Each year sudden cardiac death (SCD) claims an estimated 300,000 in the United States alone. An estimated 5-10% of these deaths occur in seemingly healthy individuals with otherwise structurally normal hearts following post-mortem investigation. Cardiac channelopathies such as Long-QT Syndrome (LQTS) and Brugada Syndrome (BrS) which arise from heritable defects in cardiac ion channel function represent the most common identifiable causes underlying autopsy negative sudden death, including 35% of Sudden Unexplained Death Syndrome (SUDS) and 10% of Sudden Infant Death Syndrome (SIDS) cases. While considerable effort has been devoted to understanding the pathogenesis of channelopathic sudden death, nearly 25% of LQTS, 70% of BrS, and a large proportion of autopsy negative sudden unexplained deaths still remain genetically elusive. While perturbations within the voltage-gated transient outward (Ito) current macromolecular complex have long been hypothesized to contribute to the pathogenesis of LQTS and BrS, there exists a relative paucity of molecular and functional evidence directly implicating genetic variation within primary Ito molecular determinants to disease. We hypothesize that mutations in the KCND3-encoded Kv4.3 1- subunit, KCNIP2-encoded KChIP2 2-subunit, or regulators of Ito channel expression such as microRNA-1-2 might lead to arrhythmic causes of sudden death. In support of this hypothesis we previously identified five potentially disease-associated non-synonymous mutations within KCND3 and KCNIP2 as well as a possible disease-associated nucleotide substitution within the stem of microRNA-1-2 in clinically robust, genotype negative LQTS (n=94) and BrS (n=91) cohorts. We will begin by assessing the full spectrum and prevalence of genetic variation within KCND3 and KCNIP2 in health and genetically elusive SCD by expanding our PCR/DHPLC-based mutational analysis to include 283 SIDS cases, 101 SUDS cases, and 780 ostensibly healthy controls. Next, to demonstrate that loss-of-function LQTS-associated mutations result in reduced Ito current and gain-of-function BrS-associated mutations result in increased Ito current, leading to prolonged or accelerated repolarization respectively we will functionally characterize all discovered mutations using the whole cell patch clamp technique. Finally, we will assess the functional impact of a disease-associated nucleotide substitution within microRNA-1-2 on Ito channel expression in the heart using quantitative RT-PCR and western blotting.

Public Health Relevance

The primary research focus of the Mayo Clinic Windland Smith Rice Sudden Cardiac Genomics Laboratory is the pathogenetics of youthful sudden cardiac death (SCD), with particular attention to primary channelopathies such as catecholaminergic polymorphic ventricular tachycardia (CPVT), Long-QT Syndrome (LQTS), and Brugada Syndrome (BrS). Unraveling the basis of genotype-negative sudden cardiac death promises to enhance clinical practice by expanding the diagnostic and therapeutic options needed to identify, risk stratify, and effectively treat individuals and families afflicted by these potentially lethal, yet highly treatable conditions. Further, it offers the possibility of unveiling novel biology through the exploration of still enigmatic pathology.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Individual Predoctoral NRSA for M.D./Ph.D. Fellowships (ADAMHA) (F30)
Project #
5F30HL106993-04
Application #
8620703
Study Section
Special Emphasis Panel (ZRG1-F10A-S (20))
Program Officer
Carlson, Drew E
Project Start
2011-03-01
Project End
2015-02-28
Budget Start
2014-03-01
Budget End
2015-02-28
Support Year
4
Fiscal Year
2014
Total Cost
$47,676
Indirect Cost
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
Bartos, Daniel C; Giudicessi, John R; Tester, David J et al. (2014) A KCNQ1 mutation contributes to the concealed type 1 long QT phenotype by limiting the Kv7.1 channel conformational changes associated with protein kinase A phosphorylation. Heart Rhythm 11:459-68
Boczek, Nicole J; Best, Jabe M; Tester, David J et al. (2013) Exome sequencing and systems biology converge to identify novel mutations in the L-type calcium channel, CACNA1C, linked to autosomal dominant long QT syndrome. Circ Cardiovasc Genet 6:279-89
Giudicessi, John R; Ackerman, Michael J (2013) Genotype- and phenotype-guided management of congenital long QT syndrome. Curr Probl Cardiol 38:417-55
Giudicessi, John R; Ackerman, Michael J (2013) Arrhythmia risk in long QT syndrome: beyond the disease-causative mutation. Circ Cardiovasc Genet 6:313-6
Giudicessi, John R; Ackerman, Michael J (2013) Determinants of incomplete penetrance and variable expressivity in heritable cardiac arrhythmia syndromes. Transl Res 161:1-14
Giudicessi, John R; Ackerman, Michael J (2013) Azithromycin and risk of sudden cardiac death: guilty as charged or falsely accused? Cleve Clin J Med 80:539-44
Dufendach, Keith A; Giudicessi, John R; Boczek, Nicole J et al. (2013) Maternal mosaicism confounds the neonatal diagnosis of type 1 Timothy syndrome. Pediatrics 131:e1991-5
Giudicessi, John R; Ackerman, Michael J (2013) Prevalence and potential genetic determinants of sensorineural deafness in KCNQ1 homozygosity and compound heterozygosity. Circ Cardiovasc Genet 6:193-200
Giudicessi, John R; Ackerman, Michael J (2013) Genetic testing in heritable cardiac arrhythmia syndromes: differentiating pathogenic mutations from background genetic noise. Curr Opin Cardiol 28:63-71
Giudicessi, John R; Brost, Brian C; Traynor, Kyle D et al. (2012) Potential depot medroxyprogesterone acetate-triggered torsades de pointes in a case of congenital type 2 long QT syndrome. Heart Rhythm 9:1143-7

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