Ankyrin-B dysfunction predisposes to arrhythmogenic cardiomyopathy and is amenable to therapy
Jason D Roberts1,2, Nathaniel P Murphy3,4, Robert M Hamilton5
1Section of Cardiac Electrophysiology, Division of Cardiology, Department of Medicine, Western University, London, Ontario, Canada.
The Journal of Clinical Investigation
|July 3, 2019
Summary
Rare ANK2 gene variants cause arrhythmogenic cardiomyopathy (ACM) by disrupting ankyrin-B function, leading to cardiac abnormalities. Activating the WNT/β-catenin pathway offers a potential therapeutic strategy for ACM.
Area of Science:
- Cardiology
- Genetics
- Molecular Biology
Background:
- Arrhythmogenic cardiomyopathy (ACM) is an inherited heart condition with limited treatment options.
- Pathophysiology of ACM is not fully understood, hindering therapeutic development.
- ANK2 gene variants and ankyrin-B dysfunction are implicated in ACM.
Purpose of the Study:
- Investigate the role of ANK2 variants and ankyrin-B in ACM.
- Identify novel molecular pathways involved in ACM.
- Explore potential therapeutic targets for ACM.
Main Methods:
- Analysis of ANK2 variants in ACM patients.
- Generation and study of an ANK2 mouse model of ACM.
- Assessment of cardiac structure, function, and molecular signaling (including β-catenin).
- Pharmacological intervention using a WNT/β-catenin pathway activator (SB-216763).
Main Results:
- ANK2 variants led to ankyrin-B loss of function and ACM-like phenotypes in mice.
- Abnormal β-catenin expression was observed, suggesting a link with ankyrin-B.
- Desmosomal structure was preserved, indicating a different mechanism than previously thought.
- SB-216763 treatment prevented and reversed ACM phenotypes in mice.
Conclusions:
- Ankyrin-B plays a crucial role in cardiac structure and signaling.
- A novel molecular link between ankyrin-B and β-catenin in ACM pathogenesis was identified.
- Targeted activation of the WNT/β-catenin pathway is a promising therapeutic strategy for ACM.
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