Reversibility of PRKAG2 Glycogen-Storage Cardiomyopathy and Electrophysiological Manifestations
Open accessAbstract
BACKGROUND: PRKAG2 mutations cause glycogen-storage cardiomyopathy, ventricular preexcitation, and conduction system degeneration. A genetic approach that utilizes a binary inducible transgenic system was used to investigate the disease mechanism and to assess preventability and reversibility of disease features in a mouse model of glycogen-storage cardiomyopathy. METHODS AND RESULTS: Transgenic (Tg) mice expressing a human N488I PRKAG2 cDNA under control of the tetracycline-repressible alpha-myosin heavy chain promoter underwent echocardiography, ECG, and in vivo electrophysiology studies. Transgene suppression by tetracycline administration caused a reduction in cardiac glycogen content and was initiated either prenatally (Tg(OFF(E-8 weeks))) or at different time points during life (Tg(OFF(4-16 weeks)), Tg(OFF(8-20 weeks)), and Tg(OFF(>20 weeks))). One group never received tetracycline, expressing transgene throughout life (Tg(ON)). Tg(ON) mice developed cardiac hypertrophy followed by dilatation, ventricular preexcitation involving multiple accessory pathways, and conduction system disease, including sinus and atrioventricular node dysfunction. CONCLUSIONS: Using an externally modifiable transgenic system, cardiomyopathy, cardiac dysfunction, and electrophysiological disorders were demonstrated to be reversible processes in PRKAG2 disease. Transgene suppression during early postnatal development prevented the development of accessory electrical pathways but not cardiomyopathy or conduction system degeneration. Taken together, these data provide insight into mechanisms of cardiac PRKAG2 disease and suggest that glycogen-storage cardiomyopathy can be modulated by lowering glycogen content in the heart.
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New data on the genetics of supraventricular tachycardia continually appear since the identification of a missense mutation in PRKAG2 as a cause of familial Wolff-Parkinson-White syndrome.
“New data on the genetics of SVT continually appear since the identification of a missense mutation in the gene PRKAG2, that encodes the regulatory g-subunit of AMP-activated protein kinase, as a cause of familial Wolff -Parkinson -White syndrome.429,430”
From European Heart Rhythm Association (EHRA) consensus document on the management of supraventricular arrhythmias, endorsed by Heart Rhythm Society (HRS), Asia-Pacific Heart Rhythm Society (APHRS), and Sociedad Latinoamericana de Estimulacion Cardiaca y Electrofisiologia (SOLAECE) (2017) · cites this paper as [430]
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A New Perspective on the Quality of Life of Children with Glycogen Storage Diseases
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Reversible Transition from a Hypertrophic to a Dilated Cardiomyopathy
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AMPKγ2 Regulates Cardiac Hypertrophy and Arrhythmias via Interacting With Myosin
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PRKAG2-associated hypertrophic cardiomyopathy
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- Authors
- Wolf, C. M., Arad, M., Ahmad, F., Sanbe, A., Bernstein, S. A., Toka, O., Konno, T., Morley, G., Robbins, J., Seidman, J. G., Seidman, C. E., & Berul, C. I.
- Affiliations
- Cincinnati Children's Hospital Medical Center (US)
- ORCID
- Venue
- Circulation
- Published
- 2008-01-15
- Volume
- 117
- Issue
- 2
- Pages
- 144-154
- ISSN
- 0009-7322 (ISSN-L)
- 1524-4539
- PMC
- PMC2957811
- OpenAlex
- W2095690908
- Cited by
- 89
- References
- 43
- Citations by year
- 2026: 3 · 2025: 5 · 2024: 3 · 2023: 4 · 2022: 7 · 2021: 5 · 2020: 2 · 2019: 7 · 2018: 4 · 2017: 5 · 2016: 6 · 2015: 4 · 2014: 4 · 2013: 4 · 2012: 4
- FWCI
- 3.68
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Circulation (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Howard Hughes Medical Institute
- National Institutes of Health
- National Heart, Lung, and Blood Institute (R01HL076751)
- Topics
- Health Sciences › Medicine › Rheumatology › Glycogen Storage Diseases and Myoclonus
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiomyopathy and Myosin Studies
- Keywords
- PRKAG2, preexcitation, accessory pathway, cardiac hypertrophy, dilated cardiomyopathy, cardiac glycogen, atrioventricular node dysfunction, sick sinus syndrome
- MeSH terms
- Age Factors, Animals, Electrocardiography, Electrophysiology, Glycogen, Humans, Mice, Transgenic, Multienzyme Complexes, Promoter Regions, Genetic, Tetracycline, Genetic Therapy, Protein Serine-Threonine Kinases, Mice, Glycogen Storage Disease Type IIb, AMP-Activated Protein Kinases
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