Understanding cardiac calcium channelopathies.

Timothy syndrome is a rare genetic disorder characterized by QT prolongation (designated LQT8), arrhythmias and sudden death, structural heart disease, cognitive defects with autism, syndactyly (webbed fingers and toes), hypoglycemia, and immune deficiencies.1,2 A single mutation (G406R) in exon 8a of the cardiac L-type calcium channel (CACNA1C, Cav1.2, 1c) was shown to cause Timothy syndrome in multiple unrelated subjects, whereas mutations (G406R, G402S) in the alternatively spliced exon 8 (which is expressed at 3-fold–higher levels than exon 8a) cause a similar syndrome lacking syndactyly.3,4 These 3 mutations decrease voltage-dependent inactivation of Cav1.2, which is predicted to slow the inactivation of ICa,L during each action potential, prolong action potential and QT interval duration, increase the amplitude and duration of Ca transients, and predispose to afterdepolarizations and arrhythmias.3–5