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Ankyrin-B dysfunction predisposes to arrhythmogenic cardiomyopathy and is amenable to therapy
Jason D. Roberts, … , Melvin M. Scheinman, Peter J. Mohler
Jason D. Roberts, … , Melvin M. Scheinman, Peter J. Mohler
Published July 2, 2019
Citation Information: J Clin Invest. 2019;129(8):3171-3184. https://doi.org/10.1172/JCI125538.
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Research Article Cardiology Cell biology

Ankyrin-B dysfunction predisposes to arrhythmogenic cardiomyopathy and is amenable to therapy

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Abstract

Arrhythmogenic cardiomyopathy (ACM) is an inherited arrhythmia syndrome characterized by severe structural and electrical cardiac phenotypes, including myocardial fibrofatty replacement and sudden cardiac death. Clinical management of ACM is largely palliative, owing to an absence of therapies that target its underlying pathophysiology, which stems partially from our limited insight into the condition. Following identification of deceased ACM probands possessing ANK2 rare variants and evidence of ankyrin-B loss of function on cardiac tissue analysis, an ANK2 mouse model was found to develop dramatic structural abnormalities reflective of human ACM, including biventricular dilation, reduced ejection fraction, cardiac fibrosis, and premature death. Desmosomal structure and function appeared preserved in diseased human and murine specimens in the presence of markedly abnormal β-catenin expression and patterning, leading to identification of a previously unknown interaction between ankyrin-B and β-catenin. A pharmacological activator of the WNT/β-catenin pathway, SB-216763, successfully prevented and partially reversed the murine ACM phenotypes. Our findings introduce what we believe to be a new pathway for ACM, a role of ankyrin-B in cardiac structure and signaling, a molecular link between ankyrin-B and β-catenin, and evidence for targeted activation of the WNT/β-catenin pathway as a potential treatment for this disease.

Authors

Jason D. Roberts, Nathaniel P. Murphy, Robert M. Hamilton, Ellen R. Lubbers, Cynthia A. James, Crystal F. Kline, Michael H. Gollob, Andrew D. Krahn, Amy C. Sturm, Hassan Musa, Mona El-Refaey, Sara Koenig, Meriam Åström Aneq, Edgar T. Hoorntje, Sharon L. Graw, Robert W. Davies, Muhammad Arshad Rafiq, Tamara T. Koopmann, Shabana Aafaqi, Meena Fatah, David A. Chiasson, Matthew R.G. Taylor, Samantha L. Simmons, Mei Han, Chantal J.M. van Opbergen, Loren E. Wold, Gianfranco Sinagra, Kirti Mittal, Crystal Tichnell, Brittney Murray, Alberto Codima, Babak Nazer, Duy T. Nguyen, Frank I. Marcus, Nara Sobriera, Elisabeth M. Lodder, Maarten P. van den Berg, Danna A. Spears, John F. Robinson, Philip C. Ursell, Anna K. Green, Allan C. Skanes, Anthony S. Tang, Martin J. Gardner, Robert A. Hegele, Toon A.B. van Veen, Arthur A.M. Wilde, Jeff S. Healey, Paul M.L. Janssen, Luisa Mestroni, J. Peter van Tintelen, Hugh Calkins, Daniel P. Judge, Thomas J. Hund, Melvin M. Scheinman, Peter J. Mohler

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Figure 1

Deceased proband harboring AnkB loss-of-function p.Glu1458Gly variant exhibits arrhythmogenic cardiomyopathy.

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Deceased proband harboring AnkB loss-of-function p.Glu1458Gly variant ex...
(A) Surface 12-lead ECG. (B) Loop recording demonstrating nonsustained polymorphic VT. (C) Cardiac magnetic resonance short-axis image revealing moderate biventricular dilation; the yellow ring highlights focal “crinkling” of the subtricuspid region of the right ventricular free wall consistent with the “accordion sign.” (D) Delayed enhancement imaging revealed scarring in the right ventricular (RV) free wall in a short-axis view (arrows) and (E) the left ventricular (LV) lateral wall (arrow) in a long-axis view. (F) Mid-transverse section of the autopsied heart revealing severe right ventricular dilation and wall thinning as well as concentric hypertrophy of the left ventricle. Histology of the (G) right ventricle showing severe fibrofatty infiltration of the free wall in association with extensive ventricular interstitial fibrosis and (H) left ventricle showing moderate hypertrophy with focal areas of fibrofatty muscular infiltration and widespread interstitial fibrosis. Scale bars: 160 μm (G) and 60 μm (H).

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