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

Nicole J. Boczek, Nieves Gomez-Hurtado, Dan Ye, Melissa L. Calvert, David J. Tester, Dmytro O. Kryshtal, Hyun Seok Hwang, Christopher N. Johnson, Walter J. Chazin, Christina G. Loporcaro, Maully Shah, Andrew L. Papez, Yung R. Lau, Ronald Kanter, Björn C. Knollmann, Michael J. Ackerman

Research output: Contribution to journalArticlepeer-review

48 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)136-146
Number of pages11
JournalCirculation: Cardiovascular Genetics
Volume9
Issue number2
DOIs
StatePublished - Apr 1 2016

Keywords

  • L-type calcium channels
  • calmodulin
  • long QT syndrome
  • ryanodine receptor
  • sodium channels

ASJC Scopus subject areas

  • Genetics
  • Cardiology and Cardiovascular Medicine
  • Genetics(clinical)

Fingerprint Dive into the research topics of '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'. Together they form a unique fingerprint.

Cite this