Down Syndrome Abstract
of the Month: Mar 2000
Gene expression relevant to Down syndrome: problems and approaches
Tassone F; Lucas R; Slavov D; Kavsan V; Crnic L; Gardiner K
J Neural Transm Suppl 1999;57:179-95
Eleanor Roosevelt Institute, Denver, CO, USA.
Abstract:
The long arm of human chromosome 21 likely contains several hundred genes. To determine which of these are responsible for specific aspects of the Down Syndrome phenotype, protein functional analysis coupled to phenotypic analysis of transgenic mice will be required. Because such experiments are both time consuming and expensive, prioritizing 21q genes for further studies would be advantageous. Here, we discuss expression analysis, specifically the use of Northern analysis, cDNA array screening and RNA tissue in situ hybridization to assess place and time of expression of forty-two genes. For a subset of these, over expression in normal versus trisomy cell lines and mouse tissues is discussed. Lastly, several examples of alternative processing and their potential for generation of brain specific proteins are described. Together, these experiments give information on time, place and level of expression of a number of 21q genes and suggest some interesting candidates worth further investigation for relevance to Down Syndrome. These data also illustrate the complexities and ambiguities inherent in interpretation and use of expression information.
My comments: This is a fairly lengthy article from our friends at ERI in Denver, and the abstract doesn't do it justice. The authors consider that in order to come up with therapies to prevent or alleviate specific features of DS, the gene-feature correlations need to be identified first. At present, there are 500 - 1,000 genes on the long arm of the 21st chromosome, all of which have to be considered candidates for playing a role in the DS "phenotype" (ie, physical and other features of the condition). Determining that a gene is relevant, and how it is relevant, is the critical issue.
How to determine what a gene does, and is it relevant to DS? Candidate genes must do the following:
1. Map to chromosome 21Most of the genes identified to the 21st chromosome to date have fulfilled numbers 1 and 2, but that's it. This paper addresses how to fulfill the other criteria ("expression analysis"), and spend a great deal of time on the sordid details:
2. Protein characteristics must suggest a relevant function
3. The products of the gene must be found ("expressed") in relevant body tissues
4. The gene must be expressed at a relevant developmental time
5. The gene must be overexpressed as a result of being triplicated
6. The known target of the gene, or interacting proteins, must suggest relevant functions.
To illustrate criteria #3, the authors discuss a handful of genes to determine how relevant they are to the DS phenotype. For instance, one gene called CD18 (also called ITGB2) is located on the 21st chromosome and is overexpressed by 50%, which is what you'd expect for a gene that has three copies instead of two. However, the genes APP (which makes amyloid protein precursor) and ETS2 (thought to be involved in skeletal formation) were not overexpressed at all in blood cells from subjects with Down syndrome. And the gene STCH was overexpressed at 500% over normal levels. So the presence of an extra gene does not necessarily mean it's relevant to Down syndrome.
The authors conclude with this caveat:
"The best evidence for relevance remains the demonstration of a phenotype arising from overexpression in a mouse model, followed by correction of this phenotype by therapy that reverts expression (or protein activity) to normal levels. Such experiments remain costly and time consuming."Yet the authors remain optimistic that other ongoing research will result in tools that will make the effort easier.