Convergent Pathways in Idiopathic Autism Revealed by Time Course Transcriptomic Analysis of Patient-Derived Neurons.

Authors:
Brooke A DeRosa
Brooke A DeRosa
University of Miami Miller School of Medicine
United States
Jimmy El Hokayem
Jimmy El Hokayem
Miller School of Medicine
United States
Elena Artimovich
Elena Artimovich
Howard Hughes Medical Institute/Center for Vaccine Development
New York | United States
Andre W Phillips
Andre W Phillips
Hugo W. Moser Research Institute at Kennedy Krieger
United States
Jonathan E Nestor
Jonathan E Nestor
The Hussman Institute for Autism
Lily Wang
Lily Wang
Vanderbilt University
United States

Sci Rep 2018 May 30;8(1):8423. Epub 2018 May 30.

John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, Florida, 33136, USA.

Potentially pathogenic alterations have been identified in individuals with autism spectrum disorders (ASDs) within a variety of key neurodevelopment genes. While this hints at a common ASD molecular etiology, gaps persist in our understanding of the neurodevelopmental mechanisms impacted by genetic variants enriched in ASD patients. Induced pluripotent stem cells (iPSCs) can model neurodevelopment in vitro, permitting the characterization of pathogenic mechanisms that manifest during corticogenesis. Taking this approach, we examined the transcriptional differences between iPSC-derived cortical neurons from patients with idiopathic ASD and unaffected controls over a 135-day course of neuronal differentiation. Our data show ASD-specific misregulation of genes involved in neuronal differentiation, axon guidance, cell migration, DNA and RNA metabolism, and neural region patterning. Furthermore, functional analysis revealed defects in neuronal migration and electrophysiological activity, providing compelling support for the transcriptome analysis data. This study reveals important and functionally validated insights into common processes altered in early neuronal development and corticogenesis and may contribute to ASD pathogenesis.

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http://dx.doi.org/10.1038/s41598-018-26495-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5976773PMC
May 2018
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