Scientists have discovered the earliest genetic changes that occur in Down's syndrome, resulting in the abnormal development of the fetus and eventually leading to the host of medical complications associated with the disorder. The findings, published in the American Journal of Human Genetics, are a step forward in our understanding of the molecular basis of this complex condition, and may pave the way for improved therapies.
Down's syndrome is a genetic disorder that is seen in approximately 1 in every thousand children born in the UK and is on the rise in the developed world as a result of increasing maternal age. It arises from a genetic abnormality known as trisomy 21, where an individual has three copies of chromosome 21 instead of the usual two.
In the new study, an international team of researchers led by Professor Dean Nizetic at Barts and the London School of Medicine and Dentistry, London, UK, examined the early developmental changes that occur in the embryonic stem cell (ES cells) of mice that have been genetically engineered to carry an extra copy of human chromosome 21. They found that trisomy 21 results in a disturbance in the activity of a key regulatory gene called REST. REST controls normal development by controlling the activity of several other genes, so the disruption to REST affects the whole cascade of genetic events that occur in development. They further found that a gene on chromosome 21 called DYRK1A triggers the disturbance to REST, and that by turning off the extra copy of DYRK1A they could restore normal REST activity in the ES cells.
Down's syndrome is generally associated with slow mental and physical development, distinctive facial features, impaired cognitive abilities and learning difficulties. Other complications can include congenital heart defects, recurrent ear infections, gastrointestinal problems and early-onset dementia. Understanding how trisomy 21 leads to these conditions may lead to better treatments for them, whether they arise from Down's syndrome or from other disorders.
Prof. Nizetic said: 'We hope that further research might lead to clues for the design of new therapeutic approaches tackling developmental delay, mental retardation, ageing and regeneration of brain cells'. There may even been implications for Alzheimer's disease, as genes on chromosome 21 are thought to be involved in the progression of this disorder.
Carol Boys, Chief Executive of the Down's Syndrome Association, commented to BBC News Online: 'Any research that helps us to understand more about some of the complex medical conditions that are commonly associated with Down's syndrome can only be a positive step forward. The development of therapeutic treatments for these sometimes complicated health problems, will hopefully lead to an improvement in the overall health of people of with Down's syndrome.'