It is well-known that monogenic disorders produce alterations of the cardiac action potential that lead to life threatening arrhythmias. Although this work on inheritable channelopathies has greatly contributed to our understanding of arrhythmia mechanisms, monogenic disorders leading to arrhythmias are rare. Interestingly, it is also recognized that even common forms of arrhythmias, such as atrial and ventricular fibrillation can be familial. However, the pattern of inheritance and clinical phenotypes of these patients are complex. In fact, similar to channelopathies such as Long QT (LQT) or Brugada Syndrome (BrS) which are autosomal dominant diseases, these more common arrhythmias also display variable penetrance. There are several prevailing hypotheses that have attempted to explain why a particular gene expression pattern might produce variable phenotypic expression i.e. genotype-phenotype discordance. Importantly, there is emerging evidence indicating that disease modifying genes such as ion channel polymorphisms, can affect the function of ion channels leading to genotype-phenotype discordance. In fact, the PI recently demonstrated that the common sodium channel polymorphism H558R is a disease modifying gene which contributes to the genotype- phenotype discordance seen in multiple families with BrS and LQT3. This polymorphism was able to restore trafficking of mutant BrS channels, and restore the gating kinetics of mutant LQT3 channels resulting in complete normalization of sodium channel function. Thus, this explains the apparent absence of a clinical phenotype in patients carrying the polymorphism along with a disease causing mutation. Therefore, the general hypothesis for this proposal is that sodium channel polymorphisms contribute to the variable penetrance phenomenon. In this proposal, the PI will shed-light on the genotype-phenotype discordance involved in these diseases by primarily using information obtained from large BrS and LQT3 families. These families affected with relatively rare inherited syndromes that relate to sudden cardiac death provide us with a unique opportunity to ascertain the complex phenomenon of variable phenotypic expression of diseases.
The specific aims are to: 1. Determine the role of sodium channel polymorphisms in Brugada and Long QT 3 Syndrome. 2. Investigate the mechanisms by which SCN5A polymorphisms can modulate the function of mutated sodium channels. 3. Develop gene therapy approaches, using genetic polymorphisms, to rescue dysfunctional channels. Assessing variability in susceptibility to LQTS and BrS will provide a framework for analysis of other complex gene-environment interactions that may apply to the more common form of sudden cardiac death. Additionally, understanding the mechanisms by which a polymorphism can modulate a mutated channel will also provide fundamental understanding of ion channels assembly and structure. Importantly, gene polymorphisms could become a target for future therapies aimed at rescuing dysfunctional ion channels.

Public Health Relevance

This work will provide important insights for the genotype-phenotype variability seen in inherited arrhythmias. This is crucial for cardiologists to select family members who will more likely benefit from an expensive and risky therapy, the implanted defibrillator. A gene therapy approach will also be developed to treat arrhythmias.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL094450-05
Application #
8628154
Study Section
Electrical Signaling, Ion Transport, and Arrhythmias Study Section (ESTA)
Program Officer
Krull, Holly
Project Start
2010-03-15
Project End
2015-02-28
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
5
Fiscal Year
2014
Total Cost
$380,804
Indirect Cost
$138,254
Name
Case Western Reserve University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
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Hoshi, Malcolm; Du, Xi X; Shinlapawittayatorn, Krekwit et al. (2014) Brugada syndrome disease phenotype explained in apparently benign sodium channel mutations. Circ Cardiovasc Genet 7:123-31
Jehle, J; Ficker, E; Wan, X et al. (2013) Mechanisms of zolpidem-induced long QT syndrome: acute inhibition of recombinant hERG K(+) channels and action potential prolongation in human cardiomyocytes derived from induced pluripotent stem cells. Br J Pharmacol 168:1215-29
Shinlapawittayatorn, Krekwit; Du, Xi X; Liu, Haiyan et al. (2011) A common SCN5A polymorphism modulates the biophysical defects of SCN5A mutations. Heart Rhythm 8:455-62
Shinlapawittayatorn, Krekwit; Dudash, Lynn A; Du, Xi X et al. (2011) A novel strategy using cardiac sodium channel polymorphic fragments to rescue trafficking-deficient SCN5A mutations. Circ Cardiovasc Genet 4:500-9