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Title: | A novel mechanism for human cardiac Ankyrin-B syndrome due to reciprocal chromosomal translocation | Austin Authors: | Huq, Aamira J;Pertile, MD;Davis, AM;Landon, H;James, PA;Kline, CF;Vohra, J;Mohler, PJ;Delatycki, Martin B | Affiliation: | Department of Clinical Genetics, Austin Health, Heidelberg, Victoria, Australia Victorian Clinical Genetics Services, Melbourne, Victoria, Australia Department of Cardiology, Royal Children's Hospital, Melbourne, Victoria, Australia Department of Genetic Medicine, Royal Melbourne Hospital, Melbourne, Victoria, Australia Department of Cardiology, Royal Melbourne Hospital, Melbourne, Victoria, Australia Department of Paediatrics, University of Melbourne, Melbourne, Victoria, Australia Dorothy M. Davis Heart and Lung Research Institute; Departments of Physiology & Cell Biology and Internal Medicine; Ohio State University Wexner Medical Center, Columbus, OH, USA Bruce Lefroy Centre, Murdoch Childrens Research Institute, Melbourne, Victoria, Australia Murdoch Childrens Research Institute, Melbourne, Victoria, Australia Department of Pathology, University of Melbourne, Melbourne, Victoria, Australia |
Issue Date: | Jun-2017 | Date: | 2016-11-16 | Publication information: | Heart, Lung and Circulation 2017; 26(6): 612-618 | Abstract: | BACKGROUND: Cardiac rhythm abnormalities are a leading cause of morbidity and mortality in developed countries. Loss-of-function variants in the ANK2 gene can cause a variety of cardiac rhythm abnormalities including sinus node dysfunction, atrial fibrillation and ventricular arrhythmias (called the "ankyrin-B syndrome"). ANK2 encodes ankyrin-B, a molecule critical for the membrane targeting of key cardiac ion channels, transporters, and signalling proteins. METHODS AND RESULTS: Here, we describe a family with a reciprocal chromosomal translocation between chromosomes 4q25 and 9q26 that transects the ANK2 gene on chromosome 4 resulting in loss-of-function of ankyrin-B. Select family members with ankyrin-B haploinsufficiency due to the translocation displayed clinical features of ankyrin-B syndrome. Furthermore, evaluation of primary lymphoblasts from a carrier of the translocation showed altered levels of ankyrin-B as well as a reduced expression of downstream ankyrin-binding partners. CONCLUSIONS: Thus, our data conclude that, similar to previously described ANK2 loss-of-function "point mutations", large chromosomal translocations resulting in ANK2 haploinsufficiency are sufficient to cause the human cardiac ankyrin-B syndrome. The unexpected ascertainment of ANK2 dysfunction via the discovery of a chromosomal translocation in this family, the determination of the familial phenotype, as well as the complexities in formulating screening and treatment strategies are discussed. | URI: | https://ahro.austin.org.au/austinjspui/handle/1/16557 | DOI: | 10.1016/j.hlc.2016.09.013 | Journal: | Heart, Lung and Circulation | PubMed URL: | https://pubmed.ncbi.nlm.nih.gov/27916589 | Type: | Journal Article | Subjects: | ANK2 Ankyrin-B Ankyrin-B syndrome Cardiac arrhythmia Chromosome 4 translocation Long QT syndrome type 4 |
Appears in Collections: | Journal articles |
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