Altered gene expression in fetal Down Syndrome brain as revealed by the gene hunting technique of subtractive hybridization

Information on gene expression in brain of patients with Down Syndrome (DS, trisomy 21) is limited and molecular biological research is focussing on m apping and sequencing chromosome 21. The information on gene expression in DS available follows the current concept of a gene dosage effect due to a t hird copy of chromosome 21 claiming overexpression of genes encoded on this chromosome. Based upon the availability of fetal brain and recent technology of gene hu nting, we decided to use subtractive hybridization to evaluate differences in gene expression between DS and control brains. Subtractive hybridization was applied on two fetal brains with DS and two a ge and sex matched controls, 23rd week of gestation, and mRNA steady state levels were evaluated generating a subtractive library. Subtracted sequence s were identified by gene bank and assigned by alignments to individual gen es. We found a series of up-and downregulated sequences consisting of chromosom al transcripts, enzymes of intermediary metabolism, hormones, transporters/ channels and transcription factors (TFs). We show that trisomy 21 or aneuploidy leads to the deterioration of gene ex pression and the derangement of transcripts describes the impairment of tra nsport, carriers, channels, signaling, known metabolic and hormone imbalanc es. The dys-coordinated expression of transcription factors including homeo box genes, POU-domain TFs, helix-loop-helix-motifs, LIM domain containing T Fs, leucine zippers, forkhead genes, maybe of pathophysiological significan ce for abnormal brain development and wiring found in patients with DS. Thi s is the first description of the concomitant expression of a large series of sequences indicating disruption of the concerted action of genes in this disorder.