Network Profiling of Brain-Expressed X-Chromosomal MicroRNA Genes Implicates Shared Key MicroRNAs in Intellectual Disability

Abstract

MicroRNAs are endogenous non-protein-coding RNA molecules that regulate post-transcriptional gene expression. The majority of human miRNAs are brain-expressed and chromosome X is enriched in miRNA genes. We analyzed the genomic regions of 12 brain-expressed pre-miRNAs located on chromosome X coding for 18 mature miRNAs, aiming to investigate the involvement of miRNA sequence variants on X-linked intellectual disability (XLID). Genomic DNA samples from 135 unrelated Brazilian males with intellectual disability, suggestive of X-linked inheritance, were amplified through polymerase chain reaction and sequenced by Sanger sequencing. Although no sequence variations have been identified, suggesting an intense selective pressure, further computational analysis evidenced that eight mature miRNAs (miR-221-3p/222-3p, miR-223-3p, miR-361-5p, miR-362-5p, miR-504-5p.1, miR-505-3p.1, and miR-505-3p.2) act as critical regulators of X-linked and autosomal ID genes in a fully connected network. Enrichment approaches identify transcription regulation, nervous system development, and regulation of cell proliferation as the main common biological processes among the target ID genes. Besides, a clustered chromosomal coverage of the imputed miRNAs target genes and related regulators was found on X chromosome. Considering the role of miRNAs as fine-tuning regulators of gene expression, a systematic analysis of miRNAs' expression could uncover part of the genetic landscape subjacent to ID, being urgently necessary in patients with this condition, particularly XLID.

Keywords: Brain; Chromosome X; Intellectual disability; MicroRNA.