Browsing by Author "Sturm, Amy C."

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    Dysfunction in the βII Spectrin-Dependent Cytoskeleton Underlies Human Arrhythmia.
    (AHA, 2015-02-24) Smith, Sakima A.; Sturm, Amy C.; Curran, Jerry; Kline, Crystal F.; Little, Sean C.; Bonilla, Ingrid M.; Long, Victor P.; Makara, Michael; Polina, Iuliia; Hughes, Langston D.; Webb, Tyler R.; Wei, Zhiyi; Wright, Patrick; Voigt, Niels; Bhakta, Deepak; Spoonamore, Katherine G.; Zhang, Chuansheng; Weiss, Raul; Binkley, Philip F.; Janssen, Paul M.; Kilic, Ahmet; Higgins, Robert S.; Sun, Mingzhai; Ma, Jianjie; Dobrev, Dobromir; Zhang, Mingjie; Carnes, Cynthia A.; Vatta, Matteo; Rasband, Matthew N.; Hund, Thomas J.; Mohler, Peter J.; Department of Medical & Molecular Genetics, IU School of Medicine
    Background: The cardiac cytoskeleton plays key roles in maintaining myocyte structural integrity in health and disease. In fact, human mutations in cardiac cytoskeletal elements are tightly linked with cardiac pathologies including myopathies, aortopathies, and dystrophies. Conversely, the link between cytoskeletal protein dysfunction in cardiac electrical activity is not well understood, and often overlooked in the cardiac arrhythmia field. Methods and Results: Here, we uncover a new mechanism for the regulation of cardiac membrane excitability. We report that βII spectrin, an actin-associated molecule, is essential for the post-translational targeting and localization of critical membrane proteins in heart. βII spectrin recruits ankyrin-B to the cardiac dyad, and a novel human mutation in the ankyrin-B gene disrupts the ankyrin-B/βII spectrin interaction leading to severe human arrhythmia phenotypes. Mice lacking cardiac βII spectrin display lethal arrhythmias, aberrant electrical and calcium handling phenotypes, and abnormal expression/localization of cardiac membrane proteins. Mechanistically, βII spectrin regulates the localization of cytoskeletal and plasma membrane/sarcoplasmic reticulum protein complexes that include the Na/Ca exchanger, RyR2, ankyrin-B, actin, and αII spectrin. Finally, we observe accelerated heart failure phenotypes in βII spectrin-deficient mice. Conclusions: Our findings identify βII spectrin as critical for normal myocyte electrical activity, link this molecule to human disease, and provide new insight into the mechanisms underlying cardiac myocyte biology.
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    Genetic Testing for Heritable Cardiovascular Diseases in Pediatric Patients: A Scientific Statement From the American Heart Association
    (American Heart Association, 2021) Landstrom, Andrew P.; Kim, Jeffrey J.; Gelb, Bruce D.; Helm, Benjamin M.; Kannankeril, Prince J.; Semsarian, Christopher; Sturm, Amy C.; Tristani-Firouzi, Martin; Ware, Stephanie M.; Medical and Molecular Genetics, School of Medicine
    Genetic diseases that affect the cardiovascular system are relatively common and include cardiac channelopathies, cardiomyopathies, aortopathies, hypercholesterolemias, and structural diseases of the heart and great vessels. The rapidly expanding availability of clinical genetic testing leverages decades of research into the genetic origins of these diseases, helping inform diagnosis, clinical management, and prognosis. Although a number of guidelines and statements detail best practices for cardiovascular genetic testing, there is a paucity of pediatric-focused statements addressing the unique challenges in testing in this vulnerable population. In this scientific statement, we seek to coalesce the existing literature around the use of genetic testing for cardiovascular disease in infants, children, and adolescents.