Investigation of patients with 22q11.2 deletion syndrome: Gene expression profile and evaluation of regulatory elements.

Abstract

The 22q11.2 deletion syndrome is caused by loss of chromosome 22 segments delimited by low copy repeats (LCRs), being more frequent deletions of 3 and 1.5 Mb. There is phenotypic heterogeneity in patients with deletions of similar extensions, as well as similar phenotypes in patients with different sized deletions in the 22q11.2 region. Thus, although genes mapped in the deleted region prone to dosage sensitivity are the main candidates for the phenotype, more complex molecular mechanisms are probably involved in the etiology of the syndrome. In addition to the deleted genes, the deletion of regulatory elements, changes in the expression of genes adjacent to the deleted region and the action of genetic modifiers located in other genomic regions can exert direct influence on the observed phenotypes. Additionally, in the critical region of the 22q11.2 deletion syndrome there is the DGCR8 gene (DiGeorge Syndrome Critical Region Gene 8), whose protein known as Pasha is involved in the machinery responsible for the biogenesis of microRNAs (miRNAs), which could influence global gene expression. Thus, this project proposes the study of gene and miRNAs expressions in peripheral blood in patients with 22q11.2 deletions of 1.5 and 3 Mb of extension and control subjects. We will study genes located on the 22q11.2 region and the miRNAs that regulate these genes, as well as the miRNAs of the 22q11.2 region and the target genes of these miRNAs. We expect to identify a network, which compose biological processes related to the clinical features of the syndrome. Also, the effect of reducing the expression (knockdown) of candidate genes, which are possible genetic modifiers of the phenotype, will be evaluated. For this, we will study lymphoblastoid cell lines from control individuals and cell lines from patients with deletions of 1.5 to 3 Mb. This study will be important for understanding the functional and regulatory mechanisms involved in this region of the genome, since only the deletion of the genes on the region is not sufficient to explain the phenotypic heterogeneity observed in the 22q11.2 deletion syndrome.