Down Syndrome Abstract
of the Month:
May 2003
Protein levels of genes encoded on chromosome 21 in fetal Down syndrome brain: Challenging the gene dosage effect hypothesis (Parts I,II,III).
Cheon MS, Kim SH, Yaspo ML, Blasi F, Aoki Y, Melen K, Lubec G.
Amino Acids 2003 Mar;24(1-2):111-7,119-125,127-134.
Department of Pediatrics, University of Vienna, Vienna, Austria.
Abstract from Part I:
Down syndrome (DS) is the most significant genetic disorder with mental retardation and is caused by trisomy 21. The phenotype of DS is thought to result from overexpression of a gene(s) located on the triplicated chromosome (region). An increasing body of evidence that challenge this "gene dosage effect" hypothesis, however, has been reported indicating that this hypothesis still remains to be elucidated. The availability of the complete sequence of genes on chromosome 21 could have an immediate impact on DS research, but no conclusions can be drawn from nucleic acid levels. This made us evaluate protein levels of six proteins, gene products, encoded on chromosome 21 (T-cell lymphoma invasion and metastasis inducing Tiam1 protein, holocarboxylase synthetase, human interferon-regulated resistance GTP-binding protein MxA, Pbx regulating protein 1, autoimmune regulator, and pericentrin) in fetal cortex from DS and controls at 18-19 weeks of gestational age using Western blot technique. None of the investigated proteins showed overexpression in DS compared to controls. Our present data showing unaltered expression of six proteins on chromosome 21 in fetal DS brain suggest that the existence of the trisomic state is not involved in abnormal development of fetal DS brain and that the gene dosage effect hypothesis is not sufficient to fully explain the DS phenotype. We are in the process of quantifying all gene products of chromosome 21 and our first results do not support the gene dosage hypothesis.Abstract from Part II:
...We therefore investigated expression levels of six proteins encoded on chromosome 21 (HACS1, DYRK1A, alphaA-crystallin, FTCD, GARS-AIRS-GART, and CBS) in fetal cerebral cortex from DS and controls at 18-19 weeks of gestational age using Western blot analysis. Protein expression of HACS1 was significantly and remarkably decreased in DS, and the expression levels of five proteins were comparable between DS and controls suggesting that the gene dosage effect hypothesis is not sufficient to fully explain the DS phenotype.Abstract from Part III:
... We therefore evaluated expression levels of six proteins whose genes are encoded on chromosome 21 (synaptojanin-1, chromosome 21 open reading frame 2, oligomycin sensitivity confering protein, peptide 19, cystatin B and adenosine deaminase RNA-specific 2) in fetal cerebral cortex from DS and controls at 18-19 weeks of gestational age using Western blot analysis. Synaptojanin-1 and C21orf2 were increased in DS, but others were comparable between DS and controls, suggesting that the DS phenotype cannot be simply explained by gene dosage effects.
My comments:
This is one large experiment broken down into three different papers. These researchers have decided to use brain tissue from fetuses with Down syndrome to check the amounts of every protein made by genes known to be on the 21st chromosome. Of the 18 proteins tested in these papers, only 2 had levels significantly higher than in normal fetal tissue.If the gene dosage theory was correct, then every protein made by the 21st chromosome involved in affecting the fetus would be increased by 150%. The fact that these experiments did not find this to be true leaves us with two different possibilities. One possibility is that the gene dosage theory is completely wrong. Another possibility is that the genes tested so far that produce proteins in normal amounts have no effect on the developing DS fetus, either because they contribute an effect later in life, or else they have no effect at all. We'll have a better idea as we see more and more of their test results.
Bottom line to all this: figuring out the exact cause of individual features of DS (cognitive difficulties, heart defects, epicanthal folds, etc) is likely to be harder than we thought.
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