title: Novel Variant in theANK2Membrane-Binding Domain Is Associated With Ankyrin-B Syndrome and Structural Heart Disease in a First Nations Population With a High Rate of Long QT Syndrome.
abstract: BACKGROUND
  Long QT syndrome confers susceptibility to ventricular arrhythmia, predisposing to syncope, seizures, and sudden death. While rare globally, long QT syndrome is ≈15× more common in First Nations of Northern British Columbia largely because of a known mutation inKCNQ1. However, 2 large multigenerational families were affected, but negative for the known mutation.
  
  
  RESULTS
  Long QT syndrome panel testing was carried out in the index case of each family, and clinical information was collected. Cascade genotyping was performed. Biochemical and myocyte-based assays were performed to evaluate the identified gene variant for loss-of-function activity. Index cases in these 2 families harbored a novelANK2c.1937C>T variant (p.S646F). An additional 16 carriers were identified, including 2 with structural heart disease: one with cardiomyopathy resulting in sudden death and the other with congenital heart disease. For all carriers of this variant, the average QTc was 475 ms (±40). Although ankyrin-B p.S646F is appropriately folded and expressed in bacteria, the mutant polypeptide displays reduced expression in cultured H9c2 cells and aberrant localization in primary cardiomyocytes. Furthermore, myocytes expressing ankyrin-B p.S646F lack normal membrane targeting of the ankyrin-binding partner, the Na/Ca exchanger. Thus, ankyrin-B p.S646F is a loss-of-function variant.
  
  
  CONCLUSIONS
  We identify the first disease-causingANK2variant localized to the membrane-binding domain resulting in reduced ankyrin-B expression and abnormal localization. Further study is warranted on the potential association of this variant with structural heart disease given the role ofANK2in targeting and stabilization of key structural and signaling molecules in cardiac cells.
authors.affiliation: From the Division of Medical Sciences, University of Victoria, BC, Canada (L.A.S., L.C., X.X., L.T.A.); University of British Columbia Island Medical Program, Victoria, BC, Canada (L.A.S., L.T.A.); Department of Medical Genetics (S.A., S.M., L.T.A.), Division of Cardiology (C.K.), and Division of Cardiology, Department of Pediatrics, BC Children's Hospital (S.S., E.S.), University of British Columbia, Vancouver, BC, Canada; Division of Cardiovascular Medicine, Department of Internal Medicine, Dorothy M. Davis Heart and Lung Research Institute (N.P.M., P.J.L., C.F.K., P.J.M.) and Department of Physiology and Cell Biology (N.P.M., P.J.L., C.F.K., P.J.M.), The Ohio State University Wexner Medical Center, Columbus, OH; Division of Life Science, State Key Laboratory of Molecular Neuroscience, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China (C.W., M.Z.); and Section of Cardiac Electrophysiology, Division of Cardiology, Department of Medicine, Western University, London, ON, Canada (J.D.R.).
authors.forename: Leigh Anne
authors.initials: LA
authors.lastname: Swayne
authors.affiliation: From the Division of Medical Sciences, University of Victoria, BC, Canada (L.A.S., L.C., X.X., L.T.A.); University of British Columbia Island Medical Program, Victoria, BC, Canada (L.A.S., L.T.A.); Department of Medical Genetics (S.A., S.M., L.T.A.), Division of Cardiology (C.K.), and Division of Cardiology, Department of Pediatrics, BC Children's Hospital (S.S., E.S.), University of British Columbia, Vancouver, BC, Canada; Division of Cardiovascular Medicine, Department of Internal Medicine, Dorothy M. Davis Heart and Lung Research Institute (N.P.M., P.J.L., C.F.K., P.J.M.) and Department of Physiology and Cell Biology (N.P.M., P.J.L., C.F.K., P.J.M.), The Ohio State University Wexner Medical Center, Columbus, OH; Division of Life Science, State Key Laboratory of Molecular Neuroscience, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China (C.W., M.Z.); and Section of Cardiac Electrophysiology, Division of Cardiology, Department of Medicine, Western University, London, ON, Canada (J.D.R.).
authors.forename: Nathaniel P
authors.initials: NP
authors.lastname: Murphy
authors.affiliation: From the Division of Medical Sciences, University of Victoria, BC, Canada (L.A.S., L.C., X.X., L.T.A.); University of British Columbia Island Medical Program, Victoria, BC, Canada (L.A.S., L.T.A.); Department of Medical Genetics (S.A., S.M., L.T.A.), Division of Cardiology (C.K.), and Division of Cardiology, Department of Pediatrics, BC Children's Hospital (S.S., E.S.), University of British Columbia, Vancouver, BC, Canada; Division of Cardiovascular Medicine, Department of Internal Medicine, Dorothy M. Davis Heart and Lung Research Institute (N.P.M., P.J.L., C.F.K., P.J.M.) and Department of Physiology and Cell Biology (N.P.M., P.J.L., C.F.K., P.J.M.), The Ohio State University Wexner Medical Center, Columbus, OH; Division of Life Science, State Key Laboratory of Molecular Neuroscience, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China (C.W., M.Z.); and Section of Cardiac Electrophysiology, Division of Cardiology, Department of Medicine, Western University, London, ON, Canada (J.D.R.).
authors.forename: Sirisha
authors.initials: S
authors.lastname: Asuri
authors.affiliation: From the Division of Medical Sciences, University of Victoria, BC, Canada (L.A.S., L.C., X.X., L.T.A.); University of British Columbia Island Medical Program, Victoria, BC, Canada (L.A.S., L.T.A.); Department of Medical Genetics (S.A., S.M., L.T.A.), Division of Cardiology (C.K.), and Division of Cardiology, Department of Pediatrics, BC Children's Hospital (S.S., E.S.), University of British Columbia, Vancouver, BC, Canada; Division of Cardiovascular Medicine, Department of Internal Medicine, Dorothy M. Davis Heart and Lung Research Institute (N.P.M., P.J.L., C.F.K., P.J.M.) and Department of Physiology and Cell Biology (N.P.M., P.J.L., C.F.K., P.J.M.), The Ohio State University Wexner Medical Center, Columbus, OH; Division of Life Science, State Key Laboratory of Molecular Neuroscience, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China (C.W., M.Z.); and Section of Cardiac Electrophysiology, Division of Cardiology, Department of Medicine, Western University, London, ON, Canada (J.D.R.).
authors.forename: Lena
authors.initials: L
authors.lastname: Chen
authors.affiliation: From the Division of Medical Sciences, University of Victoria, BC, Canada (L.A.S., L.C., X.X., L.T.A.); University of British Columbia Island Medical Program, Victoria, BC, Canada (L.A.S., L.T.A.); Department of Medical Genetics (S.A., S.M., L.T.A.), Division of Cardiology (C.K.), and Division of Cardiology, Department of Pediatrics, BC Children's Hospital (S.S., E.S.), University of British Columbia, Vancouver, BC, Canada; Division of Cardiovascular Medicine, Department of Internal Medicine, Dorothy M. Davis Heart and Lung Research Institute (N.P.M., P.J.L., C.F.K., P.J.M.) and Department of Physiology and Cell Biology (N.P.M., P.J.L., C.F.K., P.J.M.), The Ohio State University Wexner Medical Center, Columbus, OH; Division of Life Science, State Key Laboratory of Molecular Neuroscience, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China (C.W., M.Z.); and Section of Cardiac Electrophysiology, Division of Cardiology, Department of Medicine, Western University, London, ON, Canada (J.D.R.).
authors.forename: Xiaoxue
authors.initials: X
authors.lastname: Xu
authors.affiliation: From the Division of Medical Sciences, University of Victoria, BC, Canada (L.A.S., L.C., X.X., L.T.A.); University of British Columbia Island Medical Program, Victoria, BC, Canada (L.A.S., L.T.A.); Department of Medical Genetics (S.A., S.M., L.T.A.), Division of Cardiology (C.K.), and Division of Cardiology, Department of Pediatrics, BC Children's Hospital (S.S., E.S.), University of British Columbia, Vancouver, BC, Canada; Division of Cardiovascular Medicine, Department of Internal Medicine, Dorothy M. Davis Heart and Lung Research Institute (N.P.M., P.J.L., C.F.K., P.J.M.) and Department of Physiology and Cell Biology (N.P.M., P.J.L., C.F.K., P.J.M.), The Ohio State University Wexner Medical Center, Columbus, OH; Division of Life Science, State Key Laboratory of Molecular Neuroscience, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China (C.W., M.Z.); and Section of Cardiac Electrophysiology, Division of Cardiology, Department of Medicine, Western University, London, ON, Canada (J.D.R.).
authors.forename: Sarah
authors.initials: S
authors.lastname: McIntosh
authors.affiliation: From the Division of Medical Sciences, University of Victoria, BC, Canada (L.A.S., L.C., X.X., L.T.A.); University of British Columbia Island Medical Program, Victoria, BC, Canada (L.A.S., L.T.A.); Department of Medical Genetics (S.A., S.M., L.T.A.), Division of Cardiology (C.K.), and Division of Cardiology, Department of Pediatrics, BC Children's Hospital (S.S., E.S.), University of British Columbia, Vancouver, BC, Canada; Division of Cardiovascular Medicine, Department of Internal Medicine, Dorothy M. Davis Heart and Lung Research Institute (N.P.M., P.J.L., C.F.K., P.J.M.) and Department of Physiology and Cell Biology (N.P.M., P.J.L., C.F.K., P.J.M.), The Ohio State University Wexner Medical Center, Columbus, OH; Division of Life Science, State Key Laboratory of Molecular Neuroscience, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China (C.W., M.Z.); and Section of Cardiac Electrophysiology, Division of Cardiology, Department of Medicine, Western University, London, ON, Canada (J.D.R.).
authors.forename: Chao
authors.initials: C
authors.lastname: Wang
authors.affiliation: From the Division of Medical Sciences, University of Victoria, BC, Canada (L.A.S., L.C., X.X., L.T.A.); University of British Columbia Island Medical Program, Victoria, BC, Canada (L.A.S., L.T.A.); Department of Medical Genetics (S.A., S.M., L.T.A.), Division of Cardiology (C.K.), and Division of Cardiology, Department of Pediatrics, BC Children's Hospital (S.S., E.S.), University of British Columbia, Vancouver, BC, Canada; Division of Cardiovascular Medicine, Department of Internal Medicine, Dorothy M. Davis Heart and Lung Research Institute (N.P.M., P.J.L., C.F.K., P.J.M.) and Department of Physiology and Cell Biology (N.P.M., P.J.L., C.F.K., P.J.M.), The Ohio State University Wexner Medical Center, Columbus, OH; Division of Life Science, State Key Laboratory of Molecular Neuroscience, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China (C.W., M.Z.); and Section of Cardiac Electrophysiology, Division of Cardiology, Department of Medicine, Western University, London, ON, Canada (J.D.R.).
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Lancione
authors.affiliation: From the Division of Medical Sciences, University of Victoria, BC, Canada (L.A.S., L.C., X.X., L.T.A.); University of British Columbia Island Medical Program, Victoria, BC, Canada (L.A.S., L.T.A.); Department of Medical Genetics (S.A., S.M., L.T.A.), Division of Cardiology (C.K.), and Division of Cardiology, Department of Pediatrics, BC Children's Hospital (S.S., E.S.), University of British Columbia, Vancouver, BC, Canada; Division of Cardiovascular Medicine, Department of Internal Medicine, Dorothy M. Davis Heart and Lung Research Institute (N.P.M., P.J.L., C.F.K., P.J.M.) and Department of Physiology and Cell Biology (N.P.M., P.J.L., C.F.K., P.J.M.), The Ohio State University Wexner Medical Center, Columbus, OH; Division of Life Science, State Key Laboratory of Molecular Neuroscience, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China (C.W., M.Z.); and Section of Cardiac Electrophysiology, Division of Cardiology, Department of Medicine, Western University, London, ON, Canada (J.D.R.).
authors.forename: Jason D
authors.initials: JD
authors.lastname: Roberts
authors.affiliation: From the Division of Medical Sciences, University of Victoria, BC, Canada (L.A.S., L.C., X.X., L.T.A.); University of British Columbia Island Medical Program, Victoria, BC, Canada (L.A.S., L.T.A.); Department of Medical Genetics (S.A., S.M., L.T.A.), Division of Cardiology (C.K.), and Division of Cardiology, Department of Pediatrics, BC Children's Hospital (S.S., E.S.), University of British Columbia, Vancouver, BC, Canada; Division of Cardiovascular Medicine, Department of Internal Medicine, Dorothy M. Davis Heart and Lung Research Institute (N.P.M., P.J.L., C.F.K., P.J.M.) and Department of Physiology and Cell Biology (N.P.M., P.J.L., C.F.K., P.J.M.), The Ohio State University Wexner Medical Center, Columbus, OH; Division of Life Science, State Key Laboratory of Molecular Neuroscience, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China (C.W., M.Z.); and Section of Cardiac Electrophysiology, Division of Cardiology, Department of Medicine, Western University, London, ON, Canada (J.D.R.).
authors.forename: Charles
authors.initials: C
authors.lastname: Kerr
authors.affiliation: From the Division of Medical Sciences, University of Victoria, BC, Canada (L.A.S., L.C., X.X., L.T.A.); University of British Columbia Island Medical Program, Victoria, BC, Canada (L.A.S., L.T.A.); Department of Medical Genetics (S.A., S.M., L.T.A.), Division of Cardiology (C.K.), and Division of Cardiology, Department of Pediatrics, BC Children's Hospital (S.S., E.S.), University of British Columbia, Vancouver, BC, Canada; Division of Cardiovascular Medicine, Department of Internal Medicine, Dorothy M. Davis Heart and Lung Research Institute (N.P.M., P.J.L., C.F.K., P.J.M.) and Department of Physiology and Cell Biology (N.P.M., P.J.L., C.F.K., P.J.M.), The Ohio State University Wexner Medical Center, Columbus, OH; Division of Life Science, State Key Laboratory of Molecular Neuroscience, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China (C.W., M.Z.); and Section of Cardiac Electrophysiology, Division of Cardiology, Department of Medicine, Western University, London, ON, Canada (J.D.R.).
authors.forename: Shubhayan
authors.initials: S
authors.lastname: Sanatani
authors.affiliation: From the Division of Medical Sciences, University of Victoria, BC, Canada (L.A.S., L.C., X.X., L.T.A.); University of British Columbia Island Medical Program, Victoria, BC, Canada (L.A.S., L.T.A.); Department of Medical Genetics (S.A., S.M., L.T.A.), Division of Cardiology (C.K.), and Division of Cardiology, Department of Pediatrics, BC Children's Hospital (S.S., E.S.), University of British Columbia, Vancouver, BC, Canada; Division of Cardiovascular Medicine, Department of Internal Medicine, Dorothy M. Davis Heart and Lung Research Institute (N.P.M., P.J.L., C.F.K., P.J.M.) and Department of Physiology and Cell Biology (N.P.M., P.J.L., C.F.K., P.J.M.), The Ohio State University Wexner Medical Center, Columbus, OH; Division of Life Science, State Key Laboratory of Molecular Neuroscience, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China (C.W., M.Z.); and Section of Cardiac Electrophysiology, Division of Cardiology, Department of Medicine, Western University, London, ON, Canada (J.D.R.).
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Sherwin
authors.affiliation: From the Division of Medical Sciences, University of Victoria, BC, Canada (L.A.S., L.C., X.X., L.T.A.); University of British Columbia Island Medical Program, Victoria, BC, Canada (L.A.S., L.T.A.); Department of Medical Genetics (S.A., S.M., L.T.A.), Division of Cardiology (C.K.), and Division of Cardiology, Department of Pediatrics, BC Children's Hospital (S.S., E.S.), University of British Columbia, Vancouver, BC, Canada; Division of Cardiovascular Medicine, Department of Internal Medicine, Dorothy M. Davis Heart and Lung Research Institute (N.P.M., P.J.L., C.F.K., P.J.M.) and Department of Physiology and Cell Biology (N.P.M., P.J.L., C.F.K., P.J.M.), The Ohio State University Wexner Medical Center, Columbus, OH; Division of Life Science, State Key Laboratory of Molecular Neuroscience, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China (C.W., M.Z.); and Section of Cardiac Electrophysiology, Division of Cardiology, Department of Medicine, Western University, London, ON, Canada (J.D.R.).
authors.forename: Crystal F
authors.initials: CF
authors.lastname: Kline
authors.affiliation: From the Division of Medical Sciences, University of Victoria, BC, Canada (L.A.S., L.C., X.X., L.T.A.); University of British Columbia Island Medical Program, Victoria, BC, Canada (L.A.S., L.T.A.); Department of Medical Genetics (S.A., S.M., L.T.A.), Division of Cardiology (C.K.), and Division of Cardiology, Department of Pediatrics, BC Children's Hospital (S.S., E.S.), University of British Columbia, Vancouver, BC, Canada; Division of Cardiovascular Medicine, Department of Internal Medicine, Dorothy M. Davis Heart and Lung Research Institute (N.P.M., P.J.L., C.F.K., P.J.M.) and Department of Physiology and Cell Biology (N.P.M., P.J.L., C.F.K., P.J.M.), The Ohio State University Wexner Medical Center, Columbus, OH; Division of Life Science, State Key Laboratory of Molecular Neuroscience, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China (C.W., M.Z.); and Section of Cardiac Electrophysiology, Division of Cardiology, Department of Medicine, Western University, London, ON, Canada (J.D.R.).
authors.forename: Mingjie
authors.initials: M
authors.lastname: Zhang
authors.affiliation: From the Division of Medical Sciences, University of Victoria, BC, Canada (L.A.S., L.C., X.X., L.T.A.); University of British Columbia Island Medical Program, Victoria, BC, Canada (L.A.S., L.T.A.); Department of Medical Genetics (S.A., S.M., L.T.A.), Division of Cardiology (C.K.), and Division of Cardiology, Department of Pediatrics, BC Children's Hospital (S.S., E.S.), University of British Columbia, Vancouver, BC, Canada; Division of Cardiovascular Medicine, Department of Internal Medicine, Dorothy M. Davis Heart and Lung Research Institute (N.P.M., P.J.L., C.F.K., P.J.M.) and Department of Physiology and Cell Biology (N.P.M., P.J.L., C.F.K., P.J.M.), The Ohio State University Wexner Medical Center, Columbus, OH; Division of Life Science, State Key Laboratory of Molecular Neuroscience, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China (C.W., M.Z.); and Section of Cardiac Electrophysiology, Division of Cardiology, Department of Medicine, Western University, London, ON, Canada (J.D.R.).
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Mohler
authors.affiliation: From the Division of Medical Sciences, University of Victoria, BC, Canada (L.A.S., L.C., X.X., L.T.A.); University of British Columbia Island Medical Program, Victoria, BC, Canada (L.A.S., L.T.A.); Department of Medical Genetics (S.A., S.M., L.T.A.), Division of Cardiology (C.K.), and Division of Cardiology, Department of Pediatrics, BC Children's Hospital (S.S., E.S.), University of British Columbia, Vancouver, BC, Canada; Division of Cardiovascular Medicine, Department of Internal Medicine, Dorothy M. Davis Heart and Lung Research Institute (N.P.M., P.J.L., C.F.K., P.J.M.) and Department of Physiology and Cell Biology (N.P.M., P.J.L., C.F.K., P.J.M.), The Ohio State University Wexner Medical Center, Columbus, OH; Division of Life Science, State Key Laboratory of Molecular Neuroscience, Hong Kong University of Science and Technology, Clear Water Bay, Kowloon, Hong Kong, China (C.W., M.Z.); and Section of Cardiac Electrophysiology, Division of Cardiology, Department of Medicine, Western University, London, ON, Canada (J.D.R.). larbour@uvic.ca.
authors.forename: Laura T
authors.initials: LT
authors.lastname: Arbour
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D017487:Ankyrins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D001145:Arrhythmias, Cardiac / Q000175:diagnosis / Q000208:ethnology / Q000235:genetics* / Q000378:metabolism; D001955:British Columbia / Q000453:epidemiology; D002460:Cell Line; D002648:Child; D002675:Child, Preschool; D004562:Electrocardiography; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006801:Humans; D007198:Indians, North American / Q000235:genetics*; D008133:Long QT Syndrome / Q000175:diagnosis / Q000208:ethnology / Q000235:genetics* / Q000378:metabolism; D008297:Male; D018345:Mice, Knockout; D008875:Middle Aged; D032383:Myocytes, Cardiac / Q000378:metabolism; D010641:Phenotype; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D055550:Protein Stability; D051381:Rats; D019831:Sodium-Calcium Exchanger / Q000378:metabolism; D013329:Structure-Activity Relationship; D014162:Transfection
chemical_list: C498994:ANK2 protein, human; D017487:Ankyrins; D019831:Sodium-Calcium Exchanger
keywords: Wolff–Parkinson–White syndrome; arrhythmia; genetic variation; heart rate; long QT syndrome