February 18, 2000
"... it's the strongest parallel you can get."
Evidence for a credible animal version of Down syndrome mounted today with a report from Johns Hopkins scientists verifying the syndrome's signature skull and facial deformities in a genetically modified mouse.
Down syndrome (DS) occurs in one in every 700 live human births, making it the most common inherited chromosome disorder and the leading genetic cause of mental retardation. DS is marked by the presence of three copies of chromosome 21, instead of the normal two, in the body's cells.
Animal models that scientists produce by mutating or knocking out a particular gene are a staple of biomedical research. But researchers need a more complicated animal model for disorders due to chromosome abnormalities, such as DS. The mice studied at Hopkins which were developed at The Jackson Laboratory in Bar Harbor, Maine, have cells containing three copies of the entire chromosome region analogous to human chromosome 21.
The Hopkins research, presented today at the annual meeting of the American Association for the Advancement of Science in Washington, D.C., shows that in the engineered mice, the craniofacial hallmarks of DS result directly from having extra copies of a chromosome virtually identical to one in humans. The mice look mostly normal, but have shorter noses and skulls slightly flattened in the back.
The study found that the abnormal skull/facial development in the chromosome-loaded mice involves the same bones and the same pattern of shortening or lengthening found in humans with DS. "The same genetic insult that exists in humans with Down syndrome exists in the mice," says molecular biologist Roger H. Reeves, Ph.D., who co-led the Hopkins team.
While the scientists concentrated in this study on the engineered mouse as a good model for DS face and skull abnormalities, they've also published work in the January issue of Human Molecular Genetics that describes the animal's abnormally small cerebellum, the part of the brain controlling movement. A small cerebellum, along with mental retardation, is also found in DS-afflicted people. The mouse model appears so accurate that it has already predicted an abnormally low density of cerebellar brain cells in people with the disorder that scientists hadn't previously known about.
"Nobody knows exactly why having too much of a chromosome would lead to the developmental problems you see with Down syndrome," says Reeves. "We believe this model will help explain that in a way we couldn't before." The model, says Reeves, should lead scientists, within two or three years, to a key gene or genes that affect the development of the face and skull.
Knowing this, he adds, should shed light on the other craniofacial problems that hundreds in this country are born with, and which, while rarely fatal, are extremely costly to treat and are traumatic psychologically. Finally, Reeves says, having the model could answer basic questions about how genes interact during development.
In the first study, team member Joan Richtsmeier, Ph.D., marked various parts of the skulls of 12 of the engineered mice and "normal" mice with reference points and, using a laser-equipped 3D-measuring microscope, recorded distances between the points. Sophisticated statistical techniques let her compare the skulls. The researchers then matched the mouse data with well-established characteristics of skulls of DS patients and found, Reeves says, "an absolute correspondence. The changes in the mouse face are in the same bones, in the same pattern, as in humans."
The researchers also mapped the genes along a crucial part of mouse chromosome 16, the one with three copies, and compared them with a corresponding part of human chromosome 21. The mouse and human share virtually identical genes in the same order on the chromosome. "Is this model good enough to reflect what goes on in humans?" Reeves asks; "Yes. It's about the strongest parallel you can get."
Down syndrome, the most common genetic cause of mental retardation, happens most often from a mishap during sex cell production, where some cells are allotted an entire extra 21st chromosome.
People with DS always have face and skull malformations and brain abnormalities. They also often but not always, have immune system, cardiac, gut and muscle deficiencies.
All research was supported by Public Health Service grants. Timothy H. Moran, Ph.D., and Juan Troncoso, M.D., participated in the second study. Graduate student Laura L. Baxter participated in both studies.
Related Web Sites: http://faith.med.jhmi.edu details craniofacial work in the Hopkins labs and has links to other sites explaining craniofacial abnormalities and ongoing research.
http://physiology.med.jhu.edu/roger/roger.html is Roger Reeves' Web site and describes ongoing work in his lab.
This study was also published last month in the journal Developmental Dynamics, vol 217, pp 137-145. The second study on brain characteristics of DS mouse and man was in the January 2000 Human Molecular Genetics, vol 9, no 2, pp 195-202.