Abstract
Alteration in basal and depolarization induced transcriptional network in iPSC derived neurons from Timothy syndrome
Highlights
Common genetic variation and rare mutations in genes encoding calcium channel subunits have pleiotropic effects on risk for multiple neuropsychiatric disorders, including autism spectrum disorder (ASD) and schizophrenia
It has been known that calcium influx triggers massive transcriptional changes by acting through several transcription factors, including calcium response factor (CaRF) [15,16], myocyte enhancer factor-2 (MEF2) [17,18], nuclear factor of activated T-cells (NFAT) [19,20], and cAMP response element-binding proteins (CREB) [21,22,23,24], little is known about their downstream targets in human neurons and how these processes are altered in disease states such as Timothy syndrome (TS)
Using Weighted Gene Co-expression Network Analysis (WGCNA) [27,28], we identified gene co-expression modules associated with neural development, as well as depolarization shared across both patient and control lines
Summary
Common genetic variation and rare mutations in genes encoding calcium channel subunits have pleiotropic effects on risk for multiple neuropsychiatric disorders, including autism spectrum disorder (ASD) and schizophrenia. The L-type calcium channel, Cav1.2, plays a central role in regulating an activity-dependent signaling network that is essential for neuronal function [1,2,3,4,5,6]. Given the pleiotropic manifestation of CACNA1C mutations in TS and the recent implication of common variation in CACNA1C across multiple neuropsychiatric disorders [14], we reasoned that characterization of the Cav1.2-dependent signaling network in TS would help elucidate its molecular basis and prioritize genes for therapeutic development. We reasoned that identifying alterations in mRNA transcript levels in TS patient-derived cortical progenitors and developing neurons would help clarify, how calcium regulates gene expression in TS, but more broadly inform our understanding of the molecular mechanism of ASD
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