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http://purl.uniprot.org/citations/27374306http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/27374306http://www.w3.org/2000/01/rdf-schema#comment"

Background

Calmodulin (CaM) mutations are associated with cardiac arrhythmia susceptibility including congenital long QT syndrome (LQTS).

Objective

The purpose of this study was to determine the clinical, genetic, and functional features of 2 novel CaM mutations in children with life-threatening ventricular arrhythmias.

Methods

The clinical and genetic features of 2 congenital arrhythmia cases associated with 2 novel CaM gene mutations were ascertained. Biochemical and functional investigations were conducted on the 2 mutations.

Results

A novel de novo CALM2 mutation (D132H) was discovered by candidate gene screening in a male infant with prenatal bradycardia born to healthy parents. Postnatal course was complicated by profound bradycardia, prolonged corrected QT interval (651 ms), 2:1 atrioventricular block, and cardiogenic shock. He was resuscitated and was treated with a cardiac device. A second novel de novo mutation in CALM1 (D132V) was discovered by clinical exome sequencing in a 3-year-old boy who suffered a witnessed cardiac arrest secondary to ventricular fibrillation. Electrocardiographic recording after successful resuscitation revealed a prolonged corrected QT interval of 574 ms. The Ca(2+) affinity of CaM-D132H and CaM-D132V revealed extremely weak binding to the C-terminal domain, with significant structural perturbations noted for D132H. Voltage-clamp recordings of human induced pluripotent stem cell-derived cardiomyocytes transiently expressing wild-type or mutant CaM demonstrated that both mutations caused impaired Ca(2+)-dependent inactivation of voltage-gated Ca(2+) current. Neither mutant affected voltage-dependent inactivation.

Conclusion

Our findings implicate impaired Ca(2+)-dependent inactivation in human cardiomyocytes as the plausible mechanism for long QT syndrome associated with 2 novel CaM mutations. The data further expand the spectrum of genotype and phenotype associated with calmodulinopathy."xsd:string
http://purl.uniprot.org/citations/27374306http://purl.org/dc/terms/identifier"doi:10.1016/j.hrthm.2016.06.038"xsd:string
http://purl.uniprot.org/citations/27374306http://purl.uniprot.org/core/author"Webster G."xsd:string
http://purl.uniprot.org/citations/27374306http://purl.uniprot.org/core/author"Fellmann F."xsd:string
http://purl.uniprot.org/citations/27374306http://purl.uniprot.org/core/author"George A.L. Jr."xsd:string
http://purl.uniprot.org/citations/27374306http://purl.uniprot.org/core/author"Chazin W.J."xsd:string
http://purl.uniprot.org/citations/27374306http://purl.uniprot.org/core/author"Crotti L."xsd:string
http://purl.uniprot.org/citations/27374306http://purl.uniprot.org/core/author"Bhuiyan Z.A."xsd:string
http://purl.uniprot.org/citations/27374306http://purl.uniprot.org/core/author"Johnson C.N."xsd:string
http://purl.uniprot.org/citations/27374306http://purl.uniprot.org/core/author"Wren L.M."xsd:string
http://purl.uniprot.org/citations/27374306http://purl.uniprot.org/core/author"Schlaepfer J."xsd:string
http://purl.uniprot.org/citations/27374306http://purl.uniprot.org/core/author"Sekarski N."xsd:string
http://purl.uniprot.org/citations/27374306http://purl.uniprot.org/core/author"Chazin D.M."xsd:string
http://purl.uniprot.org/citations/27374306http://purl.uniprot.org/core/author"Ogorodnik K.V."xsd:string
http://purl.uniprot.org/citations/27374306http://purl.uniprot.org/core/author"Pipilas D.C."xsd:string
http://purl.uniprot.org/citations/27374306http://purl.uniprot.org/core/date"2016"xsd:gYear
http://purl.uniprot.org/citations/27374306http://purl.uniprot.org/core/name"Heart Rhythm"xsd:string
http://purl.uniprot.org/citations/27374306http://purl.uniprot.org/core/pages"2012-2019"xsd:string
http://purl.uniprot.org/citations/27374306http://purl.uniprot.org/core/title"Novel calmodulin mutations associated with congenital long QT syndrome affect calcium current in human cardiomyocytes."xsd:string
http://purl.uniprot.org/citations/27374306http://purl.uniprot.org/core/volume"13"xsd:string
http://purl.uniprot.org/citations/27374306http://www.w3.org/2004/02/skos/core#exactMatchhttp://purl.uniprot.org/pubmed/27374306
http://purl.uniprot.org/citations/27374306http://xmlns.com/foaf/0.1/primaryTopicOfhttps://pubmed.ncbi.nlm.nih.gov/27374306
http://purl.uniprot.org/uniprot/#_B2RDW0-mappedCitation-27374306http://www.w3.org/1999/02/22-rdf-syntax-ns#objecthttp://purl.uniprot.org/citations/27374306
http://purl.uniprot.org/uniprot/#_B4DJ51-mappedCitation-27374306http://www.w3.org/1999/02/22-rdf-syntax-ns#objecthttp://purl.uniprot.org/citations/27374306
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