The molecular dysfunction underlying the neurological symptoms of Angelman syndrome (AS) is revealed in a paper in the March 2007 issue of Nature Neuroscience. AS is a rare genetic disorder, characterized by movement problems, seizures and mental retardation.
The disorder is caused by the loss of a region of chromosome 15 containing a gene, Ube3a, which encodes a protein called ubiquitin protein ligase. The function of this protein is not known, but the gene has a different pattern of chemical modification in the paternal and maternal chromosomes, causing one gene copy to be silenced. In the hippocampus - a brain region important for formation of memory - the maternal copy is the one that is usually active. A deletion in the maternal copy of Ube3a therefore leads to a loss of Ube3a expression in this region. Mice with a maternally inherited Ube3a mutation show seizures and cognitive abnormalities similar to those seen in AS patients. These AS mice also show decreased activity of the protein CaMKII.
Ype Elgersma and colleagues crossed AS mice with mice expressing a CaMKII mutant that is unable to undergo a chemical modification called phosphorylation that is important for self-inhibition of the protein. This rescued all the main features of AS in these mice. The AS/CaMKII double mutants had fewer seizures than did AS mice, and also showed normal motor behavior. Cognitive deficits in AS mice, such as defects in spatial learning and fear conditioning, were also rescued by this CaMKII mutation, suggesting that abnormal CaMKII phosphorylation is entirely responsible for these defects.
Ype Elgersma, (Erasmus MC, Rotterdam, The Netherlands)
Abstract available online.
(C) Nature Neuroscience press release.
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