Calmodulin mutations associated with recurrent cardiac arrest in infants

L Crotti, CN Johnson, E Graf, GM De Ferrari… - Circulation, 2013 - Am Heart Assoc
L Crotti, CN Johnson, E Graf, GM De Ferrari, BF Cuneo, M Ovadia, J Papagiannis
Circulation, 2013Am Heart Assoc
Background—Life-threatening disorders of heart rhythm may arise during infancy and can
result in the sudden and tragic death of a child. We performed exome sequencing on 2
unrelated infants presenting with recurrent cardiac arrest to discover a genetic cause.
Methods and Results—We ascertained 2 unrelated infants (probands) with recurrent cardiac
arrest and dramatically prolonged QTc interval who were both born to healthy parents. The 2
parent-child trios were investigated with the use of exome sequencing to search for de novo …
Background
Life-threatening disorders of heart rhythm may arise during infancy and can result in the sudden and tragic death of a child. We performed exome sequencing on 2 unrelated infants presenting with recurrent cardiac arrest to discover a genetic cause.
Methods and Results
We ascertained 2 unrelated infants (probands) with recurrent cardiac arrest and dramatically prolonged QTc interval who were both born to healthy parents. The 2 parent-child trios were investigated with the use of exome sequencing to search for de novo genetic variants. We then performed follow-up candidate gene screening on an independent cohort of 82 subjects with congenital long-QT syndrome without an identified genetic cause. Biochemical studies were performed to determine the functional consequences of mutations discovered in 2 genes encoding calmodulin. We discovered 3 heterozygous de novo mutations in either CALM1 or CALM2, 2 of the 3 human genes encoding calmodulin, in the 2 probands and in 2 additional subjects with recurrent cardiac arrest. All mutation carriers were infants who exhibited life-threatening ventricular arrhythmias combined variably with epilepsy and delayed neurodevelopment. Mutations altered residues in or adjacent to critical calcium binding loops in the calmodulin carboxyl-terminal domain. Recombinant mutant calmodulins exhibited several-fold reductions in calcium binding affinity.
Conclusions
Human calmodulin mutations disrupt calcium ion binding to the protein and are associated with a life-threatening condition in early infancy. Defects in calmodulin function will disrupt important calcium signaling events in heart, affecting membrane ion channels, a plausible molecular mechanism for potentially deadly disturbances in heart rhythm during infancy.
Am Heart Assoc