Genetic changes in Down Syndrome

Sometimes mutations in one gene can be confidently linked to a disease, a textbook example is cystic fibrosis. The majority of conditions though result from the complex, overlapping effects of dozens or even hundreds of genes spread throughout the genome. If the chromosomes are not properly paired up then large clusters of genes can be affected in one go. In Down Syndrome an extra chunk of chromosome 21 is inherited, resulting in three copies or ‘trisomy’ of the genes included rather than the usual two. Having extra genetic material does not result in some kind of supergenome like a comic book hero. For the body to grow and function properly, the degree to which genes are turned on or off – their expression level – has to be tightly controlled. Too high or too low can both have unwanted effects and as the role of many genes, known as transcription factors, is to regulate the expression of other genes then altering these has wide-ranging and complicated outcomes.

The exact part of chromosome 21 that is triplicated varies between individuals but shares a common region called the Down Syndrome Critical Region. This contains about 30 genes with a host of functions, many of them are transcription factors which will control the actions of genes across all the other chromosomes.

Mouse models are very useful for investigating the overall effect of the genomic alteration but of limited use in identifying the contribution of individual gene dosages and linking these to Down Syndrome phenotypes.

We focus upon the transcription factor SIM2: it lies within the critical region and published data strongly support its potentially key role in Down Syndrome aetiology, yet its function remains poorly characterised. The extra copy of SIM2 means that it will have too strong an action turning off or on its target genes, these in turn will have a wide-ranging effect on neuronal development and function. To give an example of this, individuals with Down Syndrome have increased risk of Alzheimer Disease; SIM2 represses expression of the cytoskeletal protein drebrin, loss of which is associated with dementia. Likewise, strabismus (squint) is another common feature of Down Syndrome and we have demonstrated the important role drebrin plays in oculomotor development.

Using the latest genetic, proteomic and fluorescent imaging techniques we are able to monitor and manipulate levels of SIM2 and its targets within neurons to identify the intracellular changes that result. These data will provide insights that can be extrapolated to increasingly complex Down Syndrome models, they will also have broader application to understanding congenital neurological disorders and the neuronal changes leading to dementia.

Other research topics: