Protein levels of genes encoded on chromosome 21 in fetal Down syndrome brain: Challenging the gene dosage effect hypothesis (Part IV)

Abstract

Down syndrome (DS) is the most frequent genetic disorder with mental retardation and caused by trisomy 21. Although the molecular mechanisms of the various phenotypes of DS could be due to overexpression of gene(s) on chromosome 21, several groups have challenged this gene dosage effect hypothesis. The near completion of the sequencing of human chromosome 21 provides unprecedented opportunities to understand the molecular pathology of DS, however, functional information on gene products is limited so far. We therefore evaluated the levels of six proteins whose genes are encoded on chromosome 21 (trefoil factor 1, trefoil factor 2, trefoil factor 3, coxsackie virus and adenovirus receptor, carbonyl reductase 1 and interferon- alpha receptor) in fetal cerebral cortex from DS and controls at the early second trimester using Western blot analysis. None of the investigated proteins showed overexpression in DS compared to controls suggesting that these proteins are not involved in abnormal development of fetal DS brain and that DS phenotype can not be simply explained by the gene dosage effect hypothesis. We are systematically quantifying all proteins whose genes are encoded on chromosome 21 and these studies may provide a better understanding of genotype-phenotype correlation in DS.

Upregulation of threeDrosophilahomologs of human chromosome 21 genes alters synaptic function: Implications for Down syndrome

“…We did find an overall increase in the amount of synaptojanin protein in the brains of triple transgenic flies (as indicated by Western blot in Fig. S2) and at a level similar to those seen in DS mouse models and DS patient brain tissues (39,40). However, we discovered that dap160 overexpression creates differential synaptojanin distribution in subcellular regions of motor neurons where synaptojanin is increased in the cell body but normal at the synaptic terminal when synj is also coexpressed.…”

“…S1 and S2). It is important to note that the levels of intersectin1, synaptojanin1, and DSCR1 proteins have been shown to be elevated at a comparable amount in either human DS patient tissues or Ts65Dn mouse, a commonly used mouse DS model (ranging from Ϸ1.4-to 1.8-fold increases have been reported) (6,(39)(40)(41). Thus, our transgenic flies provide us a model system to investigate whether a dominant key gene or a subset of genes interact to affect phenotypes seen in DS.…”

Aneuploidy: Cells Losing Their Balance

“…Thirteen of the 16 proteins did not appear to exhibit a corresponding increase in protein levels. Analysis of several proteins, whose encoding genes are located on chromosome 21 in cells of trisomy 21 patients, revealed similar results (Cheon et al 2003a(Cheon et al ,b,c,d, 2007. Protein levels were not elevated in accordance with amounts of message.…”

Flow cytometric comparison of RNA content in peripheral blood mononuclear cells of down syndrome patients and control individuals

“…However, not all genes show the expected 50% increase in expression in the DS model of mice, and some genes show age-dependent changes in expression levels (15,16). Quantification of some proteins encoded on chromosome 21 revealed that not all gene products of the DS critical region are overexpressed in DS brain early in life, indicating that the DS phenotype cannot be simply explained by the gene dosage effect hypothesis (17,18). Interleukin-1 is a non-chromosome-21-based cytokine that is also overexpressed throughout life in Down syndrome (19).…”