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http://purl.uniprot.org/citations/23388215http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/23388215http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/23388215http://www.w3.org/2000/01/rdf-schema#comment"

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."xsd:string
http://purl.uniprot.org/citations/23388215http://purl.org/dc/terms/identifier"doi:10.1161/circulationaha.112.001216"xsd:string
http://purl.uniprot.org/citations/23388215http://purl.org/dc/terms/identifier"doi:10.1161/circulationaha.112.001216"xsd:string
http://purl.uniprot.org/citations/23388215http://purl.uniprot.org/core/author"Meitinger T."xsd:string
http://purl.uniprot.org/citations/23388215http://purl.uniprot.org/core/author"Meitinger T."xsd:string
http://purl.uniprot.org/citations/23388215http://purl.uniprot.org/core/author"Graf E."xsd:string
http://purl.uniprot.org/citations/23388215http://purl.uniprot.org/core/author"Graf E."xsd:string
http://purl.uniprot.org/citations/23388215http://purl.uniprot.org/core/author"Lichtner P."xsd:string
http://purl.uniprot.org/citations/23388215http://purl.uniprot.org/core/author"Lichtner P."xsd:string
http://purl.uniprot.org/citations/23388215http://purl.uniprot.org/core/author"Strom T.M."xsd:string
http://purl.uniprot.org/citations/23388215http://purl.uniprot.org/core/author"Strom T.M."xsd:string
http://purl.uniprot.org/citations/23388215http://purl.uniprot.org/core/author"Benson D.W."xsd:string
http://purl.uniprot.org/citations/23388215http://purl.uniprot.org/core/author"Benson D.W."xsd:string
http://purl.uniprot.org/citations/23388215http://purl.uniprot.org/core/author"Wieland T."xsd:string
http://purl.uniprot.org/citations/23388215http://purl.uniprot.org/core/author"Wieland T."xsd:string
http://purl.uniprot.org/citations/23388215http://purl.uniprot.org/core/author"Ovadia M."xsd:string
http://purl.uniprot.org/citations/23388215http://purl.uniprot.org/core/author"Ovadia M."xsd:string
http://purl.uniprot.org/citations/23388215http://purl.uniprot.org/core/author"George A.L. Jr."xsd:string
http://purl.uniprot.org/citations/23388215http://purl.uniprot.org/core/author"George A.L. Jr."xsd:string
http://purl.uniprot.org/citations/23388215http://purl.uniprot.org/core/author"Clark T."xsd:string
http://purl.uniprot.org/citations/23388215http://purl.uniprot.org/core/author"Clark T."xsd:string
http://purl.uniprot.org/citations/23388215http://purl.uniprot.org/core/author"Chazin W.J."xsd:string
http://purl.uniprot.org/citations/23388215http://purl.uniprot.org/core/author"Chazin W.J."xsd:string
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