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Nat Neurosci. 2019 Jan;22(1):25-36. doi: 10.1038/s41593-018-0287-x. Epub 2018 Dec 17.

Widespread RNA editing dysregulation in brains from autistic individuals.

Author information

1
Bioinformatics Interdepartmental Program, UCLA, Los Angeles, CA, USA.
2
Department of Integrative Biology and Physiology, UCLA, Los Angeles, CA, USA.
3
Department of Neurology, Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA.
4
Department of Cellular and Molecular Medicine, UCSD, La Jolla, CA, USA.
5
Stem Cell Program, UCSD, La Jolla, CA, USA.
6
Institute for Genomic Medicine, UCSD, La Jolla, CA, USA.
7
Department of Bioengineering, UCLA, Los Angeles, CA, USA.
8
Bioinformatics and Systems Biology Graduate Program, UCSD, La Jolla, CA, USA.
9
Department of Pathology and Laboratory Medicine, UC Davis School of Medicine, Sacramento, CA, USA.
10
The MIND Institute, Department of Pediatrics, UC Davis School of Medicine, Sacramento, CA, USA.
11
Department of Neurology, Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA. dhg@mednet.ucla.edu.
12
Program in Neurobehavioral Genetics, Semel Institute, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA. dhg@mednet.ucla.edu.
13
Department of Human Genetics, David Geffen School of Medicine, UCLA, Los Angeles, CA, USA. dhg@mednet.ucla.edu.
14
Bioinformatics Interdepartmental Program, UCLA, Los Angeles, CA, USA. gxxiao@ucla.edu.
15
Department of Integrative Biology and Physiology, UCLA, Los Angeles, CA, USA. gxxiao@ucla.edu.
16
Molecular Biology Institute, UCLA, Los Angeles, CA, USA. gxxiao@ucla.edu.
17
Institute for Quantitative and Computational Biology, UCLA, Los Angeles, CA, USA. gxxiao@ucla.edu.

Abstract

Transcriptomic analyses of postmortem brains have begun to elucidate molecular abnormalities in autism spectrum disorder (ASD). However, a crucial pathway involved in synaptic development, RNA editing, has not yet been studied on a genome-wide scale. Here we profiled global patterns of adenosine-to-inosine (A-to-I) editing in a large cohort of postmortem brains of people with ASD. We observed a global bias for hypoediting in ASD brains, which was shared across brain regions and involved many synaptic genes. We show that the Fragile X proteins FMRP and FXR1P interact with RNA-editing enzymes (ADAR proteins) and modulate A-to-I editing. Furthermore, we observed convergent patterns of RNA-editing alterations in ASD and Fragile X syndrome, establishing this as a molecular link between these related diseases. Our findings, which are corroborated across multiple data sets, including dup15q (genomic duplication of 15q11.2-13.1) cases associated with intellectual disability, highlight RNA-editing dysregulation in ASD and reveal new mechanisms underlying this disorder.

PMID:
30559470
PMCID:
PMC6375307
DOI:
10.1038/s41593-018-0287-x
[Indexed for MEDLINE]
Free PMC Article

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