Aberrant calcium channel splicing drives defects in cortical differentiation in Timothy Syndrome

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 thatin uteroCav1.2 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 importantin vivo insights into the pathophysiology of a syndromic ASD.
Source: eLife - Category: Biomedical Science Tags: Neuroscience Stem Cells and Regenerative Medicine Source Type: research

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Conclusions: The approach of reprograming case-parent tr ios represents a possibility of investigating disease-causing mutations and comparing cell lines with reduced variation in genetic background. Our results are indicative of an overlap between schizophrenia and autism-related phenotypes in the investigated family.
Source: GEO: Gene Expression Omnibus - Category: Genetics & Stem Cells Tags: Expression profiling by high throughput sequencing Homo sapiens Source Type: research
Authors: Larijani B, Foroughi Heravani N, Alavi-Moghadam S, Goodarzi P, Rezaei-Tavirani M, Payab M, Gholami M, Razi F, Arjmand B Abstract Autism spectrum disorders as a group of pediatric neurodevelopmental diseases is a crucial part of the worldwide disabilities which have influence in communication skills, social interactions, and ability to understand the concepts. The precise pathophysiology of autism spectrum disorders due to the abundance of involved mechanisms is unknown. Some of these involved mechanisms are related to genetic factors, chronic neuro inflammation, mitochondrial dysfunction, oxidative stress,...
Source: Advances in Experimental Medicine and Biology - Category: Research Tags: Adv Exp Med Biol Source Type: research
AbstractTuberous sclerosis complex (TSC) is an autosomal dominant disorder characterized by epilepsy, intellectual disability, and benign tumors of the brain, heart, skin, and kidney. Animal models have contributed to our understanding of normal and abnormal human brain development, but the construction of models that accurately recapitulate a human pathology remains challenging. Recent advances in stem cell biology with the derivation of human-induced pluripotent stem cells (hiPSCs) from somatic cells from patients have opened new avenues to the study of TSC. This approach combined with gene-editing tools such as CRISPR/C...
Source: Molecular Autism - Category: Molecular Biology Source Type: research
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Source: Frontiers in Neurology - Category: Neurology Source Type: research
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Source: Cell Reports - Category: Cytology Source Type: research
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Source: UCLA Newsroom: Health Sciences - Category: Universities & Medical Training Source Type: news
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Source: International Journal of Environmental Research and Public Health - Category: Environmental Health Authors: Tags: Review Source Type: research
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Source: EurekAlert! - Medicine and Health - Category: International Medicine & Public Health Source Type: news
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Source: GEO: Gene Expression Omnibus - Category: Genetics & Stem Cells Tags: Other Homo sapiens Source Type: research
Contributor : Meiyan WangSeries Type : OtherOrganism : Homo sapiensThe association between macrocephaly and autism spectrum disorder (ASD)suggests that the mechanisms underlying excessive neural growth could contribute to ASD pathogenesis. Consistently, neural progenitor cells (NPCs) derived from induced pluripotent stem cells (iPSCs) of ASD individuals with early developmental brain enlargement are inherently more proliferative than control NPCs. Here, we show that hiPSC-derived NPCs from ASD individuals with macrocephaly display an altered DNA replication program and increased DNA damage. When compared to the control NPC...
Source: GEO: Gene Expression Omnibus - Category: Genetics & Stem Cells Tags: Other Homo sapiens Source Type: research
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