Aberrant calcium channel splicing drives defects in cortical differentiation in Timothy syndrome.

ABSTRACT: 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 Ca_v1.2. Using mouse brain and human induced pluripotent stem cells (iPSCs), we provide evidence that the TS mutation prevents a normal developmental switch in Ca_v1.2 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-Ca_v1.2 channels in the embryonic mouse cortex recapitulates these differentiation defects in a calcium-dependent manner and that in utero Ca_v</

SUBMITTER: Panagiotakos G 

PROVIDER: S-EPMC6964969 | biostudies-literature | 2019 Dec

REPOSITORIES: biostudies-literature