TY - JOUR TI - Aberrant calcium channel splicing drives defects in cortical differentiation in Timothy syndrome AU - Panagiotakos, Georgia AU - Haveles, Christos AU - Arjun, Arpana AU - Petrova, Ralitsa AU - Rana, Anshul AU - Portmann, Thomas AU - Paşca, Sergiu P AU - Palmer, Theo D AU - Dolmetsch, Ricardo E A2 - Bhattacharyya, Anita A2 - Zoghbi, Huda Y A2 - Bhattacharyya, Anita A2 - Uhlén, Per VL - 8 PY - 2019 DA - 2019/12/23 SP - e51037 C1 - eLife 2019;8:e51037 DO - 10.7554/eLife.51037 UR - https://doi.org/10.7554/eLife.51037 AB - The syndromic autism spectrum disorder (ASD) Timothy syndrome (TS) is caused by a point mutation in the alternatively spliced exon 8A of the calcium channel Cav1.2. Using mouse brain and human induced pluripotent stem cells (iPSCs), we provide evidence that the TS mutation prevents a normal developmental switch in Cav1.2 exon utilization, resulting in persistent expression of gain-of-function mutant channels during neuronal differentiation. In iPSC models, the TS mutation reduces the abundance of SATB2-expressing cortical projection neurons, leading to excess CTIP2+ neurons. We show that expression of TS-Cav1.2 channels in the embryonic mouse cortex recapitulates these differentiation defects in a calcium-dependent manner and that in utero Cav1.2 gain-and-loss of function reciprocally regulates the abundance of these neuronal populations. Our findings support the idea that disruption of developmentally regulated calcium channel splicing patterns instructively alters differentiation in the developing cortex, providing important in vivo insights into the pathophysiology of a syndromic ASD. KW - Timothy syndrome KW - calcium channel splicing KW - neuronal differentiation KW - human induced pluripotent stem cells JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -