19632
Gong, Qiuming; Zhou, Zhengfeng (2017) Regulation of Isoform Expression by Blocking Polyadenylation Signal Sequences with Morpholinos. Methods Mol Biol 1565:141-150
Hashem, Sherin I; Perry, Cynthia N; Bauer, Matthieu et al. (2015) Brief Report: Oxidative Stress Mediates Cardiomyocyte Apoptosis in a Human Model of Danon Disease and Heart Failure. Stem Cells 33:2343-50
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
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
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
Stump, Matthew R; Gong, Qiuming; Zhou, Zhengfeng (2012) Isoform-specific dominant-negative effects associated with hERG1 G628S mutation in long QT syndrome. PLoS One 7:e42552

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