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http://purl.uniprot.org/citations/26969752http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/26969752http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
http://purl.uniprot.org/citations/26969752http://www.w3.org/2000/01/rdf-schema#comment"

Background

Calmodulin (CaM) is encoded by 3 genes, CALM1, CALM2, and CALM3, all of which harbor pathogenic variants linked to long QT syndrome (LQTS) with early and severe expressivity. These LQTS-causative variants reduce CaM affinity to Ca(2+) and alter the properties of the cardiac L-type calcium channel (CaV1.2). CaM also modulates NaV1.5 and the ryanodine receptor, RyR2. All these interactions may play a role in disease pathogenesis. Here, we determine the spectrum and prevalence of pathogenic CaM variants in a cohort of genetically elusive LQTS, and functionally characterize the novel variants.

Methods and results

Thirty-eight genetically elusive LQTS cases underwent whole-exome sequencing to identify CaM variants. Nonsynonymous CaM variants were over-represented significantly in this heretofore LQTS cohort (13.2%) compared with exome aggregation consortium (0.04%; P<0.0001). When the clinical sequelae of these 5 CaM-positive cases were compared with the 33 CaM-negative cases, CaM-positive cases had a more severe phenotype with an average age of onset of 10 months, an average corrected QT interval of 676 ms, and a high prevalence of cardiac arrest. Functional characterization of 1 novel variant, E141G-CaM, revealed an 11-fold reduction in Ca(2+)-binding affinity and a functionally dominant loss of inactivation in CaV1.2, mild accentuation in NaV1.5 late current, but no effect on intracellular RyR2-mediated calcium release.

Conclusions

Overall, 13% of our genetically elusive LQTS cohort harbored nonsynonymous variants in CaM. Genetic testing of CALM1-3 should be pursued for individuals with LQTS, especially those with early childhood cardiac arrest, extreme QT prolongation, and a negative family history."xsd:string
http://purl.uniprot.org/citations/26969752http://purl.org/dc/terms/identifier"doi:10.1161/circgenetics.115.001323"xsd:string
http://purl.uniprot.org/citations/26969752http://purl.org/dc/terms/identifier"doi:10.1161/circgenetics.115.001323"xsd:string
http://purl.uniprot.org/citations/26969752http://purl.uniprot.org/core/author"Ye D."xsd:string
http://purl.uniprot.org/citations/26969752http://purl.uniprot.org/core/author"Ye D."xsd:string
http://purl.uniprot.org/citations/26969752http://purl.uniprot.org/core/author"Shah M."xsd:string
http://purl.uniprot.org/citations/26969752http://purl.uniprot.org/core/author"Shah M."xsd:string
http://purl.uniprot.org/citations/26969752http://purl.uniprot.org/core/author"Ackerman M.J."xsd:string
http://purl.uniprot.org/citations/26969752http://purl.uniprot.org/core/author"Ackerman M.J."xsd:string
http://purl.uniprot.org/citations/26969752http://purl.uniprot.org/core/author"Hwang H.S."xsd:string
http://purl.uniprot.org/citations/26969752http://purl.uniprot.org/core/author"Hwang H.S."xsd:string
http://purl.uniprot.org/citations/26969752http://purl.uniprot.org/core/author"Boczek N.J."xsd:string
http://purl.uniprot.org/citations/26969752http://purl.uniprot.org/core/author"Boczek N.J."xsd:string
http://purl.uniprot.org/citations/26969752http://purl.uniprot.org/core/author"Tester D.J."xsd:string
http://purl.uniprot.org/citations/26969752http://purl.uniprot.org/core/author"Tester D.J."xsd:string
http://purl.uniprot.org/citations/26969752http://purl.uniprot.org/core/author"Chazin W.J."xsd:string
http://purl.uniprot.org/citations/26969752http://purl.uniprot.org/core/author"Chazin W.J."xsd:string
http://purl.uniprot.org/citations/26969752http://purl.uniprot.org/core/author"Kanter R."xsd:string
http://purl.uniprot.org/citations/26969752http://purl.uniprot.org/core/author"Kanter R."xsd:string
http://purl.uniprot.org/citations/26969752http://purl.uniprot.org/core/author"Calvert M.L."xsd:string
http://purl.uniprot.org/citations/26969752http://purl.uniprot.org/core/author"Calvert M.L."xsd:string
http://purl.uniprot.org/citations/26969752http://purl.uniprot.org/core/author"Gomez-Hurtado N."xsd:string
http://purl.uniprot.org/citations/26969752http://purl.uniprot.org/core/author"Gomez-Hurtado N."xsd:string
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