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

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 & 36 others David A. Chiasson, Matthew Rg Taylor, Samantha L. Simmons, Mei Han, Chantal Jm 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 Ab 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

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
JournalThe Journal of clinical investigation
Volume130
DOIs
StatePublished - Jul 2 2019

Fingerprint

Ankyrins
Catenins
Cardiomyopathies
Therapeutics
Phenotype
Premature Mortality
Sudden Cardiac Death
Cardiac Arrhythmias
Dilatation
Fibrosis
Pharmacology

Keywords

  • Arrhythmias
  • Cardiology
  • Cardiovascular disease
  • Cell Biology
  • Genetic diseases

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Roberts, J. D., Murphy, N. P., Hamilton, R. M., Lubbers, E. R., James, C. A., Kline, C. F., ... Mohler, P. J. (2019). Ankyrin-B dysfunction predisposes to arrhythmogenic cardiomyopathy and is amenable to therapy. The Journal of clinical investigation, 130. https://doi.org/10.1172/JCI125538

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

In: The Journal of clinical investigation, Vol. 130, 02.07.2019.

Research output: Contribution to journalArticle

Roberts, JD, Murphy, NP, Hamilton, RM, Lubbers, ER, James, CA, Kline, CF, Gollob, MH, Krahn, AD, Sturm, AC, Musa, H, El-Refaey, M, Koenig, S, Aneq, MÅ, Hoorntje, ET, Graw, SL, Davies, RW, Rafiq, MA, Koopmann, TT, Aafaqi, S, Fatah, M, Chiasson, DA, Taylor, MR, Simmons, SL, Han, M, van Opbergen, CJ, Wold, LE, Sinagra, G, Mittal, K, Tichnell, C, Murray, B, Codima, A, Nazer, B, Nguyen, DT, Marcus, FI, Sobriera, N, Lodder, EM, van den Berg, MP, Spears, DA, Robinson, JF, Ursell, PC, Green, AK, Skanes, AC, Tang, AS, Gardner, MJ, Hegele, RA, van Veen, TA, Wilde, AAM, Healey, JS, Janssen, PML, Mestroni, L, van Tintelen, JP, Calkins, H, Judge, DP, Hund, TJ, Scheinman, MM & Mohler, PJ 2019, 'Ankyrin-B dysfunction predisposes to arrhythmogenic cardiomyopathy and is amenable to therapy', The Journal of clinical investigation, vol. 130. https://doi.org/10.1172/JCI125538
Roberts, Jason D. ; Murphy, Nathaniel P. ; Hamilton, Robert M. ; Lubbers, Ellen R. ; James, Cynthia A. ; Kline, Crystal F. ; Gollob, Michael H. ; Krahn, Andrew D. ; Sturm, Amy C. ; Musa, Hassan ; El-Refaey, Mona ; Koenig, Sara ; Aneq, Meriam Åström ; Hoorntje, Edgar T. ; Graw, Sharon L. ; Davies, Robert W. ; Rafiq, Muhammad Arshad ; Koopmann, Tamara T. ; Aafaqi, Shabana ; Fatah, Meena ; Chiasson, David A. ; Taylor, Matthew Rg ; Simmons, Samantha L. ; Han, Mei ; van Opbergen, Chantal Jm ; Wold, Loren E. ; Sinagra, Gianfranco ; Mittal, Kirti ; Tichnell, Crystal ; Murray, Brittney ; Codima, Alberto ; Nazer, Babak ; Nguyen, Duy T. ; Marcus, Frank I. ; Sobriera, Nara ; Lodder, Elisabeth M. ; van den Berg, Maarten P. ; Spears, Danna A. ; Robinson, John F. ; Ursell, Philip C. ; Green, Anna K. ; Skanes, Allan C. ; Tang, Anthony S. ; Gardner, Martin J. ; Hegele, Robert A. ; van Veen, Toon Ab ; Wilde, Arthur A.M. ; Healey, Jeff S. ; Janssen, Paul M.L. ; Mestroni, Luisa ; van Tintelen, J. Peter ; Calkins, Hugh ; Judge, Daniel P. ; Hund, Thomas J. ; Scheinman, Melvin M. ; Mohler, Peter J. / Ankyrin-B dysfunction predisposes to arrhythmogenic cardiomyopathy and is amenable to therapy. In: The Journal of clinical investigation. 2019 ; Vol. 130.
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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.",
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T1 - Ankyrin-B dysfunction predisposes to arrhythmogenic cardiomyopathy and is amenable to therapy

AU - Roberts, Jason D.

AU - Murphy, Nathaniel P.

AU - Hamilton, Robert M.

AU - Lubbers, Ellen R.

AU - James, Cynthia A.

AU - Kline, Crystal F.

AU - Gollob, Michael H.

AU - Krahn, Andrew D.

AU - Sturm, Amy C.

AU - Musa, Hassan

AU - El-Refaey, Mona

AU - Koenig, Sara

AU - Aneq, Meriam Åström

AU - Hoorntje, Edgar T.

AU - Graw, Sharon L.

AU - Davies, Robert W.

AU - Rafiq, Muhammad Arshad

AU - Koopmann, Tamara T.

AU - Aafaqi, Shabana

AU - Fatah, Meena

AU - Chiasson, David A.

AU - Taylor, Matthew Rg

AU - Simmons, Samantha L.

AU - Han, Mei

AU - van Opbergen, Chantal Jm

AU - Wold, Loren E.

AU - Sinagra, Gianfranco

AU - Mittal, Kirti

AU - Tichnell, Crystal

AU - Murray, Brittney

AU - Codima, Alberto

AU - Nazer, Babak

AU - Nguyen, Duy T.

AU - Marcus, Frank I.

AU - Sobriera, Nara

AU - Lodder, Elisabeth M.

AU - van den Berg, Maarten P.

AU - Spears, Danna A.

AU - Robinson, John F.

AU - Ursell, Philip C.

AU - Green, Anna K.

AU - Skanes, Allan C.

AU - Tang, Anthony S.

AU - Gardner, Martin J.

AU - Hegele, Robert A.

AU - van Veen, Toon Ab

AU - Wilde, Arthur A.M.

AU - Healey, Jeff S.

AU - Janssen, Paul M.L.

AU - Mestroni, Luisa

AU - van Tintelen, J. Peter

AU - Calkins, Hugh

AU - Judge, Daniel P.

AU - Hund, Thomas J.

AU - Scheinman, Melvin M.

AU - Mohler, Peter J.

PY - 2019/7/2

Y1 - 2019/7/2

N2 - 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.

AB - 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.

KW - Arrhythmias

KW - Cardiology

KW - Cardiovascular disease

KW - Cell Biology

KW - Genetic diseases

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