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Missing Protein May Be Key to Common Type of Mental Retardation

The fragile X protein is missing in fragile X syndrome. So how does it cause the syndrome? By failing to assist in the production of some other proteins, two new studies suggest.

Only a few genes that cause neuropsychiatric diseases have actually been identified to date (Psychiatric News, May 5, 2000). One is the gene that causes fragile X syndrome—the second-leading cause of mental retardation after Down syndrome and the most common cause of inherited mental retardation. Exactly how the gene leads to the syndrome, however, has not been clear.

Now some new insights into the mechanism may have been found by Jennifer Darnell, Ph.D., of Rockefeller University and colleagues and by Stephen Warren, Ph.D., of Emory University School of Medicine and colleagues. Their results are reported in the November 16, 2001, Cell.

Mutations in the fragile X gene, which is located on the X chromosome, were already known to lead to a lack of production of the protein normally coded by this gene. But how might the absence of a fragile X protein in turn produce the fragile X syndrome—a disorder characterized not just by mental retardation, but by subtle facial malformations such as elongated ears and a prominent chin, and often a spate of other mental and physical abnormalities as well, including hyperactivity, hand flapping, an avoidance of eye contact, and heart-valve abnormalities?

Darnell, Warren, and their teams have found that the fragile X protein binds, in a test-tube environment, to messenger RNA (mRNA) molecules that in turn are known to produce proteins important for learning and memory, formation of the nervous system, and the development of facial bones. Thus, if the fragile X protein were not present to guide the mRNAs involved in the production of such proteins, the scientists conjectured, the proteins might develop in a faulty manner and lead to the mental and physical characteristics of fragile X syndrome.

Indeed, some of the mRNAs that appear to be normally shepherded by the fragile X protein are not properly regulated in cells taken from fragile X patients, the investigators likewise found. This discovery bolsters their conjecture that if the fragile X protein is not present to guide the mRNAs that need its guidance, then the mRNAs might produce proteins in an erroneous way, and this erroneous production in turn might lead to the mental and physical characteristics of fragile X syndrome.

The identification of mRNAs putatively involved in fragile X syndrome may also lead to an effective treatment for the syndrome, something that does not currently exist. For instance, drugs might be found that would manipulate the mRNAs in question and that, via this manipulation, might counter various characteristics of the syndrome.

The studies were funded by the FRAXA Research Foundation and the National Institutes of Health.

The reports by Darnell, Warren, and colleagues, "Fragile X Mental Retardation Protein Targets G Quartet mRNAs Important for Neuronal Function" and "Microarray Identification of FMRP-Associated Brain mRNAs and Altered mRNA Translational Profiles in Fragile X Syndrome," can be accessed on the Web at www.cell.com/content/vol107/issue4.

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