Researchers seek clues to
mechanisms of fragile X
Researchers from seven interrelated and collaborative projects focusing
on fragile X syndrome, the most frequent cause of inherited mental retardation,
have received a grant from the National Institutes of Health (NIH) totaling
approximately $3.7 million. The research group, assembled by Stephen Warren,
W. T. Timmie Professor of Biochemistry in the School of Medicine, will try
to further clarify the molecular basis of fragile X syndrome and expand
the scope of contemporary fragile X syndrome research.
In recent years there has been a spectacular increase in the understanding
of fragile X syndrome, with many of the major discoveries originating in
Warren's laboratory. In 1991 Warren and his colleagues discovered the gene
responsible for fragile X syndrome, FMR1, and were among the first to develop
genetic tests to diagnose the disease. In 1993 they discovered FMRP, the
protein expressed by the normal FMR1 gene, and learned fragile X syndrome
occurs when the FMR1 gene does not produce the FMRP protein. This protein
suppression is responsible for the symptoms of the disease, namely mental
retardation, attention deficit disorder and connective tissue disorders.
The scientists also learned that most affected patients share a common
genetic mutation called triplet repeats. All genes are made of combinations
of four chemicals, abbreviated A, C, G and T. Within the FMR1 gene, the
triple combination of CGG, CGG, etc., is usually repeated only 30 times
in unaffected persons but between 230 to 1,000 times in those affected by
fragile X syndrome.
With this knowledge, genetic counselors have been able to help carriers
of FMR1 predict the probability of giving birth to a child affected by the
syndrome, and pediatricians and medical geneticists have been able to provide
perinatal testing of babies to determine if they might be affected by fragile
X syndrome. Moreover, these data helped explain the "Sherman paradox,"
named after Stephanie Sherman, associate professor of genetics and a co-investigator
on the program project.
Sherman first noted nearly a decade ago that fragile X syndrome did not
get passed on to offspring with the same probability as most genetic disorders.
This variance from the norm was unexplained for a number of years-hence
the paradox-until the gene was discovered and the influence of the expanded
CGG repeat was found to be responsible for the effect.
Despite these significant breakthroughs, key questions about fragile
X remain unanswered. The new grant will use novel genetic, molecular biological,
neurobiological and biochemical approaches, including cell culture, transgenic
mice and yeast systems to help uncover additional answers.
The seven projects will be led by a diverse group of established and
newer Emory investigators, including Warren and Sherman; Ye Feng, assistant
professor of biochemistry; Judy Fridovich-Keil, assistant professor of genetics;
Steven Hersch, assistant professor of neurology; Daniel Reines, associate
professor of biochemistry; and Keith Wilkinson, professor of biochemistry.
Six out of the seven already have published one or more research papers
on fragile X syndrome, representing a total of 65 published manuscripts
from Emory on the disorder.
"It is unlikely that there are many other institutions with a similar
group of investigators with such a history or track record of fragile X
syndrome research," said Warren. "And since our investigators
represent several scientific disciplines, this program will significantly
expand the scope and breadth of contemporary fragile X research."
The team will seek clues to the mechanisms of the triple-repeat expansion
and the suppression of FMRP during transcription as well as the role of
FMRP on protein translation and the consequence of its absence on protein
synthesis in specific regions of the brain and spine.
They will develop model systems, including one to investigate yeast genes
that express proteins similar to FMRP, and a new generation of FMR1 knockout
mice in which they can closely control FMRP expression. The investigators
also will address fundamental questions relating to possible future therapeutic
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