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November 12, 2003

UW receives almost $6 million to study common cause of cognitive disability

The University of Washington 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).

Fragile-X syndrome affects an estimated one in 4,000 to 6,000 males and about half as many females in all ethnic groups, and 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.

The 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 emphasized 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 Fred Hutchinson, 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.”

Among the aspects of the grant:

? Hansen’s lab 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 will look at the effect of the mutation on the organization of the chromosome, its chromatin structure.

? Laird’s lab 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 will manage the patient recruitment and evaluation core. 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.

To reach researchers, contact:

Laurie McHale at 206-543-4037 for the UW Center on Human Development & Disability
Vince Stricherz at 206-543-2580 for Dr. Charles Laird, UW Department of Biology
Walter Neary at 206-543-3620 for the UW School of Medicine
Kristen Woodward at 206-667-5095 for the Fred Hutchinson Cancer Research Center
Martha Alcott at 916-734-9027 for the UC Davis MIND Institute

About The Center on Human Development and Disability

CHDD is one of the nation’s largest and most comprehensive interdisciplinary centers focusing on developmental disabilities. It has two major programs:

- The Mental Retardation and Developmental Disabilities Research Center studies the causes of mental retardation and other developmental disabilities, and develops behavioral and biomedical techniques to help prevent or minimize disabilities. UW faculty from various scientific disciplines are appointed as CHDD research affiliates. Supported by scientific core facilities, they work in interdisciplinary collaborations to address developmental disabilities from a broad range of perspectives, including genetic factors, neurobiological processes, and behavior.

- The University Center of Excellence in Developmental Disabilities provides interdisciplinary training of professionals to meet the needs of people with disabilities, provides clinical services and model projects, reaches out to the community with technical assistance and training, conducts applied research, and disseminates information widely.

CHDD is part of the UW’s health sciences complex, located on the Montlake Cut behind UW Medical Center. For more information see http://depts.washington.edu/chdd.