Timothy Syndrome is much rarer than FXS but also often results in syndromic ASD. It is caused by a mutation in the CACNA1C gene, which encodes an L-type voltage gated calcium channel. The mutation leads to decreased calcium- and voltage-dependent inactivation of the channel. Calcium entry into excitable cells is a crucial cellular signal and calcium- and voltage-dependent inactivation, also known as CDI and VDI, are forms of negative feedback regulation following membrane depolarization. Calcium channels play an important role in neuronal development because they control dendritic growth and arborization and excessive calcium entry due to the loss of feed-back can lead to detrimental effects on brain development and growth as seen in Timothy Syndrome. Pasca et al. showed that hiPSC-derived Timothy Syndrome neurons showed impaired calcium signaling and electrophysiology, and had defects in activity-dependent transcription compared to WT 112. Interestingly, neurons also showed a high expression of tyrosine hydroxylase (an enzyme that converts the amino acid tyrosine to the dopamine precursor) and consequently had increased production of norepinephrine and dopamine. HiPSCs derived from these patients had abnormal differentiation tendencies
