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Down Syndrome Abstract
of the Month: Feb 1999

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Evidence against the current hypothesis of "gene dosage effects" of trisomy 21: ets-2, encoded on chromosome 21, is not overexpressed in hearts of patients with Down Syndrome.

Greber-Platzer S, Schatzmann-Turhani D, Wollenek G, Lubec G
Biochem Biophys Res Commun 1999 Jan 19;254(2):395-9.

Department of Pediatrics, University of Vienna, Austria

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Background: The major current concept for the pathogenesis of the Down Syndrome (DS) phenotype including congenital heart disease (CHD) is the so-called "gene dosage effect." According to this hypothesis, genes encoded by chromosome 21 at the "critical region" (which is thought to be crucial for the development of the DS phenotype) are overexpressed in the trisomic state, thus leading to an imbalance of genes as, e.g., the protooncogene ets-2, superoxide dismutase,etc.
Methods: We studied heart biopsies obtained at surgery from 6 patients with DS and 7 patients with congenital heart disease. ets-2-mRNA steady state levels were determined by a competitive reverse transcription-polymerase chain reaction (RT-PCR) technique which allowed the determination of this gene at the attomol level.
Results: ets-2 mRNA in total ventricular tissue of DS patients showed concentrations of 0.60 +/- 0.42 fg/10 ng total RNA (mean, +/- SD). When normalized versus the housekeeping gene beta-actin to rule out general transcriptional changes in that disorder, the ratio of 0.56 +/- 0.28 (mean, +/- SD) was calculated. ets-2 mRNA in total ventricular tissue of patients with non-DS CHD showed concentrations of 0.45 +/- 0.22 fg/10 ng total RNA (mean, +/-SD) and ratios of 0.48 +/- 0.35 (mean, +/-SD). No differences could be found at the p<0.05 level.
Conclusion: No absolute quantification of a gene incriminated in the "gene dosage effect-hypothesis" was performed so far and the only approach to (semi-)quantitative determination of the ets-2 gene using northern blotting was published on one individual DS sample only. This is the first report to clearly show that no overexpression of ets-2 can be found in heart of patients with DS, thus providing evidence against the current gene dosage effect-hypothesis.

My comments:

In simpler terms, the researchers looked for evidence of overexpression of the gene ets-2 in the heart muscle by checking for RNA, the protein that takes the information from DNA and starts the protein synthesis operation. They didn't find it.

What does this mean? Either:
(a) the gene ets-2 isn't overexpressed in cardiac muscle, or
(b) the theory that features and illnesses associated with Down syndrome stem directly from the overexpression of gene products is wrong.

In 1997, Burton Shapiro, a genticist and researcher in Minnesota, published an essay entitled "Whither Down syndrome critical regions?" [Hum. Genet. 99:421-423, 1997]. In this essay, Dr. Shapiro makes the very strong argument that the features of Down syndrome are not due to a critical region of genes. He notes that there is no evidence found to date that any particular gene or locus on the 21st chromosome is singularly responsible for any individual feature of Down syndrome. He stresses that there is no single finding with the possible exception of mental retardation that occurs in every person with DS, and also every abnormality common to DS can also be found in the general population. He then notes that other chromosomal trisomies have some features in common with DS as well. Dr. Shapiro then proposes that "...it may be that the amount of superfluous transcribing genetic material that contributes significantly to the DS phenotype."

In other words, it may not be which gene that's triplicated that is important, but rather the fact that there are more gene transcriptional products gumming up the cellular works.
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