THURSDAY, Oct. 21, 2004 (HealthDayNews) -- Experiments with mice indicate that the genetics of Down syndrome aren't as simple as has been thought, Johns Hopkins University researchers report.
Down syndrome causes mental retardation and abnormalities of the face and skeleton. It is sometimes called trisomy 21 because there are three copies of chromosome 21, rather than the normal two, in people with the disorder. Research has zeroed in on a specific part of that chromosome, which has come to be called the Down syndrome critical region.
But mice genetically engineered to have three copies of that region in their chromosome 16 -- which corresponds to chromosome 21 in humans -- don't have the facial and skeletal features associated with Down syndrome, the study found. The research was led by Roger H. Reeves, professor of molecular biology and genetics, and reported in the Oct. 22 issue of the journal Science.
"These mice weren't normal, but they weren't Down syndrome mice either," Reeves said.
While the finding might seem like bad news in the short term, it is valuable "because it shows we have been barking up the wrong tree," Reeves said. "Now we can get to work on the real problem. Rather than looking at Down syndrome one gene at a time, we have to do things differently."
The discovery was the result of what Reeves called a "tour de force" by Lisa Olson, a former Hopkins graduate student who is now on faculty at the University of Redlands in California. She created the genetically engineered mice. Reeves also praised Joan Richtsmeier, a former Hopkins faculty member who has since moved to Penn State University, for developing the mathematical models that allowed for comparison of the bone structure of mice and humans who have Down syndrome.
Now the Hopkins researchers will reverse the usual method of studying the genetics of Down syndrome, which has been to go from genetic abnormalities (genotype) to physical features (phenotype), Reeves said.
"Instead of going from genotype to phenotype, we can make very good progress by going from phenotype to genotype," he said. "We can look at what processes are disrupted and work backwards from there."
David L. Nelson, a professor of molecular and human genetics at Baylor College of Medicine and co-author of an accompanying editorial in the journal, called the study's findings "mixed news" for those working on Down syndrome.
"The downside is that it makes it less likely that one or a few genes are mostly responsible for Down syndrome, which has been a cherished hope," Nelson said. "The upside is that it gives us a clearer view of how complicated the problem really is."
Nelson also noted the Hopkins work was done in mice, and "there are limits to what mice can tell us about humans." But the research does suggest that efforts to manipulate genes in humans "will be more complicated than had been thought," he said.
Down syndrome is a very complicated disorder, Reeves said. "There are over 80 things that a clinician looks for in Down syndrome, and only subsets of them are found in most individuals," he said.
Having the genetically engineered mouse model "makes it possible to study prenatal development," Reeves said. "Using the mouse model, we have been able to show when problems arise during development and which cellular mechanisms are involved."
Much work lies ahead, he said: "We aren't talking about therapy next year. We are talking about a new understanding of the development of Down syndrome."
More information
The Down Syndrome Information Network offers a guide to understanding and dealing with the disorder.
