Centre for Functional Genomics and Human Disease

Down syndrome

Down syndrome (DS) is the most common chromosomal abnormality found in humans - it occurs at a rate of 1 in 700 live births and is much more common than other genetic abnormalities. It is also the most common cause of intellectual disability in the community. Individuals with DS have abnormalities in every organ system of the body, including brain defects, heart defects, leukaemia, bone abnormalities, eye problems and immune defects which make them prone to infections. In addition, all individuals with DS develop Alzheimer's-like pathology in the brain by the age of 35. Notably, many of the problems experienced by people with DS also occur in the rest of the population - albeit at a lower frequency and later in life. Therefore, DS is very useful model for common disorders and what we learn from DS is applicable to the broader community.

Individuals with DS have three copies of chromosome 21 instead of the normal two and therefore the functional characterisation of genes from chromosome 21 is crucial for understanding the cause of the disorder. Since we are unable to experiment on humans, our research focuses on the generation of mouse models of DS. We are generating transgenic mice, where the gene of interest is over-expressed to mimic the situation in DS, and knockout mice, in order to determine the normal biological function of the gene. Genes of interest include members of the ETS family of transcription factors, ETS2 and GABP and some newly discovered genes, DSCR1, ADAMTS1 and INTERSECTIN. All have the potential to contribute to parts of the DS phenotype

DSCR1 is implicated in both the heart defects and neurological deficits observed in individuals with DS because it regulates a cellular pathway critical for heart and brain development and function. In the heart, the pathway regulated by DSCR1 is also involved in cardiac muscle cell growth, so we expect that information from our studies will have direct implications for understanding not only the genesis of congenital heart defects in DS, but also the mechanisms underpinning the development of cardiac hypertrophy, a major risk factor for cardiac morbidity and death in Western populations. We have Dscr1 transgenic and knockout mice and are currently analysing their phenotype.

ADAMTS1 belongs to a class of genes implicated in inflammatory processes and responses. We are interested in ADAMTS1 as a possible contributor to a part of the DS phenotype, particularly with regard to the altered inflammatory responses exhibited by DS individuals and to the increased incidence of arthritis and skin disorders reported in DS. Our Adamts1 knockout mice display an interesting variety of phenotypic abnormalities.

INTERSECTIN1 is implicated in general endocytosis (the uptake of extra-cellular molecules) that occurs in all cells and synaptic transmission (a specialised type of endocytosis) that occurs in the brain. A role for altered endocytosis in DS has been suggested as early endosomes in neurones are markedly enlarged in the brains of individuals with DS. Interestingly, enlarged early endosomes are one of the earliest hallmarks of Alzheimer’s disease, a condition that has a disease mechanism common to DS, since all individuals with DS develop Alzheimer’s. We are presently generating knockout mice to determine the role of INTERSECTIN in the neurological deficits observed in DS, and we anticipate that these mice will also provide insight into the potential involvement of INTERSECTIN in Alzheimer’s disease.

ETS2 is a transcription factor and has the potential to regulate a large number of genes on other chromosomes. We have previously shown by generating transgenic mice that ETS2 contributes to the skeletal abnormalities observed in DS. We have also found that over-expression of ETS2 in cells or in mice results in a deregulation of the genes that control cellular suicide (apoptosis). DS skin cells and DS neurones in addition to skin cells and cells of the immune system from ETS2 transgenic mice, undergo an increased rate of cellular suicide. The aim is to understand where and when during development the cells commit inappropriate suicide and how this contributes to DS pathology.

Another of the major clinical symptoms associated with DS is muscular hypotonia (or weak, floppy muscles). Interestingly, the ETS transcription factor GABPa, is essential for the transcriptional regulation of a number of proteins critical for the function of the neuromuscular junction. Our aim is to examine the function of GABPa in the establishment of the neuromuscular junction, and we are currently doing this by the generation of a conditional knockout mouse specifically lacking GABPa in muscle.

Furthermore, GABPa has been indirectly associated with at least two other muscle disorders (congenital myosthenic syndrome and muscular dystrophy). These findings strongly support the importance of characterising GABPa function, with a view to its use in the clinic for treatment of muscle disease.