title: Calmodulin mutations associated with recurrent cardiac arrest in infants.
abstract: 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.
  
  
  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.
authors: Section of Cardiology, Department of Molecular Medicine, University of Pavia, Pavia, Italy.
authors: Lia
authors: L
authors: Crotti
authors: Christopher N
authors: CN
authors: Johnson
authors: Elisabeth
authors: E
authors: Graf
authors: Gaetano M
authors: GM
authors: De Ferrari
authors: Bettina F
authors: BF
authors: Cuneo
authors: Marc
authors: M
authors: Ovadia
authors: John
authors: J
authors: Papagiannis
authors: Michael D
authors: MD
authors: Feldkamp
authors: Subodh G
authors: SG
authors: Rathi
authors: Jennifer D
authors: JD
authors: Kunic
authors: Matteo
authors: M
authors: Pedrazzini
authors: Thomas
authors: T
authors: Wieland
authors: Peter
authors: P
authors: Lichtner
authors: Britt-Maria
authors: BM
authors: Beckmann
authors: Travis
authors: T
authors: Clark
authors: Christian
authors: C
authors: Shaffer
authors: D Woodrow
authors: DW
authors: Benson
authors: Stefan
authors: S
authors: Kääb
authors: Thomas
authors: T
authors: Meitinger
authors: Tim M
authors: TM
authors: Strom
authors: Walter J
authors: WJ
authors: Chazin
authors: Peter J
authors: PJ
authors: Schwartz
authors: Alfred L
authors: AL
authors: George
mesh_terms: D000595:Amino Acid Sequence; D020013:Calcium Signaling / Q000235:genetics; D002147:Calmodulin / Q000235:genetics*; D002675:Child, Preschool; D015331:Cohort Studies; D005260:Female; D005500:Follow-Up Studies; D056726:Genetic Association Studies / Q000379:methods; D006323:Heart Arrest / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008133:Long QT Syndrome / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D012008:Recurrence
chemical_list: C488659:CALM2 protein, human; D002147:Calmodulin
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