@article{8fb9051c239a49d89779635704f3fa82,
title = "Ankyrin-B dysfunction predisposes to arrhythmogenic cardiomyopathy and is amenable to therapy",
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.",
author = "Roberts, {Jason D.} and Murphy, {Nathaniel P.} and Hamilton, {Robert M.} and Lubbers, {Ellen R.} and James, {Cynthia A.} and Kline, {Crystal F.} and Gollob, {Michael H.} and Krahn, {Andrew D.} and Sturm, {Amy C.} and Hassan Musa and Mona El-Refaey and Sara Koenig and Aneq, {Meriam {\AA}str{\"o}m} and Hoorntje, {Edgar T.} and Graw, {Sharon L.} and Davies, {Robert W.} and Rafiq, {Muhammad Arshad} and Koopmann, {Tamara T.} and Shabana Aafaqi and Meena Fatah and Chiasson, {David A.} and Taylor, {Matthew R.G.} and Simmons, {Samantha L.} and Mei Han and {Van Opbergen}, {Chantal J.M.} and Wold, {Loren E.} and Gianfranco Sinagra and Kirti Mittal and Crystal Tichnell and Brittney Murray and Alberto Codima and Babak Nazer and Nguyen, {Duy T.} and Marcus, {Frank I.} and Nara Sobriera and Lodder, {Elisabeth M.} and {Van Den Berg}, {Maarten P.} and Spears, {Danna A.} and Robinson, {John F.} and Ursell, {Philip C.} and Green, {Anna K.} and Skanes, {Allan C.} and Tang, {Anthony S.} and Gardner, {Martin J.} and Hegele, {Robert A.} and {Van Veen}, {Toon A.B.} and Wilde, {Arthur A.M.} and Healey, {Jeff S.} and Janssen, {Paul M.L.} and Luisa Mestroni and {Van Tintelen}, {J. Peter} and Hugh Calkins and Judge, {Daniel P.} and Hund, {Thomas J.} and Scheinman, {Melvin M.} and Mohler, {Peter J.}",
note = "Funding Information: This work was supported by the Marianne Barrie Philanthropic Fund (to JDR) and the Canadian Institutes of Health Research (RN332805; to ADK). TABV was supported by the Netherlands CardioVascular Research Initiative: the Dutch Heart Foundation, the Dutch Federation of University Medical Centers, the Netherlands Organisation for Health Research and Development, and the Royal Netherlands Academy of Sciences (CVON-PREDICT 2012-10). JPVT acknowledges funding from the Netherlands Cardiovascular Research Initiative, an initiative supported by the Dutch Heart Foundation (CVON2012-10 PREDICT CVON2018-30 PREDICT2 and CVON2015-12 eDETECT). CAJ was supported by a visitor{\textquoteright}s travel grant from the Netherlands Organization for Scientific Research (NWO) (040.11.586). HC received funding from the Fon-dation Leducq (16 CVD 02). The Johns Hopkins ARVD/C Program is supported by the Dr. Francis P. Chiramonte Private Foundation; the Leyla Erkan Family Fund for ARVD Research; the Dr. Satish, Rupal; and Robin Shah ARVD Fund at Johns Hopkins, the Bogle Foundation, the Healing Hearts Foundation; the Campanella Family; the Patrick J. Harrison Family; the Peter French Memorial Foundation; and the Wilmerding Endowments. The authors are supported by NIH grants HL135754, HL134824, HL139348, HL135096, and HL114383 (to PJM); HL135096, HL134824, and HL114893 (to TJH); HL137331 (to ERL); HL137325 (to NPM); 2UM1HG006542 (to NS); and UL1 TR 001079 (to HC). This work is supported by a grant from the Ohio State Frick Center and JB Project (to PJM). Funding Information: This work was supported by the Marianne Barrie Philanthropic Fund (to JDR) and the Canadian Institutes of Health Research (RN332805; to ADK). TABV was supported by the Netherlands CardioVascular Research Initiative: the Dutch Heart Foundation, the Dutch Federation of University Medical Centers, the Netherlands Organisation for Health Research and Development, and the Royal Netherlands Academy of Sciences (CVON-PREDICT 2012-10). JPVT acknowledges funding from the Netherlands Cardiovascular Research Initiative, an initiative supported by the Dutch Heart Foundation (CVON2012-10 PREDICT CVON2018-30 PREDICT2 and CVON2015-12 eDETECT). CAJ was supported by a visitor?s travel grant from the Netherlands Organization for Scientific Research (NWO) (040.11.586). HC received funding from the Fon-dation Leducq (16 CVD 02). The Johns Hopkins ARVD/C Program is supported by the Dr. Francis P. Chiramonte Private Foundation; the Leyla Erkan Family Fund for ARVD Research; the Dr. Satish, Rupal; and Robin Shah ARVD Fund at Johns Hopkins, the Bogle Foundation, the Healing Hearts Foundation; the Campanella Family; the Patrick J. Harrison Family; the Peter French Memorial Foundation; and the Wilmerding Endowments. The authors are supported by NIH grants HL135754, HL134824, HL139348, HL135096, and HL114383 (to PJM); HL135096, HL134824, and HL114893 (to TJH); HL137331 (to ERL); HL137325 (to NPM); 2UM1HG006542 (to NS); and UL1 TR 001079 (to HC). This work is supported by a grant from the Ohio State Frick Center and JB Project (to PJM). Publisher Copyright: {\textcopyright} 2019, American Society for Clinical Investigation.",
year = "2019",
month = aug,
day = "1",
doi = "10.1172/JCI125538",
language = "English (US)",
volume = "129",
pages = "3171--3184",
journal = "Journal of Clinical Investigation",
issn = "0021-9738",
publisher = "The American Society for Clinical Investigation",
number = "8",
}