Widespread RNA editing dysregulation in brains from autistic individuals

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

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Deaminase / genetics
  • Adenosine Deaminase / metabolism
  • Autistic Disorder / genetics
  • Autistic Disorder / metabolism*
  • Brain / metabolism*
  • Fragile X Mental Retardation Protein / genetics
  • Fragile X Mental Retardation Protein / metabolism
  • Gene Expression Profiling
  • Humans
  • Neurons / metabolism
  • RNA Editing*
  • RNA-Binding Proteins / genetics
  • RNA-Binding Proteins / metabolism

Substances

  • FXR1 protein, human
  • RNA-Binding Proteins
  • Fragile X Mental Retardation Protein
  • ADAR protein, human
  • Adenosine Deaminase