ddiseasesanddisorderssFragile X syndrome

Fragile X syndrome (FXS) is the most common form of inheritedmental retardation. An X-chromosome-linked disease, FXS is moreprevalent and its symptoms are more severe (see box, “Symptomsof fragile X syndrome”) in the male population (1:2000) than in thefemale population (1:4000). In 1991, Stephen Warren and colleagues
at the Howard Hughes Medical Institute (Chevy Chase, MD) identified mutations in a gene (FMR1) located on the X chromosomeof individuals with the disease. Unlike most disease-associatedmutations, however, the FXS mutation resides in the gene-expression control region andtakes the form of highly
repetitive stretches of thenucleotide triplet CGG
X chromosome(Figure 1). Normally, thistriplet repeats 5–54 times,
whereas in “premutation”
individuals, this sequence
FMR-1 gene
repeats 50–200 times. In
FXS-affected or “full muta- Normal
550tion” individuals, however,
the repeat occurs more thanRepeats
200 times.
CGG
In the case of FMR1, theextreme number of CGG
FMR-1 gene
repeats causes excessive
cytosine methylation in the Premutation
50200
promotor region of the genesuch that FMR1 is not tranRepeats
scribed at sufficient levels. Figure 1. Schematic of FMR1 gene responThe lack of FMR1 mRNA sible for fragile X syndrome.
leads to an equivalent ormore severe lack of the protein encoded by the gene—the fragile
X mental retardation 1 protein, or FMRP. FMRP is found predominantly in the cellular cytoplasm but can also translocate to thenucleus. Several research groups have shown that FMRP can bindto mRNA, but it preferentially binds to mRNA isolated from braintissue.
In 1999, Warren’s group used antibodies to isolate other mRNAbound proteins that might interact with FMRP. Among the proteinsassociated with FMRP, the researchers found two that belong to
the same family of proteins as FMRP, as well as nucleolin and a protein involved in mRNA unwinding during translation (Figure 2). This
indicated a possible role for FMRP in translation control.
In early 2002, Peter Carlen and colleagues at the Toronto Western
Hospital (Ontario) linked FMR1 in mice to the function of the GluR1
protein, a neurotransmitter involved in learning. The researchersfound reduced levels of GluR1 protein in brain tissue from micethat lacked FMR1, which resulted in an inability of the tissue to potentiate applied electrical signals—an in vitro model for learning.

72 MODERN DRUG DISCOVERY MAY 2003

FMRP
AAAAAAAA

Figure 2. Schematic of a protein–mRNA translation complex involving FMRP.

Other studies have similarly located FMRP at the neuronal synapse,
and its deletion has been shown to alter synaptic plasticity, whichis associated with learning and memory.
Also in 2002, Haruhiko Siomi and colleagues at the Universityof Tokushima (Japan) purified a dFMR1 complex from Drosophilacell lysates that contained two ribosomal proteins. But they also
found a third protein that is involved in RNA interference (RNAi),a cellular mechanism that inhibits infections and might beinvolved in mRNA degradation and therefore post-transcriptional gene control. Although the fly homologue of FMRP did notseem to be essential for RNAi-mediated mRNA degradation, it
might play a secondary role. This finding might have serendipitously led researchers to the real cause of FXS, a defect in RNAi
activity in neurons.
Unfortunately for people with FXS, there are still as many questions as there are answers. The complexity of the symptoms andthe unknown pathogenesis of the syndrome complicate FXS treatment, because a palliative effect on one symptom can often worsen
other symptoms. That being said, stimulants, selective serotonin reuptake inhibitors, anticonvulsants, and antipsychotics have all been used
to attack some of the symptoms associated with FXS. But as concluded at a National Institute of Mental Health (Bethesda, MD) conference on FXS, “There is [still] a critical need for controlled studiesof pharmacological and behavioral treatment approaches for thebehavioral and psychiatric manifestations of FXS.”—RANDALL C. WILLIS

Symptoms of fragile X syndrome
Researchers suggest that behavioral impairments rather thancognitive dysfunction limit the possible achievements of people
with FXS. These impairments include
L autism,
L hyperarousal and hyperactivity,
L attention deficits,
L anxiety,
L soothing repetitive behavior,
L irritability,
L aggression, andL extreme sensitivity to sensory stimuli.
(Source: Mental Health Aspects of Fragile X Syndrome:
Treatment Research Perspectives. Available at www.nimh.nih.
gov/research/fragilex.cfm.)

 2003 AMERICAN CHEMICAL SOCIETY