Cell
Volume 119, Issue 1, 1 October 2004, Pages 19-31
Journal home page for Cell

Article
CaV1.2 Calcium Channel Dysfunction Causes a Multisystem Disorder Including Arrhythmia and Autism

https://doi.org/10.1016/j.cell.2004.09.011Get rights and content
Under an Elsevier user license
open archive

Abstract

CaV1.2, the cardiac L-type calcium channel, is important for excitation and contraction of the heart. Its role in other tissues is unclear. Here we present Timothy syndrome, a novel disorder characterized by multiorgan dysfunction including lethal arrhythmias, webbing of fingers and toes, congenital heart disease, immune deficiency, intermittent hypoglycemia, cognitive abnormalities, and autism. In every case, Timothy syndrome results from the identical, de novo CaV1.2 missense mutation G406R. CaV1.2 is expressed in all affected tissues. Functional expression reveals that G406R produces maintained inward Ca2+ currents by causing nearly complete loss of voltage-dependent channel inactivation. This likely induces intracellular Ca2+ overload in multiple cell types. In the heart, prolonged Ca2+ current delays cardiomyocyte repolarization and increases risk of arrhythmia, the ultimate cause of death in this disorder. These discoveries establish the importance of CaV1.2 in human physiology and development and implicate Ca2+ signaling in autism.

Cited by (0)