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  • Down's syndrome theory shattered

    Last Updated: Friday, 22 October, 2004, 00:20 GMT 01:20 UK

    Scientists believe they have disproved a 30-year-old notion of what causes Down's syndrome.

    A particular genetic region long assumed to be a critical factor in this condition is not as important as thought, says the Johns Hopkins team.

    The US researchers studied mice engineered to have the 'culprit' genes believed to be responsible for causing Down's syndrome.

    They told the journal Science that the cause was much more complicated.

    Conflicting results

    They believe Down's syndrome arises from an interplay of complex genetic and developmental factors.

    In Down's Syndrome, an extra copy of one chromosome is inherited, giving a person three copies of chromosome 21 instead of the usual two. This is known as trisomy 21.

    Previous studies have supported the idea that extra genes within a critical region of chromosome 21 could be the root of the problem.

    Rare cases of Down's syndrome occur when only a segment of chromosome 21, and the genes housed within it, is triplicated. But Dr Roger Reeves and his colleagues say this notion can be disproved by measuring Down's syndrome-like characteristics in mice that are genetically engineered to possess the suspect genes.

    Children and adults with Down's have a distinctive facial appearance as well as possessing three copies of chromosome 21 in their cells.

    The researchers bred mice with one, two, or three copies of the critical region housed within chromosome 21, and compared them to other mice expressing both visible and genetic Down's syndrome-like characteristics.

    The mice bred to have copies of only the critical region had facial and skeletal changes different to those seen in Down's syndrome.

    Dr Reeves said: "These mice weren't normal but they weren't Down's syndrome mice either.

    "Their faces were longer and narrower than normal, but Down's syndrome is characterised by shorter than normal facial bones.

    "If anyone is going to try to treat the problems seen in Down's syndrome, we need to understand what is really happening and when in development it happens."

    Too simple

    Peter Elliott, of the Down's Syndrome Research Foundation, said the idea that there was a Critical Down Syndrome Region was too simplistic.

    "Our research is based upon an understanding of all the genes and how the extra 163 genes in Trisomy 21 affect the metabolism and so affect growth, development, health, and well being."

    Mr Elliott said it was clear that the extra 163 genes produced extra chemical messengers which could disrupt the function of any of the 22,450 genes contained in the cells of people with Down's.

    "Although the interaction of 163 extra genes affecting 22,287 other genes is very complex, we can look at the most serious outcomes, identify the particular gene at fault, then, develop a therapy to counteract the effect of that particular gene.

    "But research to find treatment therapies and a cure for Down's syndrome is very complex. Millions will be needed to find the answers."

    A spokesman from the Down's Syndrome Association said: "It is encouraging to see that research is continuing into the condition of Down's syndrome and producing results that help us understand the genetic make-up of chromosome 21 even further."

    He said although the results disagreed with the findings of previous studies, they should be viewed as positive because they suggested that further research might lead to developments in treating specific health problems common to people with Down's syndrome.
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  • #2
    Key genes may not create Down syndrome

    Paula Gould
    Published online: 21 October 2004

    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.

    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). | Article |
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    • #3
      Critical Down Syndrome genetic region isn't as important as once though

      22 Oct 2004

      After five years of work, Johns Hopkins researchers report that a particular genetic region long assumed to be a critical factor in Down syndrome isn't nearly as important as once thought.

      Their report in the Oct. 22 issue of Science, based on studies in genetically engineered mice, shreds a 30-year-old notion that genes in this region are largely responsible for the condition's characteristic facial features and some of its other common traits. Down syndrome, which affects roughly 1 in 700 live births, is the most common genetic cause of mental retardation and congenital heart disease.

      "The simplistic idea that just one of the hundreds of genes on chromosome 21 affects development no longer holds up," says Roger Reeves, Ph.D., professor of molecular biology and genetics in Johns Hopkins' Institute for Basic Biomedical Sciences and McKusick-Nathans Institute of Genetic Medicine. "Now researchers can take a deep breath, accept that the syndrome is complex, and move forward."

      Down syndrome occurs when three -- instead of two -- copies of chromosome 21 are present in a fertilized egg, although rare cases occur when a section of the chromosome -- rather than the whole chromosome -- is found in triplicate in a situation called segmental trisomy. A small region of this replicated segment is found in triplicate in all people with segmental trisomy and Down syndrome's facial features, and so it had been dubbed the "Down syndrome critical region" or DSCR. Proponents of DSCR's presumed role had focused on its consistency in people with segmental trisomy, but largely ignored the fact that no one with this condition has only that region in triplicate, Reeves says.

      To see whether DSCR is as critical as many suggested, then-graduate student Lisa Olson, Ph.D., created "chromosomally" engineered mice, and found that mice with three copies of just their DSCR equivalent actually had facial and skeletal changes opposite of those seen in Down syndrome.

      "These mice weren't normal, but they weren't Down syndrome mice, either," says Reeves, whose lab had already spent 15 years studying the mouse version of DSCR. "Their faces were longer and narrower than normal, but Down syndrome is characterized by shorter than normal facial bones."

      DSCR doesn't seem to be required for Down syndrome-like features to result, either, the researchers report. Olson found that mice with just two copies of DSCR but three copies of the rest of the chromosome did have the shorter bones characteristic of Down syndrome.

      To measure DSCR's effects in mice, former Hopkins professor Joan Richtsmeier, Ph.D., now at Pennsylvania State University, used mathematical models she developed to compare the length, angles and positions of the facial bones of the mice to Down syndrome's effects in people.

      "Some genes in the region contribute to the effects on facial bones, but, in triplicate alone, this region produces different traits than those seen in Down syndrome," says Reeves. "If anyone is going to try to treat the problems seen in Down syndrome, we need to understand what is really happening and when in development it happens.

      "Until very recently, we wouldn't have even thought it possible to 'treat' Down syndrome problems," he adds. "The task seems insurmountable -- the genetic problem is there from conception, it's in every cell. But now we're beginning to identify 'developmental cassettes' in mice in which specific problems caused by a triple genetic dose might be modifiable -- if we can figure out the key players."

      As part of this effort, Olson used a technique to precisely duplicate a defined chromosome segment and applied it to the DSCR section on mouse chromosome 16, the analog of human chromosome 21. She also made a mouse chromosome 16 that lacked DSCR entirely.

      Then scientists in Hopkins' Transgenic Mouse Facility inserted each of the engineered chromosomes into mouse embryonic stem cells, creating stem cells with either three copies of DSCR or only one copy of DSCR. These stem cells were then used to create chimeras -- animals whose make-up comes partially from their original cells and partially from the inserted, engineered stem cells.

      Physical inspection of these animals' offspring showed that triple-DSCR mice were bigger than normal mice. Mice with only one copy of DSCR were smaller than normal, similar to a well-studied mouse version of Down syndrome that has three copies of many more of the genes found on human chromosome 21.

      Breeding the single-DSCR with the well-studied Down syndrome mouse produced a mouse with only two copies of DSCR but three copies of all other genes on mouse chromosome 16. That "hybrid" mouse was similar to its Down syndrome parent but more mildly affected, the researchers report.

      Reeves' lab is now testing another long-standing but poorly supported tenet of Down syndrome research by using the mouse models to study the involvement of neural crest cells, precursors to structures affected in Down syndrome, including the face, heart and the nerves that serve the intestines.

      The research was funded by the National Institute of Child Health and Human Development. Authors are Olson and Reeves of Johns Hopkins, and Richtsmeier and Jen Leszl of Penn State. Olson was supported by a fellowship from the Howard Hughes Medical Institute and is now assistant professor of biology, University of Redlands, Calif. Sarah South and Gail Stetten, both of Hopkins, proved the DSCR status of the mice.

      On the Web:

      Contact: Joanna Downer
      [email protected]
      Johns Hopkins Medical Institutions
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