PUBLICATION
Arrhythmogenic calmodulin E105A mutation alters cardiac RyR2 regulation leading to cardiac dysfunction in zebrafish
- Authors
- Da'as, S.I., Thanassoulas, A., Calver, B.L., Beck, K., Salem, R., Saleh, A., Kontogianni, I., Al-Maraghi, A., Nasrallah, G.K., Safieh-Garabedian, B., Toft, E., Nounesis, G., Lai, F.A., Nomikos, M.
- ID
- ZDB-PUB-190403-8
- Date
- 2019
- Source
- Annals of the New York Academy of Sciences 1448(1): 19-29 (Journal)
- Registered Authors
- Da'as, Sahar, Nasrallah, Gheyath
- Keywords
- arrhythmia, calcium, calmodulin, long QT syndrome, ryanodine receptor 2, zebrafish
- MeSH Terms
-
- Animals
- Arrhythmias, Cardiac/genetics*
- Arrhythmias, Cardiac/pathology
- Calcium/metabolism
- Calcium Signaling/physiology
- Calmodulin/genetics*
- Calmodulin/metabolism*
- Child
- Excitation Contraction Coupling/physiology
- Heart Rate/genetics
- Heart Rate/physiology
- Humans
- Male
- Myocytes, Cardiac/metabolism
- Ryanodine Receptor Calcium Release Channel/metabolism*
- Tachycardia, Ventricular/genetics*
- Tachycardia, Ventricular/physiopathology
- Zebrafish
- PubMed
- 30937913 Full text @ Ann N Y Acad Sci
Citation
Da'as, S.I., Thanassoulas, A., Calver, B.L., Beck, K., Salem, R., Saleh, A., Kontogianni, I., Al-Maraghi, A., Nasrallah, G.K., Safieh-Garabedian, B., Toft, E., Nounesis, G., Lai, F.A., Nomikos, M. (2019) Arrhythmogenic calmodulin E105A mutation alters cardiac RyR2 regulation leading to cardiac dysfunction in zebrafish. Annals of the New York Academy of Sciences. 1448(1):19-29.
Abstract
Calmodulin (CaM) is a universal calcium (Ca2+ )-binding messenger that regulates many vital cellular events. In cardiac muscle, CaM associates with ryanodine receptor 2 (RyR2) and regulates excitation-contraction coupling. Mutations in human genes CALM1, CALM2, and CALM3 have been associated with life-threatening heart disorders, such as long QT syndrome (LQTS) and catecholaminergic polymorphic ventricular tachycardia. A novel de novo LQTS-associated missense CaM mutation (E105A) was recently identified in a 6-year-old boy, who experienced an aborted first episode of cardiac arrest. Herein, we report the first molecular characterization of the CaM E105A mutation. Expression of the CaM E105A mutant in zebrafish embryos resulted in cardiac arrhythmia and increased heart rate, suggestive of ventricular tachycardia. In vitro biophysical and biochemical analysis revealed that E105A confers a deleterious effect on protein stability and a reduced Ca2+ -binding affinity due to loss of cooperativity. Finally, the CaM E105A mutation resulted in reduced CaM-RyR2 interaction and defective modulation of ryanodine binding. Our findings suggest that the CaM E105A mutation dysregulates normal cardiac function by a complex mechanism involving alterations in both CaM-Ca2+ and CaM-RyR2 interactions.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping