October 30, 2000
Warren study examines Fragile X syndrome
By Holly Korshcun
Emory scientists have announced the discovery of important new clues
to the molecular basis of Fragile X syndrome, the most frequent cause
of inherited mental retardation in humans.
The findings, which identify additional proteins that are affected by
a mutation in the Fragile X gene, could lead to new targets for drug therapy
as well as help explain numerous related psychiatric and developmental
The findings also demonstrate for the first time that the genetic mutation
leading to Fragile X goes well beyond the original protein expression
of the gene, said Stephen Warren, Timmie Professor of Biochemistry and
a Howard Hughes Medical Institute Investigator. The Fragile X mutation
also leads to downstream cellular consequences that appear
to exert a variety of effects on neurons that could negatively influence
development and behavior, he said.
In addition, the researchers discovered that intermediate forms of the
genetic mutation that are known to affect 45 percent of the population
as carriersbut previously were believed to cause no mental problemscould
be responsible for a variety of learning disabilities, psychiatric disorders
and behavioral difficulties.
In 1991 Warren and his colleagues discovered the FMR1 gene and were among
the first to develop genetic tests to diagnose Fragile X syndrome. In
1993 they discovered FMRP, the protein expressed by the normal FMR1 gene,
and learned that Fragile X syndrome occurs when the FMR1 gene does not
produce the FMRP protein. That protein suppression is responsible for
the symptoms of the disease, namely mental retardation, attention deficit
disorder and connective tissue disorders.
In the past few years, there has been a tremendous increase in the understanding of the molecular basis of Fragile X syndrome, with many of the major discoveries originating in Warrens laboratory.
For example, the scientists learned that most Fragile X 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
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 test babies to determine if they might be affected by Fragile X.
In their new research, Warren and his colleagues used the advanced technology
of DNA microarray to review 60,000 genes and identify 150 that appear
to interact with the FMR protein.
Of these 150 genes, about one-third seem to change expression with
the Fragile X mutation compared to cells that do not have the mutation,
This is the first clue to illuminating what might be going on in
a neuron that could lead to mental retardation besides the simple absence
of the protein, he continued. Our next step will be to understand
and modulate these downstream proteins that are the real cause of Fragile
X. Already we know some of these proteins affect the ability of a neuron
to form a connection with another neuron. We hope the novel proteins we
have identified will lead to novel pathways involved in learning and memory.
In the intermediate form of Fragile X, mutated gene carriers
produce genes that repeat triplet combinations more than the normal 30
times but less than the 200 or more times of mentally retarded persons.
Until now, we believed that this group4-to-5 percent of the
populationwere only carriers of the Fragile X gene but were otherwise
normal, Warren said. We now have found that the amount of
protein made by this intermediate group correlates with the
number of triple repeats. The more triple repeats, the less protein.
By matching this information to anecdotal information about learning disabilities, psychiatric disease, hyperactivity, etc., we now believe that any degree of FMRP protein deficit could cause a negative effect. Our next step will be to study patients with this genetic phenotype and correlate this to clinical findings.