Angelman Syndrome

The use of traditional (i.e., non-inducible) knockout mouse models to try to study the signal transduction events involved in synaptic plasticity and memory has been widely and legitimately criticized because of the great confound of secondary effects of loss of the gene. In particular, developmental derangements can contribute to any observed phenotype, and there is a real concern that the effect of loss of the gene product is not an indication of the protein having any necessary role in an acute, learning-related signal transduction event. Need for caution in interpreting these types of experiments is highlighted by the numerous demonstrations that these types of developmental and secondary effects do occur in knockout animals.

However, this weakness in the context of one type of experiment is a strength of knockout models in another context. In making a model of a human inherited (i.e., genetic) disorder such as a mental retardation syndrome, one wishes to have the defect present from the point of conception, as is typically the case for the analogous human. The generation of secondary molecular and developmental effects is desirable in that they model the same secondary effects that are likely to occur in the human. Thus, a strength of the knockout approach in mouse models of human mental retardation is that, by characterizing the knockout mice, one can gain insights into the entire range of molecular and anatomical effects that contribute to the human learning disorder.

In this section, we will be discussing a mouse model for human Angelman Mental Retardation Syndrome. Current thinking in the area is that the Angelman gene product is not itself directly involved in signaling events necessary for learning and memory (although it is too early to really rule this out!), but that secondary changes in targets of the gene product lead to disruption of signaling events necessary for memory. Tracking down these secondary changes has been an interesting "detective story" that Ed Weeber in my laboratory has been pursuing in collaboration with Yong-hui Jiang and Art Beaudet in the Genetics Department here at Baylor College of Medicine. While we are only part of the way there, our recent results suggest that one culprit in Angelman Syndrome is dysregulation of CaMKII.

Angelman Syndrome is a fairly rare (~1/15,000) but severe human learning and behavioral disorder characterized by four principal features: (1) developmental delay and pronounced mental retardation: (2) near or total absence of the capacity for language and speech; (3) motor dysfunction; (4) an abnormally cheerful disposition, propensity for laughter, and cheerful affect. In addition, a history of seizures often presents. The principal features of Angelman Syndrome led to the unfortunate use of the description "Happy Puppet Syndrome" for these patients at one point in time.

As with most mental retardation syndromes the underlying genetic etiology is mixed, in large part due to heterogeneity of deletion mutations that can lead to the disorder. Despite this complexity, recent efforts have identified the gene for Angelman Syndrome as UBE3A, which codes for the E6-AP ubiquitin ligase. E6-AP is an E3 ubiquitin ligase, which covalently attaches

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