Angelman Syndrome (AS) is a genetic disorder that is characterized by movement disorders, seizures and mental retardation. Although relatively rare (affecting 1 in 15,000 people), this disorder is currently untreatable. On page 280, van Woerden and colleagues report that aberrant phosphorylation of calcium/calmodulin-dependent kinase type 2 (CaMKII) is the main molecular dysfunction underlying the neurological phenotype of AS.

AS is caused by the loss of normal maternal contribution to a region of chromosome 15. This region contains a gene, UBE3A, encoding a ubiquitin protein ligase. Although the function of this protein is not known, the gene has different patterns of methylation in the paternal and maternal chromosomes. One of these gene copies is silenced; in the hippocampus and cerebellum, the maternal allele is the one that is usually active. A deletion in the maternal allele of UBE3A therefore leads to a loss of UBE3A expression in these regions. Mice with a maternally inherited UBE3A mutation show seizures and cognitive abnormalities similar to those seen in humans with AS.

These AS mice also show decreased activity of CaMKII, known to be important for neuronal function. Van Woerden and colleagues now report that if they cross AS mice with an CaMKII mutant that is unable to undergo phosphorylation at the Thr305/306 site (which prevents self-inhibition of CaMKII), they can rescue all the main features of AS in these mice. The AS/CaMKII double mutants show a reduction of seizure propensity compared to AS mice and also show normal motor behavior. Whereas the AS mice have increased body weight, the double mutants have normal weight. Moreover, the deficits in long-term potentiation seen in the AS mice are ameliorated in the AS/CaMKII mutants. Cognitive deficits associated with AS mice, such as defects in spatial learning and fear conditioning, are also rescued by introducing this CaMKII mutation. These findings show conclusively that increased inhibitory phosphorylation of CaMKII is responsible for many of the neurological deficits observed in AS.