Arthur L. Beaudet, M.D.

Molecular & Human Genetics

Molecular genetics of Angelman syndrome in the mouse and human

After a long positional cloning effort, Dr. Beaudet's laboratory identified the locus encoding E6-AP ubiquitin-protein ligase as the mutated gene in Angelman syndrome. Extensive mutation studies were performed. This gene was shown to be subject to genomic imprinting in the mouse with silencing of the paternal allele in Purkinje cells and hippocampal neurons. A null mutation for the Angelman gene was introduced into the mouse germline. Mice inheriting the mutation on the maternal chromosome provide a model of Angelman syndrome with motor dysfunction, inducible seizures, a contextual-dependent learning deficit, impaired hippocampal long-term potentiation, and increased cytoplasmic abundance of the p53 oncoprotein.

Dr. Beaudet’s nomination was based on the following publications:

Matsuura T, Sutcliffe JS, Fang P, Galjaard RJ, Jiang YH, Benton CS, Rommens JM, Beaudet AL." De novo truncating mutations in E6-AP ubiquitin-protein ligase gene (UBE3A) in Angelman syndrome.". Nat Genet. 1997 Jan;15(1):74-7.

Albrecht U, Sutcliffe JS, Cattanach BM, Beechey CV, Armstrong D, Eichele G, Beaudet AL. " Imprinted expression of the murine Angelman syndrome gene, Ube3a, in hippocampal and Purkinje neurons.". Nat Genet. 1997 Sep;17(1):75-8.

Jiang YH, Armstrong D, Albrecht U, Atkins CM, Noebels JL, Eichele G, Sweatt JD, Beaudet AL. " Mutation of the Angelman ubiquitin ligase in mice causes increased cytoplasmic p53 and deficits of contextual learning and long-term potentiation. ". Neuron. 1998 Oct;21(4):799-811.