Abstract 16441: Novel Calmodulin Mutations Cause Congenital Long QT Syndrome and Affect Calcium Current in Human Cardiomyocytes
Calmodulin (CaM) mutations are associated with cardiac arrhythmia susceptibility including the congenital long QT syndrome (LQTS). We identified two novel CaM mutations in children with LQTS associated with cardiac arrest, and performed studies to elucidate the functional consequences of each molecular defect. The first mutation was discovered in a male infant with a ventricular septal defect and fetal bradycardia born to healthy parents. His ECG on postnatal day 1 revealed bradycardia and very prolonged QTc (651 msec). At age 2-days, he developed 2:1 AV block, profound bradycardia (50 bpm) and cardiogenic shock. He was resuscitated and received a pacemaker. Targeted DNA sequencing revealed a de novo mutation in CALM2 (D132H). A second novel mutation was discovered in a three year-old boy who suffered witnessed cardiac arrest. His initial rhythm was ventricular fibrillation, and after successful defibrillation an ECG recording revealed a QTc of 574 msec. The parents were healthy with normal QTc intervals. Exome sequencing of the parent-child trio demonstrated a de novo mutation in CALM1 (D132V). Both novel mutations affect the same conserved aspartate residue within the C-domain EF-hand-IV Ca2+ binding motif. Further studies elucidated biochemical and functional effects of the mutations. Measurements of Ca2+ binding affinity of CaM-D132H indicated extremely weak binding to the C-domain (Kd > 150 μM) with significant structural perturbations. Voltage-clamp recordings of human induced pluripotent stem cell (iPSC) derived cardiomyocytes transiently expressing wildtype or mutant CaM demonstrated that both mutations caused impaired Ca2+-dependent inactivation (CDI) of voltage-gated Ca2+ current. Neither mutant affected voltage-dependent inactivation of Ba2+ currents. Our findings implicate impaired CDI in human cardiomyocytes as the plausible mechanism for LQTS associated with CaM mutations.
Author Disclosures: D.C. Pipilas: Research Grant; Significant; Research fellowship from HHMI. R. Webster: None. J. Schlaepfer: None. F. Fellmann: None. N. Sekarski: None. C.N. Johnson: None. P.J. Schwartz: None. W.J. Chazin: None. L. Crotti: None. Z.A. Bhuiyan: None. A.L. George: Research Grant; Significant; NIH grant HL083374. Other Research Support; Significant; Research grant from Gilead Sciences, Research grant from Merck, Research grant from Xenon Pharmaceuticals. Consultant/Advisory Board; Significant; Consultant to Gilead Sciences, Consultant to Xenon Pharmaceuticals.
- © 2015 by American Heart Association, Inc.