A CACNA1C Mutation that Causes a Subset of Timothy Syndrome Phenotypes Correlates

Abstract

Background Timothy syndrome (TS) is a rare congenital long QT syndrome (LQTS) associated with extracardiac manifestations including craniofacial dysmorphia and dental abnormalities. The locus for TS is CACNA1C , which encodes the Ca V 1.2 L-type Ca 2+ channel, for which canonical mutations lead to a decrease in voltage-dependent inactivation (VDI). However, a recent report of a patient with LQTS in isolation and a CACNA1C mutation that did not affect VDI raised the question whether altered VDI is necessary for extracardiac phenotypes. In a patient with a maternally inherited microdeletion with a chromosomal translocation who presented with LQTS and associated ventricular tachyarrhythmias (Figure A), a subset of TS phenotypes, and a skeletal myopathy not readily explained by the translocation, we sought to identify a causative mutation for the TS phenotypes. Methods A candidate gene approach identified a mutation in CACNA1C that was absent in the mother. We performed electrophysiologic studies on the mutant and characterized CACNA1C expression in skeletal muscle with a mouse CACNA1C reporter line. Results We identified a glycine to arginine mutation at position 1911 (G1911R) in Ca V 1.2. Functional studies revealed that G1911R increased Ca V 1.2 channel availability (Figures B and C) and decreased VDI (Figure D). The CACNA1C reporter mouse showed no Ca V 1.2 expression in skeletal muscle. Conclusions We describe a CACNA1C mutation that leads to a subset of TS phenotypes. In the context of a recently described CACNA1C mutation that does not affect VDI in an LQTS patient without extracardiac phenotypes, these data suggest that the extracardiac phenotypes seen in TS require effects on VDI.