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Down Syndrome Abstract
of the Month: July 2009

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Molecular genetic analysis of Down syndrome

Patterson D
Hum Genet. 2009 Jun 13.

Eleanor Roosevelt Institute, University of Denver, 2101 E. Wesley Avenue, Denver, CO, USA.

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Down syndrome (DS) is caused by trisomy of all or part of human chromosome 21 (HSA21) and is the most common genetic cause of significant intellectual disability. In addition to intellectual disability, many other health problems, such as congenital heart disease, Alzheimer's disease, leukemia, hypotonia, motor disorders, and various physical anomalies occur at an elevated frequency in people with DS. On the other hand, people with DS seem to be at a decreased risk of certain cancers and perhaps of atherosclerosis. There is wide variability in the phenotypes associated with DS. Although ultimately the phenotypes of DS must be due to trisomy of HSA21, the genetic mechanisms by which the phenotypes arise are not understood. The recent recognition that there are many genetically active elements that do not encode proteins makes the situation more complex. Additional complexity may exist due to possible epigenetic changes that may act differently in DS. Numerous mouse models with features reminiscent of those seen in individuals with DS have been produced and studied in some depth, and these have added considerable insight into possible genetic mechanisms behind some of the phenotypes. These mouse models allow experimental approaches, including attempts at therapy, that are not possible in humans. Progress in understanding the genetic mechanisms by which trisomy of HSA21 leads to DS is the subject of this review.

My comments:

This is a review article but a very nice one that summarizes where we are in our current research of the 21st chromosome. There were a couple of items in it that were new to me, so I thought I'd hit the highlights of the paper here.

First, Patterson mentions that the long arm of the 21st chromosome has been completely sequenced (21q) and the short arm (21p) is still being researched. So far there are about 420 genes on 21q, of which we have information about 145 of them. You can find information about the genes we know about on this webpage: http://chr21.egr.vcu.edu:8888/.

Next, the different mouse models currently used to investigate DS are described. The current model most used is Ts65Dn since this mouse is trisomic for all except 24 of the genes found on the mouse 16th chromosome (which is analogous to the human 21st chromosome). Patterson notes that over time, we are finding that this mouse has more and more features associated with DS, such as increased risk of blood disorders similar to leukemia. Researchers are also developing mice strains that are trisomic for only a few chromosomes ("knock-out" mice) to study certain genes or combinations. Finally, researchers have developed mice that contain human chromosomes to better understand their function.

Patterson then summarizes the research we have that tries to connect genotype (trisomy of certain genes) to phenotype (physical features). More and more, it appears that there are several ways that the increased number of genes affect the individual cells. The third gene present in the cell may cause an increased number of proteins that have a specific effect, or the phenotype may be due to the interaction of several different proteins, some of whom are even encoded on other chromosomes. This is an area of research that is ongoing.

Another interesting item from the article deals with microRNAs, which are small RNAs that bind to messenger RNA and either enhances or degrades the translation of genes to proteins. There are five microRNAs encoded on the 21st chromosome and all appear to be overexpressed in the brain and hearts of people with DS. The significance isn't known, but this may be yet another way that trisomy 21 interferes with gene function on other chromosomes.

There's a lot more to the article than I can summarize here. However, for people strongly interested in the work being done on the genetic level, this is a good summary of our current state.
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