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              <keywords scheme="author">
                <term xml:lang="en">ankyrin-b; arrhythmia; bradycardia; cardiovascular disease; fibrosis; heart failure; heart rate variability; incomplete penetrance; stress; variant</term>
              </keywords>
              <classCode scheme="mesh">Animals</classCode>
              <classCode scheme="mesh">Humans</classCode>
              <classCode scheme="mesh">Phenotype</classCode>
              <classCode scheme="mesh">Aging</classCode>
              <classCode scheme="mesh">Mice</classCode>
              <classCode scheme="mesh">Adrenergic Agents</classCode>
              <classCode scheme="mesh">Ankyrins</classCode>
              <classCode scheme="mesh">Disease Models, Animal</classCode>
              <classCode scheme="mesh">Ion Channels</classCode>
              <classCode scheme="mesh">Mice, Knockout</classCode>
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              <p>Encoded by ANK2, ankyrin-B (AnkB) is a multifunctional adapter protein critical for the expression and targeting of key cardiac ion channels, transporters, cytoskeletal-associated proteins, and signaling molecules. Mice deficient for AnkB expression are neonatal lethal, and mice heterozygous for AnkB expression display cardiac structural and electrical phenotypes. Human ANK2 loss-of-function variants are associated with diverse cardiac manifestations; however, human clinical 'AnkB syndrome' displays incomplete penetrance. To date, animal models for human arrhythmias have generally been knock-out or transgenic overexpression models and thus the direct impact of ANK2 variants on cardiac structure and function in vivo is not clearly defined. Here, we directly tested the relationship of a single human ANK2 disease-associated variant with cardiac phenotypes utilizing a novel in vivo animal model. At baseline, young AnkBp.E1458G+/+ mice lacked significant structural or electrical abnormalities. However, aged AnkBp.E1458G+/+ mice displayed both electrical and structural phenotypes at baseline including bradycardia and aberrant heart rate variability, structural remodeling, and fibrosis. Young and old AnkBp.E1458G+/+ mice displayed ventricular arrhythmias following acute (adrenergic) stress. In addition, young AnkBp.E1458G+/+ mice displayed structural remodeling following chronic (transverse aortic constriction) stress. Finally, AnkBp.E1458G+/+ myocytes harbored alterations in expression and/or localization of key AnkB-associated partners, consistent with the underlying disease mechanism. In summary, our findings illustrate the critical role of AnkB in in vivo cardiac function as well as the impact of single AnkB loss-of-function variants in vivo. However, our findings illustrate the contribution and in fact necessity of secondary factors (aging, adrenergic challenge, pressure-overload) to phenotype penetrance and severity.</p>
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