Emory Report

January 20, 1998

 Volume 50, No. 17

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 strategies.

-Holly Korschun

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