Novel calmodulin mutations associated with congenital long QT syndrome affect calcium current in human cardiomyocytes
- Heart Rhythm. 2016 Oct;13(10):2012-9. doi: 10.1016/j.hrthm.2016.06.038.
- 1. Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
- 2. Department of Biochemistry and Center for Structural Biology, Vanderbilt University, Nashville, Tennessee.
- 3. Division of Cardiology, Ann and Robert H. Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, Illinois.
- 4. University Hospital Lausanne (CHUV), Lausanne, Switzerland.
- 5. IRCCS Istituto Auxologico Italiano, Center for Cardiac Arrhythmias of Genetic Origin and Laboratory of Cardiovascular Genetics, Milan, Italy; and Department of Molecular Medicine, University of Pavia, Pavia, Italy.
- 6. Department of Pharmacology, Northwestern University Feinberg School of Medicine, Chicago, Illinois. Electronic address: [email protected].
Background: Calmodulin (CaM) mutations are associated with cardiac arrhythmia susceptibility including congenital long QT syndrome (LQTS).
Objective: The purpose of this study was to determine the clinical, genetic, and functional features of 2 novel CaM mutations in children with life-threatening ventricular arrhythmias.
Methods: The clinical and genetic features of 2 congenital arrhythmia cases associated with 2 novel CaM gene mutations were ascertained. Biochemical and functional investigations were conducted on the 2 mutations.
Results: A novel de novo CALM2 mutation (D132H) was discovered by candidate gene screening in a male infant with prenatal bradycardia born to healthy parents. Postnatal course was complicated by profound bradycardia, prolonged corrected QT interval (651 ms), 2:1 atrioventricular block, and cardiogenic shock. He was resuscitated and was treated with a cardiac device. A second novel de novo mutation in CALM1 (D132V) was discovered by clinical exome Sequencing in a 3-year-old boy who suffered a witnessed cardiac arrest secondary to ventricular fibrillation. Electrocardiographic recording after successful resuscitation revealed a prolonged corrected QT interval of 574 ms. The CA(2+) affinity of CaM-D132H and CaM-D132V revealed extremely weak binding to the C-terminal domain, with significant structural perturbations noted for D132H. Voltage-clamp recordings of human induced pluripotent stem cell-derived cardiomyocytes transiently expressing wild-type or mutant CaM demonstrated that both mutations caused impaired CA(2+)-dependent inactivation of voltage-gated CA(2+) current. Neither mutant affected voltage-dependent inactivation.
Conclusion: Our findings implicate impaired CA(2+)-dependent inactivation in human cardiomyocytes as the plausible mechanism for long QT syndrome associated with 2 novel CaM mutations. The data further expand the spectrum of genotype and phenotype associated with calmodulinopathy.