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
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
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
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.