Common human ANK2 variant confers in vivo arrhythmia phenotypes.
Human ANK2 (ankyrin-B) loss-of-function variants are directly linked with arrhythmia phenotypes. However, in atypical non-ion channel arrhythmia genes such as ANK2 that lack the same degree of robust structure/function and clinical data, it may be more difficult to assign variant disease risk based simply on variant location, minor allele frequency, and/or predictive structural algorithms. The human ankyrin-B p.L1622I variant found in arrhythmia probands displays significant diversity in minor allele frequency across populations.



The objective of this study was to directly test the in vivo impact of ankyrin-B p.L1622I on cardiac electrical phenotypes and arrhythmia risk using a new animal model.



We tested arrhythmia phenotypes in a new "knock-in" animal model harboring the human ankyrin-B p.L1622I variant.



Ankyrin-B p.L1622I displays reduced posttranslational expression in vivo, resulting in reduced cardiac ankyrin-B expression and reduced association with binding-partner Na/Ca exchanger. Ankyrin-B(L1622I/L1622I) mice display changes in heart rate, atrioventricular and intraventricular conduction, and alterations in repolarization. Furthermore, ankyrin-B(L1622I/L1622I) mice display catecholamine-dependent arrhythmias. At the cellular level, ankyrin-B(L1622I/L1622I) myocytes display increased action potential duration and severe arrhythmogenic afterdepolarizations that provide a mechanistic rationale for the arrhythmias.



Our findings support in vivo arrhythmogenic phenotypes of an ANK2 variant with unusual frequency in select populations. On the basis of our findings and current clinical data, we support classification of p.L1622I as a "mild" loss-of-function variant that may confer arrhythmia susceptibility in the context of secondary risk factors including environment, medication, and/or additional genetic variation.
Dorothy M. Davis Heart and Lung Research Institute, College of Medicine, The Ohio State University Wexner Medical Center, Columbus, OH; Department of Physiology & Cell Biology College of Medicine, The Ohio State University, Columbus, OH.
Hassan
H
Musa
Dorothy M. Davis Heart and Lung Research Institute, College of Medicine, The Ohio State University Wexner Medical Center, Columbus, OH; Department of Physiology & Cell Biology College of Medicine, The Ohio State University, Columbus, OH.
Nathaniel P
NP
Murphy
Dorothy M. Davis Heart and Lung Research Institute, College of Medicine, The Ohio State University Wexner Medical Center, Columbus, OH; Department of Physiology & Cell Biology College of Medicine, The Ohio State University, Columbus, OH.
Jerry
J
Curran
Dorothy M. Davis Heart and Lung Research Institute, College of Medicine, The Ohio State University Wexner Medical Center, Columbus, OH; Department of Physiology & Cell Biology College of Medicine, The Ohio State University, Columbus, OH.
John D
JD
Higgins
Dorothy M. Davis Heart and Lung Research Institute, College of Medicine, The Ohio State University Wexner Medical Center, Columbus, OH; Department of Physiology & Cell Biology College of Medicine, The Ohio State University, Columbus, OH.
Tyler R
TR
Webb
Dorothy M. Davis Heart and Lung Research Institute, College of Medicine, The Ohio State University Wexner Medical Center, Columbus, OH; Department of Physiology & Cell Biology College of Medicine, The Ohio State University, Columbus, OH.
Michael A
MA
Makara
Dorothy M. Davis Heart and Lung Research Institute, College of Medicine, The Ohio State University Wexner Medical Center, Columbus, OH.
Patrick
P
Wright
Dorothy M. Davis Heart and Lung Research Institute, College of Medicine, The Ohio State University Wexner Medical Center, Columbus, OH; Department of Physiology & Cell Biology College of Medicine, The Ohio State University, Columbus, OH.
Peter J
PJ
Lancione
Dorothy M. Davis Heart and Lung Research Institute, College of Medicine, The Ohio State University Wexner Medical Center, Columbus, OH; Department of Physiology & Cell Biology College of Medicine, The Ohio State University, Columbus, OH.
Ellen R
ER
Lubbers
Department of Biochemistry and Howard Hughes Medical Institute, Duke University Medical Center, Durham, NC.
Jane A
JA
Healy
Dorothy M. Davis Heart and Lung Research Institute, College of Medicine, The Ohio State University Wexner Medical Center, Columbus, OH; Department of Internal Medicine, Division of Cardiovascular Medicine.
Sakima A
SA
Smith
Department of Biochemistry and Howard Hughes Medical Institute, Duke University Medical Center, Durham, NC.
Vann
V
Bennett
Dorothy M. Davis Heart and Lung Research Institute, College of Medicine, The Ohio State University Wexner Medical Center, Columbus, OH; Department of Internal Medicine, Division of Cardiovascular Medicine,; Department of Biomedical Engineering, College of Engineering, The Ohio State University, Columbus, OH.
Thomas J
TJ
Hund
Dorothy M. Davis Heart and Lung Research Institute, College of Medicine, The Ohio State University Wexner Medical Center, Columbus, OH; Department of Physiology & Cell Biology College of Medicine, The Ohio State University, Columbus, OH.
Crystal F
CF
Kline
Dorothy M. Davis Heart and Lung Research Institute, College of Medicine, The Ohio State University Wexner Medical Center, Columbus, OH; Department of Physiology & Cell Biology College of Medicine, The Ohio State University, Columbus, OH; Department of Internal Medicine, Division of Cardiovascular Medicine,. Electronic address: peter.mohler@osumc.edu.
Peter J
PJ
Mohler
D000200:Action Potentials / Q000235:genetics; D000818:Animals; D017487:Ankyrins / Q000235:genetics*; D001145:Arrhythmias, Cardiac / Q000208:ethnology / Q000235:genetics* / Q000503:physiopathology; D044383:Black People / Q000235:genetics; D004195:Disease Models, Animal; D059647:Gene-Environment Interaction; D020022:Genetic Predisposition to Disease / Q000208:ethnology; D014644:Genetic Variation; D006801:Humans; D000073658:Loss of Function Mutation; D051379:Mice; D008810:Mice, Inbred C57BL; D010641:Phenotype; D018570:Risk Assessment / Q000208:ethnology; D012307:Risk Factors
C498994:ANK2 protein, human; D017487:Ankyrins
Ankyrin; Arrhythmia; Ion channel; Mouse models of disease; Myocyte