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 problems.

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 4–5 percent of the population as carriers—but previously were believed to cause no mental problems—could 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 Warren’s 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,” Warren said.

“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 group—4-to-5 percent of the population—were 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.”