Researchers begin to unlock genetic mysteries of Down syndrome

December 04, 2002

One of the most common genetic abnormalities is Down syndrome, which occurs when a person inherits three copies of chromosome 21 instead of the normal complement of two. Although the association has long been known, no one understands how the extra genetic material produces the syndrome, which is the most common genetic cause of mental retardation.

Now, new research is helping to provide an answer to this medical mystery. Researchers at NYU School of Medicine and colleagues in France and Germany, have taken a genetic tour of chromosome 21. They have identified where the chromosomes' switched-on genes are found in the brain, a significant accomplishment that may lead to the identification of the genes that contribute to Down syndrome.

"Our study provides a road map with clear signposts to the culprits of Down syndrome," says Ariel Ruiz i Altaba, Ph.D., Associate Professor of Cell Biology at NYU School of Medicine's Skirball Institute of Biomolecular Medicine, and one of the lead authors of the study. "There are now clearly defined candidate genes in the brain, heart and elsewhere that we can look at," says Dr. Ruiz i Altaba, whose laboratory is devoted to understanding brain development. "The next step is to understand how these genes function normally. Once we know which ones cause defects in the brain when their expression is altered, we will be in a position to see if rational therapies for Down syndrome are possible."

Down syndrome affects one in about 800 to 1,000 live births, according to the National Down Syndrome Society, an advocacy organization, which estimates that more than 350,000 people in the United States have the syndrome. In addition to affecting cognitive abilities, it is associated with abnormalities in the head and face, the heart, and other organs.

The complete DNA sequence of human chromosome 21 was published two years ago. Using sophisticated genetic techniques, Dr. Ruiz i Altaba and his colleagues found the mouse genes that correlated with the human genes on chromosome 21, and looked at where the mouse genes were turned on most strongly in the early developing mouse, as well as in the brain of two-day-old mice. There is a syndrome, similar to Down, that occurs in mice.

Dr. Ruiz i Altaba's interest in chromosome 21 stems from his studies in developmental genetics. He is particularly interested in genes that determine patterns of development, such as Sonic hedgehog and Gli. His laboratory has linked defects in these genes to cancer and holoprosencephaly, a congenital brain defect. These discoveries were made using embryos and genes from experimental animals, such as mice and frogs, and then linking these genes to their human counterparts. This is possible because mice and humans (as well as other animals) have many similar genes, a process biologists call "conservation."

Dr. Ruiz i Altaba and colleagues' study, published in the Dec. 5 issue of the journal Nature, accompanies the landmark publication of the entire genome of mouse in the same issue of the journal. The completion of the mouse genome, along with the recently completed sequencing of the human genome, is expected to greatly advance the understanding of human genetic diseases because humans and mice share many genes, and unlike humans, mice can be laboratory models for human disease. The mouse is the first mammal, other than humans, to have its genome, the DNA sequences along all of its chromosomes, completely sequenced.

In addition to Dr. Ruiz i Altaba, the NYU researchers included Nadia Dahmane, who now has her own lab at the Universite de la Mediterrannee in Marseille, France, Yorick Gitton, and Sonya Balk. Co-authors were from the Max Planck Institute for Molecular Genetics in Berlin and the Max Planck Institute for Immunology in Freiburg.
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NYU Langone Medical Center / New York University School of Medicine

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