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 - 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
SN - 1942-325X
VL - 9
SP - 136
EP - 146
JO - Circulation: Cardiovascular Genetics
JF - Circulation: Cardiovascular Genetics
IS - 2
ER -