Abstract
BackgroundThe Down syndrome phenotype has been attributed to overexpression of chromosome 21 (Hsa21) genes. However, the expression profile of Hsa21 genes in trisomic human subjects as well as their effects on genes located on different chromosomes are largely unknown. Using oligonucleotide microarrays we compared the gene expression profiles of hearts of human fetuses with and without Hsa21 trisomy.ResultsApproximately half of the 15,000 genes examined (87 of the 168 genes on Hsa21) were expressed in the heart at 18–22 weeks of gestation. Hsa21 gene expression was globally upregulated 1.5 fold in trisomic samples. However, not all genes were equally dysregulated and 25 genes were not upregulated at all. Genes located on other chromosomes were also significantly dysregulated. Functional class scoring and gene set enrichment analyses of 473 genes, differentially expressed between trisomic and non-trisomic hearts, revealed downregulation of genes encoding mitochondrial enzymes and upregulation of genes encoding extracellular matrix proteins. There were no significant differences between trisomic fetuses with and without heart defects.ConclusionWe conclude that dosage-dependent upregulation of Hsa21 genes causes dysregulation of the genes responsible for mitochondrial function and for the extracellular matrix organization in the fetal heart of trisomic subjects. These alterations might be harbingers of the heart defects associated with Hsa21 trisomy, which could be based on elusive mechanisms involving genetic variability, environmental factors and/or stochastic events.
Highlights
The Down syndrome phenotype has been attributed to overexpression of chromosome 21 (Hsa21) genes
The phenotype of the fetuses with Hsa21 trisomy was found to be consistent with Down syndrome (DS)
Analysis of the fetal heart transcriptome The gene expression profile of the 15 fetal hearts was determined by DNA microarray analysis using Affymetrix HG-U133A oligonucleotide arrays
Summary
The Down syndrome phenotype has been attributed to overexpression of chromosome 21 (Hsa21) genes. Down syndrome (DS) is the most frequent autosomal aneuploidy that is compatible with post-natal life It results from complete or partial trisomy of chromosome 21 (Hsa21) and is characterized by a complex phenotype in which over 80 features occur with various degrees of expression and frequency [1]. The DSCR hypothesis was tested in mice [9,10] and it was found that trisomy for DSCR alone is necessary but not sufficient for brain phenotypes in trisomic mice. These results suggest that the origins of trisomic phenotypes are even more complicated than formerly assumed and that they probably involve multiple gene interactions [10]. It has been proposed that the complex phenotypic alterations of DS could result from an interplay between Hsa genes and developmentally regulated genes elsewhere on the genome [11] and that the loss of genetic balance in pivotal processes regulating development might increase susceptibility to genetic and environmental insults [12]
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