2. Academic Validation
  3. 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

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

  • Circ Cardiovasc Genet. 2016 Apr;9(2):136-146. doi: 10.1161/CIRCGENETICS.115.001323.
Nicole J Boczek # 1,  Nieves Gomez-Hurtado # 2,  Dan Ye # 1,  Melissa L Calvert 1,  David J Tester 1,  Dmytro Kryshtal 2,  Hyun Seok Hwang 2,  Christopher N Johnson 3,  Walter J Chazin 3,  Christina G Loporcaro 1 4,  Maully Shah 5,  Andrew L Papez 6,  Yung R Lau 7,  Ronald Kanter 8,  Bjorn C Knollmann 2,  Michael J Ackerman 1 9 10
Affiliations

Affiliations

  • 1 Department Molecular Pharmacology & Experimental Therapeutics, Windland Smith Rice Sudden Death Genomics Laboratory, Mayo Clinic, Rochester, MN.
  • 2 Department of Medicine, Vanderbilt University, Nashville, TN.
  • 3 Departments of Biochemistry & Chemistry and Center for Structural Biology, Vanderbilt University, Nashville, TN.
  • 4 Mayo Medical School, Mayo Clinic, Rochester, MN.
  • 5 Children's Hospital of Philadelphia, Philadelphia, PA.
  • 6 Department of Pediatric Cardiology, Phoenix Children's Hospital, Phoenix, AZ.
  • 7 Department of Pediatrics, Division of Pediatric Cardiology, University of Alabama at Birmingham, Birmingham, AL.
  • 8 Division of Cardiology, Nicklaus Children's Hospital, Miami, FL.
  • 9 Department of Medicine, Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN.
  • 10 Department of Pediatrics, Division of Pediatric Cardiology, Mayo Clinic, Rochester, MN.
  • # Contributed equally.
PMID: 26969752 DOI: 10.1161/CIRCGENETICS.115.001323
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 (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.

Keywords

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

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