Can mutations in Calmodulin cause ventricular fibrillation?
['We characterized a family presenting with a history of ventricular fibrillation (VF) and sudden death without ECG or echocardiographic abnormalities at rest. Two siblings died suddenly at the ages of 9 and 10 years, and another two were resuscitated from out-of-hospital cardiac arrest with documented VF at age 10 and 16, respectively. Exome sequencing identified a missense mutation affecting a highly conserved residue (p.Phe90Leu) in the CALM1 gene encoding calmodulin. This mutation was also carried by one of the sibs who died suddenly, for whom DNA was available. The mutation was present in the mother and in an sibling, both asymptomatic but displaying a marginally prolonged QT-interval during exercise. CONCLUSIONS: We identified a mutation in CALM1 underlying IVF manifesting in childhood and adolescence. The causality of the mutation is supported by previous studies demonstrating that Phe90 mediates the direct interaction of CaM with target peptides', "Here we show that calmodulin (CaM), a ubiquitous Ca2+-sensing protein, binds to the carboxy-terminal 'IQ' domain of the human cardiac Na channel (hH1) in a Ca2+-dependent manner. This binding interaction significantly enhances slow inactivation-a channel-gating process linked to life-threatening idiopathic ventricular arrhythmias. Mutations targeted to the IQ domain disrupted CaM binding and eliminated Ca2+/CaM-dependent slow inactivation, whereas the gating effects of Ca2+/CaM were restored by intracellular application of a peptide modelled after the IQ domain. "]
['Yes, mutations in CALM underly IVF manifesting in childhood and adolescence.']
['yes']