Bridging Timothy syndrome Cav1.2 calcium channel mutations (TS1 and TS2) to autism spectrum disorders

The Timothy syndrome (TS) is a rare genetic disease characterized by body malformations and neuropsychiatric disorders. TS-patients have heart beating defects (long-QT and arrhythmias), syndactyly (webbing of fingers and toes), cognitive abnormalities and autism. TS often leads to early childhood death and was first described in the 1990s by observing syndactyly, electrocardiograms with long QT and other malformations. It was, however, only in 2004 that TS was associated with the Cav1.2 calcium channel (CACNA1C) mutations. The name "Timothy syndrome" is in honor of Katherine Timothy, who first identified a case and performed most of the clinical analysis that characterize the syndrome. TS derives from a single amino acid substitution (mutation) in a single protein. A missense mutation at position 406 (classical TS) and a mutation at position 402 (atypical TS) have been identified in the pore forming subunit of the Cav1.2 L-type calcium channel (CACNA1C). Cav1.2 channels are integral membrane proteins that open readily during electrical stimulation (action potentials) and allow the entry of calcium ions in cells of vital organs, like: heart, neurons, skeletal and smooth muscles and neuroendocrine glands. Given this strategic role, it is not surprising that a "gain-of-function" of Cav1.2 channels (increased calcium entry) induced by the TS-mutation causes heart beating arrhythmias (long-QT) and autism spectrum disorders. In this project we plan to identify how the functional changes that the TS induces on Cav1.2 channels alter neuronal activity, synaptic plasticity and brain network maturation. Given this, the next important goal is the identification of the pathways that regulate Cav1.2 channel functioning and new compounds that may rescue the normal activity of TS-mutated channels. This should lead to a strategy for the pharmacological treatment of this rare genetic disease and more in general for the treatment of autism spectrum disorders.