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Key genes may not create Down syndrome

October 21, 2004 By Paula Gould This article courtesy of Nature News.

Mice model suggests cause is more complex than thought.

The small group of genes long believed to cause Down syndrome are unlikely to be the real culprits, according to recent research in mice. The finding is bad news for those devising therapeutic strategies, whose job would be simplified if blame could be laid at the door of just a few genes.

Down syndrome occurs in around 1 in 700 live births. The vast majority of people with the condition are born with three complete copies of chromosome 21 instead of two. But a small proportion of individuals with Down syndrome have only certain portions of chromosome 21 in triplicate.

The very simplistic explanation we had before was wrong.
Physiologist Roger Reeves
Johns Hopkins University School of Medicine, Baltimore
Although chromosome 21 contains over 200 genes, comparison of people with complete and partial repetition led researchers to believe that most features of Down syndrome are caused by a so-called 'critical region' of chromosome 21, which contains just 30 or so genes. This idea has held sway for the past 30 years.

Now researchers have used genetically engineered mice to disprove the theory. They bred mice with one, two and three copies of the mouse equivalents of genes from the critical region of human chromosome 21. They then compared visible, Down-like characteristics of these animals, such as face, head and growth measurements, with those from a known mouse model of Down syndrome.

The team reports in Science on 21 October that mice with three copies of the critical region did not look significantly different from mice with only one or two copies of these genes1. They also did not share the characteristic face and head shape present in the established mouse model.

Developing interactions

This demonstrates, in mice at least, that having just a few genes present in three copies is not enough to cause key features of Down syndrome. The researchers are confident that the finding applies to humans too, and believe that the condition is likely to be caused by complex genetic interactions between much larger numbers of tripled genes.

"The very simplistic explanation we had before was wrong," says Roger Reeves, from the Johns Hopkins University School of Medicine, Baltimore, who is one of the study's co-authors.

Reeves suggests that researchers should examine how characteristics of Down syndrome develop, as well as studying the genetic make-up of those with the condition.

"You can't look at any of this in isolation. You can't just look at one gene at a time. We need to be looking at the whole developing system," he says.

Such a complex system of interdependence will make it more difficult to treat Down syndrome by targeting particular genes. But researchers should not necessarily abandon this approach, according to David Nelson from Baylor College of Medicine, Texas.

"This is just part of the story. There may be a small number of genes responsible for other aspects of Down syndrome, such as heart defects. So I don't think it completely rules out that line of thinking," Nelson says.


  1. Olson L. E., Richtsmeier J. T., Leszl J & Reeves R. H. Science, 306. 687 - 690 (2004).


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