A Medical Device Daily
More than 17,000 people in the U.S. are diagnosed with Fragile X Syndrome each year, a condition which severely impedes a person's cognitive process and is called the single-most commonly inherited cause of intellectual impairment. Now researchers at UC Davis (Davis, California) have developed a new test that will measure the protein deficit responsible for fragile X syndrome.
The test, described in a study appearing online in the July 2009 issue of The Journal of Molecular Diagnostics, is the first to measure an individual's level of the fragile X mental retardation 1 (FMR1) protein.
Fragile X syndrome is the result of low levels of the FMR1 protein, which is known to play a role in communication between nerve cells.
In patients with fragile X syndrome, a sequence of one cytosine and two gaunine bases (CGG) in the FMR1 gene, repeated 10 to 40 times in normal individuals, is expanded to more than 200 repeats, leading to gene silencing and decreasing levels of the protein.
The fragile X syndrome is a genetic disorder caused by mutation of the FMR1 gene on the X chromosome. Mutation at that site is found in 1 out of about every 2000 males and 1 out of about every 259 females. (Incidence of the disease itself is about 1 in every 4000 females.)
Normally, the FMR1 gene contains between 6-55 repeats of the CGG codon (trinucleotide repeats). In people with the fragile X syndrome, the FMR1 allele has over 230-4000 repeats of this codon.
Expansion of the CGG repeating codon to such a degree results in a methylation of that portion of the DNA, effectively silencing the expression of the FMR1 protein.
This methylation of the FMR1 locus in chromosome band Xq27.3 is believed to result in constriction of the X chromosome which appears 'fragile' under the microscope at that point.
Study senior author Paul Hagerman, a professor in the Department of Biochemistry and Molecular Medicine in the UC Davis School of Medicine and director of the NeuroTherapeutics Research Institute (NTRI), said the study describes "a powerful tool to further investigate the relationship between FMR1 and the broad range of clinical involvement in fragile X syndrome."
Existing tests for fragile X syndrome determine the presence of the fragile X mutation by measuring the number of CGG repeats in the gene. The new test, called ELISA — for enzyme-linked immunosorbent assay — measures the level of FMR1 protein (FMRP) in individuals with the mutated gene.
"This test is quantitative and we think it will correlate with clinical involvement including the cognitive and behavioral problems that are part of fragile X syndrome. In addition, some carriers may be mildly deficient in this protein and we will see how this deficit relates to the emotional and attention problems that some experience," said Randi Hagerman, professor of pediatrics, and director of the Fragile X Treatment and Research Center at the UC Davis M.I.N.D. Institute.
In addition to fragile X syndrome, deficits in FMRP are linked to a variety of disorders, including developmental delay, behavioral difficulties, anxiety and attention-deficit/hyperactivity disorder (ADHD). Altered FMRP levels may also contribute to clinical involvement in children who carry smaller numbers of ("premutation") CGG expansions, and to the neurodegenerative disorder, fragile X-associated tremor/ataxia syndrome (FXTAS), and primary ovarian insufficiency.
Other study authors include Christine Iwahashi, Dag Yasui and Greg Mayeur of the Department of Biochemistry and Molecular Medicine in the UC Davis School of Medicine; Randi Hagerman and Flora Tassone of the UC Davis M.I.N.D. Institute; Danh Nguyen of the UC Davis Department of Public Health Sciences; and George Parrott of the CSU Sacramento Department of Psychology.
The study was funded by grants from the National Institutes of Health Interdisciplinary Research Consortium, the National Center for Research Resources and the UC Davis M.I.N.D. Institute.