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Down Syndrome Abstract
of the Month: Jan 2005

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A chromosome 21 critical region does not cause specific Down syndrome phenotypes

Olson LE, Richtsmeier JT, Leszl J, Reeves RH
Science. 2004 Oct 22; 306:687-90

Department of Physiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.

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The "Down syndrome critical region" (DSCR) is a chromosome 21 segment purported to contain genes responsible for many features of Down syndrome (DS), including craniofacial dysmorphology. We used chromosome engineering to create mice that were trisomic or monosomic for only the mouse chromosome segment orthologous to the DSCR and assessed dysmorphologies of the craniofacial skeleton that show direct parallels with DS in mice with a larger segmental trisomy. The DSCR genes were not sufficient and were largely not necessary to produce the facial phenotype. These results refute specific predictions of the prevailing hypothesis of gene action in DS.

My comments:

As early as 1974, researchers looking at the 21st chromosome wondered if a certain section of the chromosome, when triplicated, was responsible for the features of Down syndrome. Researchers then attempted to find as many people with "partial trisomies" (an uncommon situation in which only part of the 21st chromosome is triplicated in the cells) to determine which part of the 21st chromosome caused Down syndrome. Eventually, a "Down Syndrome Critical Region" was marked out as having most, if not all, of the genes needed to cause the physical features associated with DS (the "phenotype"). By the 1990s, many researchers began wondering if this was too simplistic a response. In 1994, a landmark study involving 23 researchers from 9 institutions was published that looked at 16 different individuals with partial trisomy 21. Each person had a complete study of which chromosomes were replicated and which features they had, and the researchers came to the conclusion that there was not one particular cluster of genes that was responsible for all features of DS. (Korenberg et al, Proc Natl Acad Sci USA 91:4997-5001, 1994)

The study I'm presenting today looks at the same question, but from a different angle. The researchers wished to determine if they could produce mice with the same skull characteristics as seen in people with Down syndrome by engineering their genes to have most of the same genes found in the "Critical Region" of the 21st human chromosome (the genes in question are pretty much the same between mice and humans). The researchers started with the basic Ts65Dn mouse line, which is the current trisomy 21 model as it has three of almost all the genes on the human 21st chromosome. It should be noted that the Ts65Dn mice do have skull changes compatible with the changes seen in the skulls of people with DS. These mice were then engineered to have trisomy of only the genes found in the human "DS Critical Region." As the abstract mentions, the new mice did not have any changes in the skull that could be compatible with the DS skull.

The basic result is that the genes that were triplicated in the engineered mice are not responsible for the skull changes seen in the Ts65Dn mice, or people with DS. Therefore, the human "DS Critical Region" cannot be responsible for the skull changes in people with DS, and then the idea that a handful of specific genes that are triplicated could cause all the changes seen in DS doesn't work.

So if that theory doesn't hold true, what could be the cause of the physical features of DS? One alternate theory states that the mere presence of extra genes is enough to cause a disruption of the normal workings of the cell, causing abnormalities that show up as physical changes. However, the physical changes in DS are fairly specific in people with DS and may be different from those found in other trisomies, so there has to be some input of the genes involved in some way. The answer is most likely a combination of these two theories, or as the authors of this study write:
...a triplicated gene, the solitary effect of which is inconspicuous, could contribute to a trisomic phenotype in combination with other genes based on the specificity of effects and interactions of these genes.
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