ClinVar Genomic variation as it relates to human health

In 13 patients with Timothy syndrome (TS; 601005), Splawski et al. (2004) analyzed the alternatively spliced exon 8A of the CACNA1C gene and identified heterozygosity for a de novo c.1216G-A transition, resulting in a gly406-to-arg (G406R) substitution at a highly conserved residue at the C-terminal end of the sixth transmembrane segment of domain I. Functional analysis revealed that the G406R mutation produced maintained inward Ca(2+) currents by causing nearly complete loss of voltage-dependent channel inactivation. The G406R mutation was not identified in 180 ethnically matched control samples. In 1 family with 2 affected children, the clinically unaffected mother was mosaic for the G406R mutation. In a girl who died at age 6 years with severe Timothy syndrome (see 601005) without syndactyly, Splawski et al. (2005) identified a G406R mutation in exon 8 of the CACNA1C gene, which is analogous to that previously found in exon 8A (Splawski et al., 2004). The exon 8 splice variant was found to be highly expressed in heart and brain (80% of CACNA1C mRNA), and this patient had a longer average QT interval and more severe arrhythmias than patients with the analogous mutation in exon 8A. She was born by cesarean section at 38 weeks' gestation due to severe bradycardia, and at birth had 2:1 atrioventricular block with a QTc of 730 ms. Despite receiving an implantable pacemaker in the neonatal period, she had multiple episodes of severe arrhythmias requiring cardioversion or resuscitation in infancy. Cervical sympathetic ganglionectomy and ventricular pacemaker placement at 4 months of age were unsuccessful in reducing arrhythmias. She also experienced seizures, static encephalopathy, and severe developmental delay. She died at age 6 years due to ventricular fibrillation. In a severely affected infant with Timothy syndrome, Etheridge et al. (2011) identified heterozygosity for the G406R mutation in exon 8 of the CACNA1C gene. The proband's mildly affected father, who had cutaneous syndactyly of the feet and a prolonged QTc of 480 ms, but who had never experienced syncope or seizure, was also heterozygous for G406R; however, he was found to be mosaic for the mutation, showing only a minor peak for the mutant allele. An unrelated, moderately affected 14-year-old girl, who was not symptomatic until adolescence, was also mosaic for G406R, with a minor peak for the mutant allele. Variant Function By measuring whole-cell currents in transfected HEK293 cells, Barrett and Tsien (2008) demonstrated that the G406R mutation powerfully and selectively slows voltage-dependent inactivation (VDI), while sparing or possibly speeding the kinetics of Ca(2+)-dependent inactivation (CDI). Dissociation of VDI and CDI was further substantiated by measurements of Ca(2+) channel gating currents. In addition, CDI did not proceed to completeness but leveled off at approximately 50%, consistent with a change in gating modes and not an absorbing inactivation process. To explore the effect of the Timothy syndrome mutation G406R in the CaV1.2 channel on the electrical activity and contraction of human cardiomyocytes, Yazawa et al. (2011) reprogrammed human skin cells from Timothy syndrome patients to generate induced pluripotent stem cells, and differentiated those cells into cardiomyocytes. Electrophysiologic recording and calcium imaging studies of these cells revealed irregular contraction, excess calcium influx, prolonged action potentials, irregular electrical activity, and abnormal calcium transients in ventricular-like cells. Yazawa et al. (2011) found that roscovitine, a compound that increases the voltage-dependent inactivation of CaV1.2, restored the electrical and calcium signaling properties of cardiomyocytes from Timothy syndrome patients. Yazawa et al. (2011) concluded that their study provided new opportunities for studying the molecular and cellular mechanisms of cardiac arrhythmias in humans and provided a robust assay for developing drugs to treat these diseases. (less)