• About
    • Login
    View Item 
    •   Institutional Repository Home
    • Electronic Theses and Dissertations
    • Electronic Theses and Dissertations
    • View Item
    •   Institutional Repository Home
    • Electronic Theses and Dissertations
    • Electronic Theses and Dissertations
    • View Item
    JavaScript is disabled for your browser. Some features of this site may not work without it.

    Browse

    All of Institutional RepositoryCommunities & CollectionsBy Issue DateAuthorsTitlesSubjectsDepartmentThis CollectionBy Issue DateAuthorsTitlesSubjectsDepartment

    My Account

    LoginRegister

    Mutant Cardiac Sodium Channel Dysfunction Associated with Cardiomyopathy

    Beckermann, Thomas Martin
    : https://etd.library.vanderbilt.edu/etd-06252014-102905
    http://hdl.handle.net/1803/12694
    : 2014-06-26

    Abstract

    The goal of this project is to better understand the relationship between cardiac sodium channel dysfunction and cardiomyopathy. Mutations in the gene SCN5A, encoding the cardiac sodium channel, typically cause ventricular arrhythmia or conduction slowing. Recently, SCN5A mutations have been associated with heart failure combined with variable atrial and ventricular arrhythmia. Here we present the clinical, genetic and functional features of an amiodarone-responsive multifocal ventricular ectopy-related cardiomyopathy associated with a novel mutation in a NaV1.5 voltage sensor domain. A novel, de novo SCN5A mutation (NaV1.5-R225P) was identified in a boy with prenatal arrhythmia and impaired cardiac contractility followed by postnatal multifocal ventricular ectopy suppressible by amiodarone. We investigated the functional consequences of NaV1.5-R225P and noted that mutant channels exhibited significant abnormalities in both activation and inactivation leading to large, hyperpolarized window- and ramp-currents that predict aberrant sodium influx at potentials near the cardiomyocyte resting membrane potential. Mutant channels also exhibited significantly increased persistent (late) sodium current. This profile of channel dysfunction shares features with other SCN5A voltage sensor mutations associated with cardiomyopathy and overlapped that of congenital long-QT syndrome. Amiodarone stabilized fast inactivation, suppressed persistent sodium current and enhanced frequency-dependent rundown of channel availability. Comparisons with other cardiomyopathy-associated NaV1.5 voltage sensor mutations revealed a pattern of abnormal voltage dependence of activation that manifested in large, hyperpolarized ramp currents near resting membrane potentials as a shared molecular mechanism of the syndrome. Because the sodium gradient is critical to many processes in the myocyte, we endeavored to determine if expression of R814W or R222Q could affect calcium regulation within cardiomyocytes expressing the mutant channels. To test this, we produced lentiviral vectors capable of transducing isolated rabbit ventricular myocytes. Subsequent experiments examining calcium levels in myocytes transduced with exogenous NaV1.5 or mutant channels revealed little to no difference among all the parameters tested. Therefore, we conclude, that in these experiments there is no alteration of calcium handling resulting from overexpression of the mutations R222Q or R814W compared to WT channels.
    Show full item record

    Files in this item

    Icon
    Name:
    Beckermann.pdf.pdf
    Size:
    7.734Mb
    Format:
    PDF
    View/Open

    This item appears in the following collection(s):

    • Electronic Theses and Dissertations

    Connect with Vanderbilt Libraries

    Your Vanderbilt

    • Alumni
    • Current Students
    • Faculty & Staff
    • International Students
    • Media
    • Parents & Family
    • Prospective Students
    • Researchers
    • Sports Fans
    • Visitors & Neighbors

    Support the Jean and Alexander Heard Libraries

    Support the Library...Give Now

    Gifts to the Libraries support the learning and research needs of the entire Vanderbilt community. Learn more about giving to the Libraries.

    Become a Friend of the Libraries

    Quick Links

    • Hours
    • About
    • Employment
    • Staff Directory
    • Accessibility Services
    • Contact
    • Vanderbilt Home
    • Privacy Policy