A Mouse Model for the Human Angelman Syndrome

 Children born with Angelman syndrome (AS), also known as the "happy puppet syndrome," suffer from severe mental retardation, motor delay, seizures, and behavioral manifestations such as absence of speech, sleep disorders, unbalanced gait, stiff and puppet-like limb movements, and inappropriate laughter. Mutations in a gene, ubiquitin ligase enzyme 3A (UBE3A), found in human chromosome 15q, have been implicated in causing AS.

 Among the radiation-induced mutations generated in ORNL's Mammalian Genetics program is a deletion (p30PUb) in mouse chromosome 7 that includes the mouse version of the AS gene, Ube3a. Since large deletions in human 15q cause 70 percent of known cases of AS, this similar deletion in a strain of mice allows us to determine which of the physical, mental, and behavioral symptoms characteristic of AS can be studied in mice as well. To date, tests have proven that "AS" mice are quite below normal in their ability to maintain position on a rotating rod; this test measures balance and coordination. "AS" mice are also much less active than normal mice in a test for exploratory behavior in an activity-test chamber. Interestingly, the performance of mice on these tests improves somewhat with age, mirroring the gradually-improving (up to a point) clinical picture seen in AS children as they mature. Further tests are under way to measure the ability of "AS" mice to remember and try to avoid an unpleasant stimulus as a model for mental retardation, and to assess their 24-hour biorhythms as a model for sleep disturbance.

 We have used dissected mouse brains to show which specific brain regions express the AS gene, an experiment obviously not possible in humans. Ube3a is normally expressed in the cerebellum, the center for motor control, and in the hippocampus, thought to control some kinds of learning and memory. Importantly, in both humans and mice, AS occurs only when the mutant gene is inherited maternally. This genetic phenomenon, known as genomic imprinting, is poorly understood and we hope to gather crucial information not only about the functional causes of AS but also about the mechanisms that control imprinting.

Contact: D. K. Johnson Phone:574-0953
E-mail: k29@ornl.gov