Expression of the transcription factor ETS2 in brain of patients with Down Syndrome - evidence against the overexpression-gene dosage hypothesis

Overexpression of the transcription factor ETS2 and other genes localized in the socalled critical Down Syndrome region of chromosome 21 due to a gene dosage effect, is an attractive hypothesis for the explanation of the Down Syndrome phenotype. The overexpression of ETS2, however, has never been demonstrated in a human organ. We therefore challenged this hypothesis determining ETS2 levels in several brain regions of patients with Down Syndrome as compared to controls. We used a highly sensitive and quantitative RT-PCR method for the determination of ETS2 mRNA steady state levels in frontal, parietal, temporal, occipital lobe and cerebellum of 9 adult Down Syndrome patients and 9 adult controls. Significantly decreased ETS2 mRNA steady state levels (16,9 +/- 26,7 attogram mRNA ETS2/10 ng total RNA versus 87,7 +/- 92,9 in controls) in frontal lobe of Down Syndrome brain and decreased ETS2 mRNA steady state levels (6,99 +/- 6,4 attogram mRNA ETS2/100 pg beta-actin versus 19,8 +/- 15,7 in controls) in temporal lobe of Down Syndrome brain were found. In the other brain regions no statistically significant difference was detected. Our data provide evidence against the overexpression hypothesis for the development of the Down Syndrome phenotype. Decreased ETS2 transcripts found in temporal and frontal lobe of patients with Down Syndrome, however, may be involved in the pathogenesis of Down Syndrome including specific neurodegenerative processes and deteriorated plasticity of the brain taking place in Down Syndrome brain, as the concerted action of transcription factors may be seriously impaired.