Expressão diferencial de microRNAs em células mononucleares do sangue periférico de crianças com síndrome de Down

Abstract

Trisomy 21 is the genetic basis of Down syndrome (DS), the most common human chromosomal disorder. DS phenotype may include several dysmorphic features, intellectual disability, immunological alteration, congenital heart disease, high risk for specific types of leukemia and neurological alterations. There are basically two hypotheses to explain how the presence of three copies of chromosome 21 results in DS phenotype. The gene dosage effect hypothesis states that over-expression in about 50% of a specific gene or a group of genes located on chromosome 21 present in triplicate in DS individuals is directly responsible for DS features. The second hypothesis suggests the existence of secondary effects of trissomic genes that affect multiple metabolic pathways, resulting in cellular dysfunction. Recent studies show that trisomy 21 results in the over-expression of microRNAs, small molecules of noncoding RNA involved in post-transcriptional gene regulation, which could result in low expression of specific proteins and contribute to DS phenotype. Objective: To identify differentially expressed microRNAs in peripheral blood mononuclear cells of DS and non-DS children and to identify biological processes relevant to DS pathogenesis associated with predicted gene targets of microRNAs differentially expressed in DS children. Casuistic and Methods: Six children with free trisomy 21 and six control children were included in the study. Mature microRNAs were quantified using TaqMan® Low Density Arrays (Applied Biosystems), which enable the quantification of 754 mature microRNAs by real time quantitative polymerase chain reaction (qPCR) using fluorescent probes. The target prediction was performed using the software TargetScanHuman v. 5.2. Information about gene targets was obtained using the software Bioprocess, a database that obtains data from the National Center for Abstract xvi Biotechnology Information (NCBI). Results: Of the 490 mature microRNAs expressed in this cell type, 49 are low-expressed in DS group. The microRNAs located in chromosome 21 did not present differential expression between the groups. Bioinformatics analysis showed that genes involved in several relevant biological process to DS, including apoptosis, reactive oxygen species metabolism, mitochondrial metabolism, immune system, cell aging, cycle and division and control of gene expression, are predicted targets of microRNAs differentially expressed in DS children. Conclusion: DS children present low expression of microRNAs not located on chromosome 21 in peripheral blood mononuclear cells, as compared to children without DS. Biological processes relevant to DS pathogenesis are associated with predicted gene targets of microRNAs differentially expressed in DS children.