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October 24, 2003

New center will study fragile X syndrome

The UW has received an award of $5.86 million for a research center to study fragile-X syndrome, the most common inherited cause of mental retardation. The five-year award, from the National Institute of Child Health and Human Development at the National Institutes of Health, will be administered by the UW Center on Human Development and Disability (CHDD).

Affecting an estimated one in 4,000 to 6,000 males and about half as many females in all ethnic groups, fragile-X syndrome is second only to Down syndrome as a cause of cognitive disability. About one in 100 to 600 females is an unaffected carrier of the mutation in a gene called FMR1. This gene, which was identified in 1991, is located on the long arm of the X chromosome.

Since females have two X chromosomes and hence two copies of FMR1, females with the fragile-X mutation usually also have a normally functioning copy of the gene. This normal copy of the gene can partially compensate for the mutant one. Males have only one X chromosome, and therefore usually have more severe symptoms than girls when they carry a fragile-X mutation. Physical features can include enlarged ears, a long face, connective tissue problems and skeletal problems. Some males exhibit speech disturbances, hand biting or hand flapping, and autistic behaviors. Because of the variability in symptoms, the diagnosis of fragile-X syndrome is often delayed.

Lead researchers are Dr. Charles Laird, UW professor of biology and director of the Fragile X Research Center; Dr. R. Scott Hansen, UW research assistant professor of medical genetics; Dr. Stephen Tapscott, member of the Fred Hutchinson Cancer Research Center and UW associate professor of neurology, and Dr. Randi Hagerman, director of the MIND Institute at the University of California at Davis. She is a co-director of the grant and will direct patient recruitment and evaluation.

Laird emphasizes the interdisciplinary nature of the project. “CHDD has an outstanding record of bringing together faculty from different units, in this case the UW College of Arts and Sciences and the UW School of Medicine, the Hutchinson Cancer Research Center, and the University of California. This coalescence of interested groups and approaches is crucial to understanding the biology of this astonishingly complex genetic disease. We also expect that fragile-X research will provide new insights into normal cellular processes. For example, our work on fragile X has made us re-think our understanding of the process of cell division.”

• Hansen’s lab in the UW Division of Medical Genetics will focus on the timing of DNA replication during the cell cycle, including the disruption of replication and its consequences in fragile-X syndrome.

• Tapscott and colleagues at the Hutchinson Center will look at the effect of the mutation on the organization of the chromosome, its chromatin structure.

• Laird’s lab in the UW Department of Biology will examine mosaicism, in which different cells of an individual with fragile-X syndrome may contain different forms of the mutation. Mosaicism is observed in 15 to 20 percent of fragile-X patients.

• Hagerman and colleagues at UC Davis will manage the patient recruitment and evaluation core. This core will interface with the three Seattle projects and CHDD core facilities as correlations between molecular characteristics and clinical manifestations are sought. Initially, about 50 patients will be enrolled in the study.

Fragile-X syndrome involves a type of genetic mutation called a trinucleotide repeat expansion, in which a specific combination of the building blocks of DNA—in this case the nucleotides CGG—repeat themselves over and over beyond a normal threshold. The number of repeats appears to influence the severity of the disease. Fragile X also involves inappropriate methylation of DNA. Normally, DNA methylation is a process by which a methyl group—one carbon and three hydrogen atoms—is added to one of the nucleotides in DNA, which can shut down the activity of a nearby gene. In most cases this shutdown is needed for normal function, as in the inactivation of genes on the second, mostly inactive, X chromosome in females. In fragile-X syndrome, however, there is excess, or hypermethylation, of the FMR1 gene. This hypermethylation leads to abnormal silencing of FMR1, resulting in decreased or absent FMR1 protein that is needed for normal cognitive function.