TY - JOUR
T1 - Spectrum and prevalence of CALM1-, CALM2-, and CALM3-encoded calmodulin variants in long QT syndrome and functional characterization of a novel long QT syndrome-associated calmodulin missense variant, E141G
AU - Boczek, Nicole J.
AU - Gomez-Hurtado, Nieves
AU - Ye, Dan
AU - Calvert, Melissa L.
AU - Tester, David J.
AU - Kryshtal, Dmytro O.
AU - Hwang, Hyun Seok
AU - Johnson, Christopher N.
AU - Chazin, Walter J.
AU - Loporcaro, Christina G.
AU - Shah, Maully
AU - Papez, Andrew L.
AU - Lau, Yung R.
AU - Kanter, Ronald
AU - Knollmann, Björn C.
AU - Ackerman, Michael J.
N1 - Funding Information:
This work was supported by the Mayo Clinic Windland Smith Rice Comprehensive Sudden Cardiac Death Program, the Sheikh Zayed Saif Mohammed Al Nahyan Fund in Pediatric Cardiology Research, the Dr Scholl Fund, and the Hannah M. Wernke Memorial Fund. This project was also supported, in part, by funding from Mayo Clinic's Center for Individualized Medicine. Dr Johnson was supported by fellowships from the American Heart Association (13POST14380036) and the National Institutes of Health (5 F32 HL117612-02). Research on calcium-binding proteins in the Chazin laboratory is supported by an endowed chair. This work was also partly supported by the United States National Institutes of Health (HL88635, HL71670, and HL124935 to Dr Knollmann)
Publisher Copyright:
© 2016 American Heart Association, Inc.
PY - 2016/4/1
Y1 - 2016/4/1
N2 - 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 (Ca V 1.2). CaM also modulates Na V 1.5 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 Ca V 1.2, mild accentuation in Na V 1.5 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.
AB - 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 (Ca V 1.2). CaM also modulates Na V 1.5 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 Ca V 1.2, mild accentuation in Na V 1.5 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.
KW - L-type calcium channels
KW - calmodulin
KW - long QT syndrome
KW - ryanodine receptor
KW - sodium channels
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U2 - 10.1161/CIRCGENETICS.115.001323
DO - 10.1161/CIRCGENETICS.115.001323
M3 - Article
C2 - 26969752
AN - SCOPUS:84966344023
VL - 9
SP - 136
EP - 146
JO - Circulation. Genomic and precision medicine
JF - Circulation. Genomic and precision medicine
SN - 1942-325X
IS - 2
ER -