Results

RDF/XMLNTriplesTurtleShow queryShare ▶
SubjectPredicateObject
http://purl.uniprot.org/citations/27516456http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/27516456http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/27516456http://www.w3.org/2000/01/rdf-schema#comment"

Background

Calmodulin (CaM) mutations are associated with severe forms of long QT syndrome and catecholaminergic polymorphic ventricular tachycardia (CPVT). CaM mutations are found in 13% of genotype-negative long QT syndrome patients, but the prevalence of CaM mutations in genotype-negative CPVT patients is unknown. Here, we identify and characterize CaM mutations in 12 patients with genotype-negative but clinically diagnosed CPVT.

Methods and results

We performed mutational analysis of CALM1, CALM2, and CALM3 gene-coding regions, in vitro measurement of CaM-Ca(2+) (Ca)-binding affinity, ryanodine receptor 2-CaM binding, Ca handling, L-type Ca current, and action potential duration. We identified a novel CaM mutation-A103V-in CALM3 in 1 of 12 patients (8%), a female who experienced episodes of exertion-induced syncope since age 10, had normal QT interval, and displayed ventricular ectopy during stress testing consistent with CPVT. A103V modestly lowered CaM Ca-binding affinity (3-fold reduction versus WT-CaM), but did not alter CaM binding to ryanodine receptor 2. In permeabilized cardiomyocytes, A103V-CaM (100 nmol/L) promoted spontaneous Ca wave and spark activity, a cellular phenotype of ryanodine receptor 2 activation. Even a 1:3 mixture of A103V-CaM:WT-CaM activated Ca waves, demonstrating functional dominance. Compared with long QT syndrome D96V-CaM, A103V-CaM had significantly less effects on L-type Ca current inactivation, did not alter action potential duration, and caused delayed afterdepolarizations and triggered beats in intact cardiomyocytes.

Conclusions

We discovered a novel CPVT mutation in the CALM3 gene that shares functional characteristics with established CPVT-associated mutations in CALM1. A small proportion of A103V-CaM is sufficient to evoke arrhythmogenic Ca disturbances via ryanodine receptor 2 dysregulation, which explains the autosomal dominant inheritance."xsd:string
http://purl.uniprot.org/citations/27516456http://purl.org/dc/terms/identifier"doi:10.1161/circep.116.004161"xsd:string
http://purl.uniprot.org/citations/27516456http://purl.org/dc/terms/identifier"doi:10.1161/circep.116.004161"xsd:string
http://purl.uniprot.org/citations/27516456http://purl.uniprot.org/core/author"Sun J."xsd:string
http://purl.uniprot.org/citations/27516456http://purl.uniprot.org/core/author"Sun J."xsd:string
http://purl.uniprot.org/citations/27516456http://purl.uniprot.org/core/author"Ackerman M.J."xsd:string
http://purl.uniprot.org/citations/27516456http://purl.uniprot.org/core/author"Ackerman M.J."xsd:string
http://purl.uniprot.org/citations/27516456http://purl.uniprot.org/core/author"Boczek N.J."xsd:string
http://purl.uniprot.org/citations/27516456http://purl.uniprot.org/core/author"Boczek N.J."xsd:string
http://purl.uniprot.org/citations/27516456http://purl.uniprot.org/core/author"Tester D.J."xsd:string
http://purl.uniprot.org/citations/27516456http://purl.uniprot.org/core/author"Tester D.J."xsd:string
http://purl.uniprot.org/citations/27516456http://purl.uniprot.org/core/author"Chazin W.J."xsd:string
http://purl.uniprot.org/citations/27516456http://purl.uniprot.org/core/author"Chazin W.J."xsd:string
http://purl.uniprot.org/citations/27516456http://purl.uniprot.org/core/author"Calvert M.L."xsd:string
http://purl.uniprot.org/citations/27516456http://purl.uniprot.org/core/author"Calvert M.L."xsd:string
http://purl.uniprot.org/citations/27516456http://purl.uniprot.org/core/author"Cornea R.L."xsd:string
http://purl.uniprot.org/citations/27516456http://purl.uniprot.org/core/author"Cornea R.L."xsd:string
http://purl.uniprot.org/citations/27516456http://purl.uniprot.org/core/author"Gomez-Hurtado N."xsd:string
http://purl.uniprot.org/citations/27516456http://purl.uniprot.org/core/author"Gomez-Hurtado N."xsd:string
http://purl.uniprot.org/citations/27516456http://purl.uniprot.org/core/author"Johnson C.N."xsd:string
http://purl.uniprot.org/citations/27516456http://purl.uniprot.org/core/author"Johnson C.N."xsd:string
http://purl.uniprot.org/citations/27516456http://purl.uniprot.org/core/author"Knollmann B.C."xsd:string
http://purl.uniprot.org/citations/27516456http://purl.uniprot.org/core/author"Knollmann B.C."xsd:string
▶