The mainstream view of Down syndrome has been that just a few genes may be the culprits. But a study of mice reveals that the genetics may be more complex than researchers had hoped.
Trisomy 21, also known as Down syndrome, affects 1 out of every 700 babies. Mental retardation and other developmental abnormalities are known to be the result of having three rather than two copies of chromosome 21. The prevailing theory for decades has been that extra copies of genes on a specific area of chromosome 21, known as the Down syndrome critical region (DSCR), cause the mental and physical features of Down syndrome. Researchers have thought that a boost in the expression of a handful of key regulatory genes from this region derails development. But the theory has been difficult to test.
A team led by Roger Reeves, a geneticist at Johns Hopkins University School of Medicine in Baltimore, Maryland, approached the problem by creating a mouse with three copies of the DSCR. They accomplished this by using mouse embryonic stem cells to manipulate the mouse genome at the very start of development. Because Down syndrome involves specific changes to the shape of the skull, and because the genes of skull development are highly conserved between mice and humans, they compared the skulls of these extra-DSCR-containing mice with those of normal mice, as well as with those of mice with the equivalent of trisomy 21.
The team reports 22 October in Science that having three copies of the DSCR does not cause the distinctive skull features of Down syndrome in mice. According to Reeves, the result suggests that genes in the DSCR make their mischief by interacting with other abnormal genes far away on chromosome 21, and that the genetics of Down syndrome are probably more complex than has been generally thought.
The study corrects an oversimplification that has dogged the field, says Marie-Claude Potier, a geneticist at the Institute of Physics and Chemistry in Paris: "I never believed that correcting a few genes from the DSCR would cure Down syndrome." The next step, says Potier, is to examine whether an extra copy of the DSCR accounts for neurological or other features of Down syndrome.