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Ankyrin-B Q1283H Variant Linked to Arrhythmias Via Loss of Local Protein Phosphatase 2A Activity Causes Ryanodine Receptor Hyperphosphorylation.
Zhu, Wengen; Wang, Cen; Hu, Jinzhu; Wan, Rong; Yu, Jianhua; Xie, Jinyan; Ma, Jianyong; Guo, Linjuan; Ge, Jin; Qiu, Yumin; Chen, Leifeng; Liu, Hualong; Yan, Xia; Liu, Xiuxia; Ye, Jin; He, Wenfeng; Shen, Yang; Wang, Chao; Mohler, Peter J; Hong, Kui.
  • Zhu W; Department of Cardiovascular Medicine (W.Z., C.W., J.H., J.Y., J.M., L.G., J.G., H.L., K.H.), Second Affiliated Hospital of Nanchang University, China.
  • Wang C; Department of Cardiovascular Medicine (W.Z., C.W., J.H., J.Y., J.M., L.G., J.G., H.L., K.H.), Second Affiliated Hospital of Nanchang University, China.
  • Hu J; Department of Cardiovascular Medicine (W.Z., C.W., J.H., J.Y., J.M., L.G., J.G., H.L., K.H.), Second Affiliated Hospital of Nanchang University, China.
  • Wan R; Jiangxi Key Laboratory of Molecular Medicine (R.W., J.X., X.Y., X.L., W.H., Y.S., K.H.), Second Affiliated Hospital of Nanchang University, China.
  • Yu J; Department of Cardiovascular Medicine (W.Z., C.W., J.H., J.Y., J.M., L.G., J.G., H.L., K.H.), Second Affiliated Hospital of Nanchang University, China.
  • Xie J; Jiangxi Key Laboratory of Molecular Medicine (R.W., J.X., X.Y., X.L., W.H., Y.S., K.H.), Second Affiliated Hospital of Nanchang University, China.
  • Ma J; Department of Cardiovascular Medicine (W.Z., C.W., J.H., J.Y., J.M., L.G., J.G., H.L., K.H.), Second Affiliated Hospital of Nanchang University, China.
  • Guo L; Department of Cardiovascular Medicine (W.Z., C.W., J.H., J.Y., J.M., L.G., J.G., H.L., K.H.), Second Affiliated Hospital of Nanchang University, China.
  • Ge J; Department of Cardiovascular Medicine (W.Z., C.W., J.H., J.Y., J.M., L.G., J.G., H.L., K.H.), Second Affiliated Hospital of Nanchang University, China.
  • Qiu Y; Department of General Surgery (Y.Q., L.C.), Second Affiliated Hospital of Nanchang University, China.
  • Chen L; Department of General Surgery (Y.Q., L.C.), Second Affiliated Hospital of Nanchang University, China.
  • Liu H; Department of Cardiovascular Medicine (W.Z., C.W., J.H., J.Y., J.M., L.G., J.G., H.L., K.H.), Second Affiliated Hospital of Nanchang University, China.
  • Yan X; Jiangxi Key Laboratory of Molecular Medicine (R.W., J.X., X.Y., X.L., W.H., Y.S., K.H.), Second Affiliated Hospital of Nanchang University, China.
  • Liu X; Jiangxi Key Laboratory of Molecular Medicine (R.W., J.X., X.Y., X.L., W.H., Y.S., K.H.), Second Affiliated Hospital of Nanchang University, China.
  • Ye J; Hefei National Laboratory for Physical Sciences at the Microscale, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui (J.Y., C.W.).
  • He W; Jiangxi Key Laboratory of Molecular Medicine (R.W., J.X., X.Y., X.L., W.H., Y.S., K.H.), Second Affiliated Hospital of Nanchang University, China.
  • Shen Y; Jiangxi Key Laboratory of Molecular Medicine (R.W., J.X., X.Y., X.L., W.H., Y.S., K.H.), Second Affiliated Hospital of Nanchang University, China.
  • Wang C; Hefei National Laboratory for Physical Sciences at the Microscale, School of Life Sciences, University of Science and Technology of China, Hefei, Anhui (J.Y., C.W.).
  • Mohler PJ; Department of Physiology and Cell Biology, The Ohio State University Wexner Medical Center, College of Medicine, The Dorothy M. Davis Heart and Lung Research Institute, Departments of Physiology and Cell Biology and Internal Medicine, Columbus (P.J.M.).
  • Hong K; Department of Cardiovascular Medicine (W.Z., C.W., J.H., J.Y., J.M., L.G., J.G., H.L., K.H.), Second Affiliated Hospital of Nanchang University, China.
Circulation ; 138(23): 2682-2697, 2018 12 04.
Article en En | MEDLINE | ID: mdl-30571258
ABSTRACT

BACKGROUND:

Human loss-of-function variants of ANK2 (ankyrin-B) are linked to arrhythmias and sudden cardiac death. However, their in vivo effects and specific arrhythmogenic pathways have not been fully elucidated.

METHODS:

We identified new ANK2 variants in 25 unrelated Han Chinese probands with ventricular tachycardia by whole-exome sequencing. The potential pathogenic variants were validated by Sanger sequencing. We performed functional and mechanistic experiments in ankyrin-B knockin (KI) mouse models and in single myocytes isolated from KI hearts.

RESULTS:

We detected a rare, heterozygous ANK2 variant (p.Q1283H) in a proband with recurrent ventricular tachycardia. This variant was localized to the ZU5C region of ANK2, where no variants have been previously reported. KI mice harboring the p.Q1283H variant exhibited an increased predisposition to ventricular arrhythmias after catecholaminergic stress in the absence of cardiac structural abnormalities. Functional studies illustrated an increased frequency of delayed afterdepolarizations and Ca2+ waves and sparks accompanied by decreased sarcoplasmic reticulum Ca2+ content in KI cardiomyocytes on isoproterenol stimulation. The immunoblotting results showed increased levels of phosphorylated ryanodine receptor Ser2814 in the KI hearts, which was further amplified on isoproterenol stimulation. Coimmunoprecipitation experiments demonstrated dissociation of protein phosphatase 2A from ryanodine receptor in the KI hearts, which was accompanied by a decreased binding of ankyrin-B to protein phosphatase 2A regulatory subunit B56α. Finally, the administration of metoprolol or flecainide decreased the incidence of stress-induced ventricular arrhythmias in the KI mice.

CONCLUSIONS:

ANK2 p.Q1283H is a disease-associated variant that confers susceptibility to stress-induced arrhythmias, which may be prevented by the administration of metoprolol or flecainide. This variant is associated with the loss of protein phosphatase 2A activity, increased phosphorylation of ryanodine receptor, exaggerated delayed afterdepolarization-mediated trigger activity, and arrhythmogenesis.
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Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Arritmias Cardíacas / Ancirinas / Canal Liberador de Calcio Receptor de Rianodina / Proteína Fosfatasa 2 Tipo de estudio: Etiology_studies / Prognostic_studies Límite: Animals / Female / Humans / Middle aged Idioma: En Año: 2018 Tipo del documento: Article

Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Arritmias Cardíacas / Ancirinas / Canal Liberador de Calcio Receptor de Rianodina / Proteína Fosfatasa 2 Tipo de estudio: Etiology_studies / Prognostic_studies Límite: Animals / Female / Humans / Middle aged Idioma: En Año: 2018 Tipo del documento: Article