Síndrome de Down: da expressão de genes envolvidos no sistema imune ao modelo animal de fenótipos potencialmente relacionados à produção da fala

Abstract

Down syndrome (DS) is caused by the trisomy of human chromosome 21 (HSA21) and has an incidence of approximately one in 660 live births. Individuals with DS show a variety of phenotypic features including an impaired immune system with increased susceptibility to bacterial and viral infections and high frequency of autoimmune disorders, and speech and language impairments with difficulties in acquiring language. Objective: Identify differentially expressed immune-related genes in peripheral blood mononuclear cells of children with DS compared with individuals without the syndrome; characterize the properties of the ultrasonic vocalizations (USVs) emitted by Ts65Dn males (the most extensively used DS animal model) during courtship episodes with female partners and compare with those emitted by euploid control mice. Casuistic and Methods: The expression analysis of 92 immune-related genes was performed using the TaqMan® Human Immune Array kit and total RNA extracted from six healthy individuals with DS and six healthy control individuals without the syndrome. USVs analysis was performed using data collected from 22 Ts65Dn mice and 22 of their euploid littermates. Vocalizations were recorded over a five-minute period and then analyzed and categorized into syllable types using the Avisoft Bioacustics SasLab Pro software. Each syllable was classified as one of the nine waveform categories based on internal pitch change, length and shape. Results: In the group with DS, we identified 17 differentially expressed genes involved in immune pathways including 13 genes (BCL2, CCL3, CCR7, CD19, CD28, CD40, CD40LG, CD80, EDN1, IKBKB, IL6, NOS2 and SKI) with decreased expression and four genes (BCL2L1, CCR2, CCR5 and IL10) with increased expression compared with the control group. In our study with the mouse model of DS, Ts65Dn, we found that both minimum and maximum peak frequencies of Ts65Dn calls were lower than those produced by euploid mice, whereas the mean individual duration of ―down‖ and ―complex‖ syllable types was significantly longer. Peak, minimal and maximal, and fundamental frequencies of short syllables generated by Ts65Dn mice were lower compared to those by euploid mice. Finally, Ts65Dn emitted fewer multiple jumps calls during courtship and the mean total duration of their ―arc‖, ―u‖, and ―complex‖ syllables was longer. Conclusion: Children with DS have 17 differentially expressed non-HSA21 genes in peripheral blood mononuclear cells compared with children without the syndrome. These findings reinforce the secondary effects of the presence of a third copy of HSA21. There are differences between adult Ts65Dn and euploid control mice with respect to USVs. Some correlation with human condition resulting from the trisomy 21 can be drawn, however further studies are necessary. Global gene expression profiling of differentially expressed genes, located or not on HSA21, and the study of mouse models will help elucidate the genetic and developmental mechanisms that contribute to the clinical features of DS and provide important information for the emerging field of translational research of potential pharmacotherapies designed to enhance the quality of life of individuals with DS.