Fragile X syndrome is among the most common of the human disorders that are caused by disruption of a single gene, and is the leading cause of inherited mental retardation. The estimated frequency of this disorder worldwide is 1/2000-1/4000. In addition to the mental retardation and family history (especially a male relative) seen in this disorder, Fragile X syndrome is also associated with large testicles, a large size, a tendency to avoid eye contact, hyperactive behavior, a large forehead and/or ears, and a prominent jaw.

The most common mutation found in Fragile X syndrome is expansion and methylation of an unstable region of DNA (deoxyribonucleic acid) that contains multiple copies of a unit of three particular nucleotides (cytosine-guanine-guanine, or CGG). This expansion and methylation disrupts the expression of a gene called FMR1, and the largest forms of the expansion result in that portion of the X chromosome being particularly fragile when being examined cytogenetically (hence the name "Fragile X syndrome"). Two similar unstable CGG repeats have been found nearby on the X chromosome. Of these three Fragile X sites, two appear to be associated with mental retardation (FRAXA affects the FMR1 gene in Fragile X syndrome, while FRAXE affects the FMR2 gene in FRAXE disease). The third site, FRAXF, appears to be benign.

The FMR1 gene that is defective in Fragile X syndrome was discovered in 1991 by a collaboration of investigators, including several from Baylor College of Medicine. The FMR1 protein that is normally produced from this gene interacts with messenger RNA (ribonucleic acid) molecules in a variety of cell types, and has also been shown to associate with ribosomes, where protein assembly takes place. However, its function and the consequences of its absence are still unknown.

Ongoing research at the Baylor College of Medicine Mental Retardation Developmental Disabilities Research Center:

Further understanding of the disease
One approach to determining the function of the proteins produced by the FMR1 and FMR2 genes is to produce animal models that are defective in one of the equivalent genes in that organism, and then to examine what is different when compared to normal animals. Investigators at Baylor College of Medicine are doing such analysis with mice and fruit flies.

An observation from the animal model studies is that some biochemical signals occurring in activated cells of the hippocampus region of the brain are altered in mouse models of Fragile X syndrome. Further study of such altered cellular signals may help us to understand impairments in learning and memory that are associated with diseases such as Fragile X syndrome.

The fact that the mental retardation associated with Fragile X syndrome and FRAXE disease is relatively mild suggests that perhaps there is some overlap in the function of the FMR1 and FMR2 genes. In other words, if one of these genes is disrupted by mutation, is the other able to compensate in some way? This hypothesis will be tested by generating and investigating mouse models that lack both these genes.

Another line of study at Baylor College of Medicine is an investigation into the behavioral aspects of Fragile X syndrome (hyperactivity, hyperarousal, and increased anxiety in social situations). Mice that lack the equivalent of the human FMR1 gene and mice that have an overabundance of the gene protein product will both be tested for differences in various types of social and anxiety-related behaviors. Physiological tests will also be performed to see if there is any correlation between those results and the observed behaviors.

Investigators at Baylor College of Medicine work closely with researchers at Emory University School of Medicine in Atlanta, GA, in collaborative projects to characterize and investigate mutations causing Fragile X syndrome. Such collaboration makes more efficient use of resources.

Work towards therapy
With a better knowledge of the function of the human FMR1 and FMR2 genes in normal brain development, and of the effect of mutations in these genes that lead to mental retardation, researchers hope to find avenues that lead to therapy for Fragile X syndrome and FRAXE disease. The mouse models that lack the equivalent of the human FMR1 gene are especially useful in tests of drug or other therapeutic strategies.

Baylor investigators working on Fragile X syndrome:

Baylor MRDDRC projects associated with Fragile X syndrome:

• » Study of tremor/ataxia premutation carriers, Stephanie Sherman, Ph.D., Emory University.
• » RNA-dependent machanisms for FMR1 premutation phenotypes, Stephen T. Warren, Ph.D., Emory University.

Fragile X syndrome resources:

Organizations: