Scientists Identify Specific Genes
in the Brain Affected by Fragile X Syndrome
Scientists have identified for the first time specific
genes in the brain that are affected by the lack of FMRP - the protein
that is absent in individuals with fragile X syndrome, the most frequent
cause of inherited mental retardation in humans. The finding, published
in the Nov. 16 issue of the journal Cell, provides the first clear evidence
that fragile X syndrome may be caused by the dysregulation of specific
mRNA (messenger RNA) molecules and their encoded proteins. The research
group included scientists from Emory University, the Rockefeller University,
Duke University and the Howard Hughes Medical Institute.
"We expect these discoveries to elucidate the proximal cause of fragile
X syndrome as well as to provide new targets for drug therapy ," said
principal investigator Stephen T. Warren, Ph.D., W. T. Timmie professor
and chairman of the department of human genetics at Emory University
School of Medicine and a Howard Hughes Medical Institute investigator.
The paper's first authors are Emory School of Medicine investigators
Victoria Brown, Ph.D., and Peng Jin, Ph.D. Dr. Jin also is a Howard
Hughes Medical Institute associate.
Using DNA microarray "chip" technology, the scientists identified 432
mRNAs (expressed genes) from cells in the mouse brain that normally
are associated with FMRP. When they compared these to cells derived
from patients with fragile X syndrome, they identified 251 of those
same mRNAs (approximately 2% of the expressed genes) that were dysregulated
in the absence of FMRP.
Although scientists have known that FMRP is a protein that binds with
RNA and is involved in the regulation of translation, they have not
known until now the specific identify of the mRNAs associated with FMRP
nor the consequences of the lack of FMRP for message translation. In
related research, led by Robert B. Darnell, M.D., Ph.D., of The Rockefeller
University, working with Dr. Warren's laboratory at Emory, the scientists
discovered specific binding sites for FMRP on RNA - molecular structures
G-quartets are unusual structures of RNA formed by specific guanine
bases in series. Guanine is one of the four amino-acid bases (A, T,
G, and C) that are combined in different sequences within the DNA to
make genes. The research also is published in the Nov. 16 issue of Cell.
"Learning the actual binding site of the FMRP allows us to actually
dissect the interaction between FMRP and its associated messages, including
constructing a 'reporter' gene that could be a key to drug discovery,"
Dr. Warren said.
In 1991, Dr. 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. Suppression of the FMRP
protein is responsible for the symptoms of the disease, namely mental
retardation, attention deficit disorder and connective tissue disorders.
The most recently identified genes reported in the Cell manuscript also
provide candidate genes responsible for the genetic causes of these
associated problems, such as autism, of which nearly 20% of fragile
X patients suffer.
In the past few years there has been a dramatic increase in the understanding
of the molecular basis of the fragile X syndrome, with many of the major
discoveries originating in Dr. Warren's laboratory. For example, the
scientists have learned that most affected 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, 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.
"Our current research illuminates what might be going on in a neuron
that could lead to mental retardation besides the simple absence of
the FMRP protein," said Dr. Warren. "Our next step will be to further
understand and modulate these proteins that are the real cause of fragile
X. Already we know that 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 pathways involved in learning
The research was supported by the National Institutes of Health and
the Howard Hughes Medical Institute.