Abstract
Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by a wide spectrum of deficits in social interaction, communication, and behavior. There is a significant genetic component to ASD, yet no single gene variant accounts for >1% of incidence. Posttranscriptional mechanisms such as microRNAs (miRNAs) regulate gene expression without altering the genetic code. They are abundant in the developing brain and are dysregulated in children with ASD. Patterns of miRNA expression are altered in the brain, blood, saliva, and olfactory precursor cells of ASD subjects. The ability of miRNAs to regulate broad molecular pathways in response to environmental stimuli makes them an intriguing player in ASD, a disorder characterized by genetic predisposition with ill-defined environmental triggers. In addition, the availability and extracellular stability of miRNAs make them an ideal candidate for biomarker discovery. Here, we discuss 27 miRNAs with overlap across ASD studies, including 3 miRNAs identified in 3 or more studies (miR-23a, miR-146a, and miR-106b). Together, these 27 miRNAs have 1245 high-confidence mRNA targets, a significant number of which are expressed in the brain. Furthermore, these mRNA targets demonstrate over-representation of autism-related genes with enrichment of neurotrophic signaling molecules. Brain-derived neurotrophic factor, a molecule involved in hippocampal neurogenesis and altered in ASD, is targeted by 6 of the 27 miRNAs of interest. This neurotrophic pathway represents one intriguing mechanism by which perturbations in miRNA signaling might influence central nervous system development in children with ASD.
Highlights
In 1993, the first non-coding antisense RNA sequence was described in Caenorhabditis elegans [1, 2] and termed microRNA
It is clear that miRNA profiles are dysregulated across multiple tissue types in subjects with autism spectrum disorder (ASD)
This review encapsulated 219 target miRNAs from 12 human studies of ASD and identified 27 that were dysregulated in ≥2 investigations
Summary
In 1993, the first non-coding antisense RNA sequence was described in Caenorhabditis elegans [1, 2] and termed microRNA (miRNA). Four studies examining postmortem brain tissue of human subjects with ASD have identified 91 miRNAs with differential expression compared with typically developing controls. In a study of 12 subjects with ASD, expression of miR-142 was increased in Brodmann’s area 10 compared with healthy controls – a change accompanied by hypomethylation of the miR-142 promoter region [53] Another possible mechanism is that individual miRNAs sequences are altered in children with ASD. Pooled analysis of common and rare single nucleotide polymorphisms (SNPs) in 449 cases of ASD using whole exome sequencing has identified 2 miRNA clusters: miR-133b/miR-206 and mir-17/miR/18a/miR19a/miR20a/miR-19b-1/miR-92a [62] Four of these individual components have disrupted expression levels in children with ASD, and miR-92a is downregulated in multiple studies [9, 14]. This highlights how the utility of miRNA extends beyond simple ASD diagnosis and may 1 day be used to predict ASD phenotype and severity
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