Autism affects 0.5% of children around the world and causes great distress, but little is known about the molecular mechanisms involved in this disorder and no therapy is yet available. Reporting in Cell, Splawski and colleagues implicate abnormal calcium signalling in autism, and highlight the therapeutic potential of calcium channel blockers.

The authors characterized the phenotypes and molecular basis of Timothy syndrome — a novel disorder that is associated with conditions in multiple organ systems, including lethal arrhythmias, immune deficiency and autism. They discovered a de novo missense mutation in a splice variant of the calcium L-type channel, Cav1.2, in 13 patients with the syndrome. The mutation, G406R, caused a substitution of glycine with arginine at residue 406.

This splice variant of Cav1.2 is expressed in many human adult and fetal tissues including the brain, gastrointestinal system, lungs, immune system, smooth muscle and testis — a pattern that is consistent with the phenotypic abnormalities associated with Timothy syndrome. In the brain, it is expressed in regions such as the hippocampus, cerebellum and amygdala where abnormalities have been implicated in autism.

Splawski and colleagues compared the biophysical properties of the wild-type and mutant Cav1.2, which were heterologously expressed in Chinese hamster ovary cells and Xenopus laevis oocytes. The G406R mutation completely abolishes voltage-dependent channel inactivation of Cav1.2 and results in persistence of inward Ca2+ currents in the cell. Computer simulation indicates that a prolonged Ca2+ current in cardiomyocytes might lengthen cardiac action potentials and delay repolarization, which would lead to an increased risk of arrhythmia. As the mutant Cav1.2 remains sensitive to calcium channel blockers such as dihydrophyridines, these drugs might be useful for treating Timothy syndrome and autism.

These findings hint at a potential mechanism that might underlie autism. Future studies will focus on the genetic analysis of Cav1.2 and other calcium channels in the disorder and the potential application of calcium channel blocker therapy.