Warren and his colleagues discovered in 1991 the gene responsible for fragile X syndrome, FMR1, and in 1993 discovered FMRP, the protein expressed by the normal gene. They 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.
The scientists also learned that most affected patients share a common genetic mutation: the unstable expansion of a triplet of CGG nitrogenous base pairs within the FMR1 gene. The CGG, CGG, etc., triplet is usually repeated between 230 to 1,000 times in those affected by fragile X syndrome but only 30 times in unaffected persons.
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.
Mosaic patients, however, have continued to puzzle clinicians and researchers alike, because their FMR1 genes are turned "on," yet they can be as severely affected as a typical patient. Predicting prognosis in babies with the unusual mosaic combination of an expanded repeat and active gene/expression has, until now, been difficult.
"For a long time we thought mosaic patients would be less severely affected," Warren said. "But in fact, they are usually just as affected as classic fragile X patients whose gene is turned `off.' "
The team reported that even though the activated FMR1 gene in mosaics begins the process of protein synthesis (by forming messenger RNA, known as mRNA), there is a malfunction of the ribosomes responsible for translating that mRNA into the amino acid sequence of a protein.
"We believe ribosome malfunction is triggered by the long sets of CGG triplet base pairs common to mosaics," Warren said. "Clinicians may now measure protein production to better gauge disease outcome."
The paper also settles the controversy about how ribosomes function. For years scientists have debated about whether ribosomes "scan" the whole chain of base pairs to begin to make proteins or whether they are able to "hop" to the start of protein synthesis. This paper settles the debate: ribosomes scan.
Fragile X syndrome is the most common inherited form of mental retardation, affecting approximately one in 1,000 persons. Other authors of the paper, all from the School of Medicine, include: first author Yue Feng, assistant professor; Fuping Zhang, Laurie K. Lokey, Jane L. Chastain and Lisa Lakkis, all Emory research assistants and staff of Howard Hughes Medical Institute; and graduate student Derek Eberhart.
-- Lorri Preston