Novel Variant in the ANK2 Membrane-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

• Published in: Circulation. Cardiovascular genetics Vol. 10; no. 1; p. e001537
• Main Authors: Swayne, Leigh Anne, Murphy, Nathaniel P, Asuri, Sirisha, Chen, Lena, Xu, Xiaoxue, McIntosh, Sarah, Wang, Chao, Lancione, Peter J, Roberts, Jason D, Kerr, Charles, Sanatani, Shubhayan, Sherwin, Elizabeth, Kline, Crystal F, Zhang, Mingjie, Mohler, Peter J, Arbour, Laura T
• Format: Journal Article
• Language: English
• Published: United States American Heart Association, Inc 01.01.2017
• Subjects: Adolescent; Adult; Aged; Animals; Ankyrins; Ankyrins - chemistry; Ankyrins - genetics; Ankyrins - metabolism; Arrhythmia; Arrhythmias, Cardiac - diagnosis; Arrhythmias, Cardiac - ethnology; Arrhythmias, Cardiac - genetics; Arrhythmias, Cardiac - metabolism; British Columbia - epidemiology; Cardiomyocytes; Cardiomyopathy; Cardiovascular disease; Cell Line; Child; Child, Preschool; Coronary artery disease; Electrocardiography; Female; Genetic Predisposition to Disease; Genetic Variation; Genotyping; Heart; Heart diseases; Humans; Indians, North American - genetics; KCNQ1 protein; Localization; Long QT syndrome; Long QT Syndrome - diagnosis; Long QT Syndrome - ethnology; Long QT Syndrome - genetics; Long QT Syndrome - metabolism; Male; Mice, Knockout; Middle Aged; Mutation; Myocytes; Myocytes, Cardiac - metabolism; Na+/Ca2+ exchanger; Phenotype; Potassium channels (voltage-gated); Protein Binding; Protein Interaction Domains and Motifs; Protein Stability; Rats; Seizures; Sodium-Calcium Exchanger - metabolism; Structure-Activity Relationship; Syncope; Transfection; Ventricle; genetic variation; heart rate; long QT syndrome; arrhythmia; Wolff–Parkinson–White syndrome
• ISSN: 1942-325X; 1942-3268
• DOI: 10.1161/CIRCGENETICS.116.001537

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 in KCNQ1. However, 2 large multigenerational families were affected, but negative for the known mutation. METHODS AND 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 novel ANK2 c.1937C>T variant (p.S646F). An additional 16 carriers were identified, including 2 with structural heart diseaseone 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-causing ANK2 variant 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 of ANK2 in targeting and stabilization of key structural and signaling molecules in cardiac cells.