My brother, Michael, is 52 and probably the happiest, most fun-loving person I know. Yet Michael is intellectually and physically disabled due to a condition known as Down syndrome. First characterized by the English physician, John Langdon, in 1862, Down syndrome manifests as a spectrum disorder in which intellectual and physical ability ranges from individuals who can function independently to individuals completely dependent on round-the-clock care, as is the case with Michael. Michael is not unusual; the Centers for Disease Control note that Down syndrome remains the most common chromosomal condition diagnosed in the United States with approximately 6,000 babies born each year. This means that Down syndrome occurs in about 1 out of every 700 babies.
Down syndrome is caused by the presence of an extra copy of the genes on chromosome 21. This can result from either a complete extra copy of the chromosome or the duplication of sections of chromosome 21 elsewhere within the genome. Whatever the mechanism, the result is that genes from chromosome 21 are overexpressed, resulting in a constellation of development disorders. The most prominent effects are physical and intellectual disabilities. Other effects include poor immune function and a variety of different health problems, both congenital, such as heart disease, and acquired, such as an increased risk of cancer.
Chromosome 21 is the smallest human chromosome and probably contains only a few hundred genes. So why does the overexpression of multiple genes from chromosome 21 result in such a global genetic impact? The answer appears to be that “overdoses” of several critical gene products may cause metabolic and structural disruptions. For example, the over-expression of the superoxide dismutase protein encoded on chromosome 21 may cause premature aging and decreased function of the immune system. Similarly, an extra dose of the protein encoded by the ETS2 gene may cause skeletal abnormalities. But perhaps the most interesting disruption is the overexpression of amyloid beta peptide in the brain. This peptide is processed from amyloid precursor protein, whose gene is located on chromosome 21 and is linked to Alzheimer’s disease. It is perhaps unsurprising that early Alzheimer’s symptoms, including plaques in the brain, are present in nearly all Down syndrome patients before the age of 40.
The prevailing view has been that the outward effects of Down syndrome reflect the summation of the overexpression of several, or perhaps all, of the genes on the chromosome. However, recent studies are suggesting that this might not be the whole story. A research team in Switzerland studied a pair of twin fetuses aborted at 16 weeks, one with an extra copy of chromosome 21 and the other without. This allowed the researchers to directly identify the effect of an extra chromosome while controlling for the other genetic differences that are typically present between different individuals. Their findings were surprising, inasmuch as the impact of chromosome 21 was global and affected other chromosomes in the genome. Specific genes were up-regulated and down-regulated in a manner that was not obviously correlated with gene dosage. Further, the researchers concluded that the addition of even a small piece of chromosome 21 disturbed the expression of all genes in the genome. This means that the syndrome is a global perturbation of the whole “transcriptome” (gene expression from the entire genome or genetic make-up of an individual). The finding explains why Down syndrome is manifest as a spectrum disorder, with wide differences of effects between individuals. The finding also has implications for other genetic disorders linked to duplicated chromosomes, such as Edwards syndrome (chromosome 18) and Patau syndrome (chromosome 13).
One feature of Down syndrome is that it is associated with a zest for life and a very positive outlook. Almost all Down syndrome individuals are fun-loving and exceptionally friendly. With Michael and my parents just visiting from the UK for several weeks, I have been lucky enough to be reminded of this every day.
David L. “Woody” Woodland, Ph.D. is the Chief Scientific Officer of Silverthorne-based Keystone Symposia on Molecular and Cellular Biology, a nonprofit dedicated to accelerating life science discovery by convening internationally renowned research conferences in Summit County and worldwide. Woody can be reached at 970-262-1230 ext. 131 or firstname.lastname@example.org.
Almost all Down syndrome individuals are fun-loving and exceptionally friendly. With Michael and my parents just visiting from the UK for several weeks, I have been lucky enough to be reminded of this every day.