Key result
The CaM(F90L) mutation reduces protein stability, Ca2+-binding affinity, and RyR2 interaction, suggesting aberrant CaM-RyR2 interaction as a mechanism for familial idiopathic ventricular fibrillation.
The CaM(F90L) mutation disrupts RyR2-mediated Ca(2+) release, providing a potential biochemical mechanism for familial idiopathic ventricular fibrillation.
No immediate clinical implications; hypothesis-generating for CaM-RyR2 disruption in familial idiopathic VF.
Calmodulin (CaM) association with the cardiac muscle ryanodine receptor (RyR2) regulates excitation-contraction coupling. Defective CaM-RyR2 interaction is associated with heart failure. A novel CaM mutation (CaM(F90L)) was recently identified in a family with idiopathic ventricular fibrillation (IVF) and early onset sudden cardiac death. We report the first biochemical characterization of CaM(F90L). F90L confers a deleterious effect on protein stability. Ca(2+)-binding studies reveal reduced Ca(2+)-binding affinity and a loss of co-operativity. Moreover, CaM(F90L) displays reduced RyR2 interaction and defective modulation of [(3)H]ryanodine binding. Hence, dysregulation of RyR2-mediated Ca(2+) release via aberrant CaM(F90L)-RyR2 interaction is a potential mechanism that underlies familial IVF.
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Nomikos et al. (2014) studied Idiopathic ventricular fibrillation and early sudden cardiac death. CaM(F90L) mutation was evaluated on Biochemical characterization of CaM(F90L). The CaM(F90L) mutation reduces protein stability, Ca2+-binding affinity, and RyR2 interaction, suggesting aberrant CaM-RyR2 interaction as a mechanism for familial idiopathic ventricular fibrillation.
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