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Learning Disorder Gene in Down Syndrome Identified

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By Lynn Yarris, [email protected]

April 29, 1997

BERKELEY, CA -- A major genetic factor contributing to mental retardation in Down syndrome has been identified by researchers at the Ernest Orlando Lawrence Berkeley National Laboratory (Berkeley Lab).

Working with transgenic mice that carry segments of human chromosome 21 in their DNA, the scientists have linked learning deficits to DYRK, a gene named for the protein it produces. Any deviation from the normal complement of two copies of this gene appears to impair the ability to learn.

This research was led by Drs. Edward Rubin and Desmond Smith, geneticists with Berkeley Lab's Life Sciences Division. It has been reported in Nature Genetics (May 1, 1997).

"We've demonstrated that DYRK is a gene for which dosage plays an important role in how neuronal pathways are put together," says Rubin, who heads biology research for Berkeley Lab's Human Genome Center. "Our work suggests that you need exactly two copies of DYRK for normal development."

Down syndrome occurs in about one out of every 800 newborns with the incidence increasing markedly in the offspring of women over 35. Affecting an estimated one million Americans, it is the leading genetic cause of mental retardation and is associated with a shorter-than-average life expectancy (55). Other symptoms are heart and intestinal defects, problems with the immune and endocrine systems, and a raft of tissue and skeletal deformities.

Individuals with Down syndrome carry a complete extra copy of chromosome 21 in all of their cells, giving each cell a total of 47 chromosomes rather than the normal 46. For this reason, the condition is also known as "Trisomy 21." There are, however, rare forms of Down syndrome in which only part of chromosome 21 is present in triplicate.

The existence of these rare forms of Down syndrome suggested that the condition may be due to a limited number of genes and led Smith and Rubin to create a special series of transgenic mice containing different adjacent segments of human chromosome 21.

To identify which gene was responsible for mental retardation, Rubin and Smith assessed the learning and memory skills of their genetically altered mice using a standardized test. The mice were placed in a tank filled with opaque water and clocked for how long it took them to find their way to a platform hidden just below the water's surface.

"Our strategy made no prior assumptions about individual genes, but rather, allowed the behavior of the mice to guide us to a crucial gene on chromosome 21," says Rubin. "This approach of using the whole animal is likely to become increasingly important as geneticists attempt to investigate the basis of other complex human conditions such as hypertension or schizophrenia."

The strain of mouse that performed the most poorly on the test carried a human DYRK gene in addition to a pair of mouse DYRK genes. That the extra copy of DYRK was the culprit, the researchers say, was supported with the discovery that DYRK is almost identical to a fruit fly gene called minibrain. Fruit flies that carry only a single copy of minibrain instead of the the normal two copies also display impaired learning -- they are unable to find their way to a particular smell.

"Obviously a large leap of faith must be taken to equate learning in flies to that in humans," says Rubin. "However, the corresponding findings in both flies and mice concerning the effect of an altered copy number of DYRK or minibrain support the idea that altered expression of this gene may be an important contributor to the learning defects in humans with Down syndrome."

In addition to Smith and Rubin, other contributors to this research included Mary Stevens, Sharmila Sudanagunta, Jingly Fung, Heinz-Ulrich Weier, and Jan-Fang Cheng at the Berkeley Lab Human Genome Center, plus Roderick Bronson of the U.S. Department of Agriculture, and Michael Makhinson, Ayako Watabe, and Thomas O'Dell of UCLA.

The Berkeley Lab is a U.S. Department of Energy national laboratory located in Berkeley, California. It conducts unclassified scientific research and is managed by the University of California.

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