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

Boston University, Boston, Massachusetts, United States
Cell (Impact Factor: 32.24). 11/2004; 119(1):19-31. DOI: 10.1016/j.cell.2004.09.011
Source: PubMed


Ca(V)1.2, 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 Ca(V)1.2 missense mutation G406R. Ca(V)1.2 is expressed in all affected tissues. Functional expression reveals that G406R produces maintained inward Ca(2+) currents by causing nearly complete loss of voltage-dependent channel inactivation. This likely induces intracellular Ca(2+) overload in multiple cell types. In the heart, prolonged Ca(2+) current delays cardiomyocyte repolarization and increases risk of arrhythmia, the ultimate cause of death in this disorder. These discoveries establish the importance of Ca(V)1.2 in human physiology and development and implicate Ca(2+) signaling in autism.

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    • "Many types of channelopathies may have similar influence on neural dynamics, leading to a great heterogeneity of symptoms in autism spectrum disorder and other attention-related disorders. In particular the role of calcium signaling abnormalities, linked to the L-type voltage-gated calcium channelopathies, has been documented in the literature (McEnery et al. 1998; Gargus 2009; Splawski et al. 2004; Krey and Dolmetsch 2007). This hypothesis of the etiology of ASD and other disorders is modelled at the neural network level changing the biophysical properties of neurons to reflect influence of channelopathies on neural dynamics. "
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