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Calmodulin mutations associated with recurrent cardiac arrest in infants Crotti L; Johnson CN; Graf E; De Ferrari GM; Cuneo BF; Ovadia M; Papagiannis J; Feldkamp MD; Rathi SG; Kunic JD; Pedrazzini M; Wieland T; Lichtner P; Beckmann BM; Clark T; Shaffer C; Benson DW; Kaab S; Meitinger T; Strom TM; Chazin WJ; Schwartz PJ; George AL JrCirculation 2013[Mar]; 127 (9): 1009-17BACKGROUND: 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.|Amino Acid Sequence[MESH]|Calcium Signaling/genetics[MESH]|Calmodulin/*genetics[MESH]|Child, Preschool[MESH]|Cohort Studies[MESH]|Female[MESH]|Follow-Up Studies[MESH]|Genetic Association Studies/methods[MESH]|Heart Arrest/diagnosis/*genetics/physiopathology[MESH]|Humans[MESH]|Infant[MESH]|Infant, Newborn[MESH]|Long QT Syndrome/diagnosis/*genetics/physiopathology[MESH]|Male[MESH]|Molecular Sequence Data[MESH]|Mutation[MESH]|Pedigree[MESH]|Recurrence[MESH] |
