Testing for Correction of the Angelman Syndrome Phenotype of UBE3A-Maternal-Deficient Mice by UBE3A Transgene

Dr. Joseph Wagstaff – Carolinas Medical Center

This project was continued funding for an important AS investigator to enable his laboratory to work on studies of UBE3A in the mouse model in the hope of developing novel therapeutic initiatives. The experimental approach in this grant was to use genetic engineering so as to insert the human UBE3A into embryonic mouse cells (e.g., create a transgene) and then, ultimately, to attempt therapeutic expression of UBE3A to correct some of the features exhibited by the Angelman mice. Theoretically, this approach would represent a correction of the abnormalities in the mouse model. This research subsequently showed how difficult it was to control and enable transgene expression of UBE3A.

Control of monoallelic expression of the Angelman gene UBE3A

Aaron Razin – The Hebrew University, Hadassah Medical, Haifa, Israel

The gene disrupted in AS, UBE3A, is unique because its action is controlled by a remote DNA region that is called the imprinting center(IC). In the normal brain, this IC turns off the UBE3A that the father contributed (on chromosome 15) but turns on UBE3A on the number 15 chromosome contributed by the mother. Individuals with AS are thus missing the function of the maternally derived UBE3A. ASF funded this investigator to learn more about how the IC turns UBE3A on and off. This was an effort by ASF to promote molecular research on the IC and complement ASF’s promotion of human clinical trials to provide dietary supplements in hope of modulating the action of the imprinting center. Many publications arose from this work and more evidence supports the fact that the paternal IC is not methylated while the maternal IC is methylated.

Dissecting the roles of Ube3a in synaptic plasticity by analyzing synaptic function at the single cell level and utilizing ‘Network Analysis Proteomics’ strategy

Yong-Hui Jiang – Baylor College of Medicine

This grant-funded research was to a premier AS researcher who was instrumental in developing a mouse model for AS and who demonstrated that an important enzyme associated with the synapse, CAMKII, was inhibited or partially inactivated in Angelman mice. Subsequent experiments by others were able to release this CAMKII inhibition and provided an impressive correction of the features of AS thereby opening the door to the possibility of new therapeutic strategies to treat some of the symptoms of AS. Additional work from this grant showed that the physical structure of the synapse was generally intact and also began to identify additional proteins that interact with UBE3A.

Evaluating the effectiveness of ABA-based approaches for teaching functional skills to children with AS

Jane Summers – McMaster Children’s Hospital, Ontario, Canada

For educational planning, it is important to know that children with AS can be effective learners and to understand how this learning occurs under simple paradigms of behavioral modification and analysis. Jane Summers’ work has been instrumental in documenting the learning abilities of those with AS and in illustrating to other educators and therapists how applied behavioral analysis (ABA) can improve learning and change behaviors in AS.