Abstract
The role of microRNAs (miRNAs) in the etiology of schizophrenia is increasingly recognized. Microdeletions at chromosome 22q11.2 are recurrent structural variants that impart a high risk for schizophrenia and are found in up to 1% of all patients with schizophrenia. The 22q11.2 deletion region overlaps gene DGCR8, encoding a subunit of the miRNA microprocessor complex. We identified miRNAs overlapped by the 22q11.2 microdeletion and for the first time investigated their predicted target genes, and those implicated by DGCR8, to identify targets that may be involved in the risk for schizophrenia. The 22q11.2 region encompasses seven validated or putative miRNA genes. Employing two standard prediction tools, we generated sets of predicted target genes. Functional enrichment profiles of the 22q11.2 region miRNA target genes suggested a role in neuronal processes and broader developmental pathways. We then constructed a protein interaction network of schizophrenia candidate genes and interaction partners relevant to brain function, independent of the 22q11.2 region miRNA mechanisms. We found that the predicted gene targets of the 22q11.2 deletion miRNAs, and targets of the genome-wide miRNAs predicted to be dysregulated by DGCR8 hemizygosity, were significantly represented in this schizophrenia network. The findings provide new insights into the pathway from 22q11.2 deletion to expression of schizophrenia, and suggest that hemizygosity of the 22q11.2 region may have downstream effects implicating genes elsewhere in the genome that are relevant to the general schizophrenia population. These data also provide further support for the notion that robust genetic findings in schizophrenia may converge on a reasonable number of final pathways.
Highlights
MicroRNAs are small non-coding RNAs that regulate gene expression at the level of translation of messenger RNA to protein [1, 2]
We explored the role of these targets, considering those of miRNAs outside of the 22q11.2 region reported to be dysregulated by hemizygosity of DGCR8, in a newly created protein interaction network composed of schizophrenia candidate genes and interaction partners relevant to brain function
The 22q11.2 deletion region is characterized by high miRNA density: the number of miRNA primary transcripts within this 2.6 Mb window is greater than the number found in 73.3% of same-sized regions surrounding other miRNA loci genome-wide
Summary
MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression at the level of translation of messenger RNA to protein [1, 2]. A recent review documents the ever increasing number of miRNAs identified throughout the human genome and the emerging knowledge about their target genes [2]. Individual miRNAs can target multiple messenger RNAs, effectively controlling expression of a suite of genes. The alteration of a single miRNA with respect to its genomic sequence, copy number, and/or expression can have broad implications for both normal development and cellular function throughout life. A single gene’s messenger RNA can be targeted for modulation by several miRNAs. Mature miRNAs are processed from double-stranded primary miRNA transcripts by a microprocessor complex comprised of two main cofactors: the RNA-binding protein Pasha, encoded by the DGCR8 gene located within the typical 22q11.2 deletion region, and Drosha, the endonuclease responsible for cleaving RNA [1]. Up to 1% of patients with schizophrenia have a 22q11.2 deletion associated with 22q11.2DS [8], and individuals with 22q11.2DS have a 20–25% lifetime www.frontiersin.org
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
