Angelman syndrome (AS) is a genetic disorder characterized by developmental delay, absent speech, intellectual disability, severe epilepsy, ataxia, and abnormal sleep. AS is caused by mutations in or deletion of Ube3a, an E3 ubiquitin ligase that is expressed biallelically in most tissues but is monoallelically expressed in the brain. Maternal-specific expression of Ube3a in the brain is thought to be due to production of an antisense transcript that overruns the paternal copy of Ube3a in mice and humans. Mice with maternal-specific deletions of Ube3a model many of the neurodevelopmental symptoms associated with AS, including epilepsy, learning deficits, and motor abnormalities. Using a high-throughput, unbiased screen with neurons from a Ube3a- YFP knockin mouse, we identified several small molecules that unsilence the paternal Ube3a allele at nanomolar concentrations. We hypothesize that the physiological and behavioral dysfunctions associated with Angelman syndrome can be treated by unsilencing the paternal Ube3a allele in vivo with one of these drugs. In this proposal we will: (1) Test the hypothesis that our lead compound upregulates paternal Ube3a in vivo;(2) Test the hypothesis that our lead compound can rescue physiological and behavioral deficits in Angelman syndrome model mice;(3) Test the hypothesis that genetic knockdown/out of the molecular target of our lead compound unsilences paternal Ube3a;(4) Test the hypothesis that the expression of the Ube3a-sense and Ube3a-antisense transcript levels can be used as biomarkers of drug efficacy (i.e. Ube3a unsilencing). Our research could lead to the first pharmacological treatment for Angelman syndrome (an autism spectrum disorder), and indeed for any disorder caused by mutation of an imprinted gene.

Public Health Relevance

The health care costs associated with treating Angelman syndrome are high, especially considering that individuals with this disorder live a normal lifespan but are incapable of caring for themselves. Our proposed research could provide the first treatment for Angelman syndrome and reduce the economic and medical burden associated with this severe epigenetic disorder.

National Institute of Health (NIH)
National Institute of Mental Health (NIMH)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-MDCN-C (56))
Program Officer
Driscoll, Jamie
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of North Carolina Chapel Hill
Schools of Medicine
Chapel Hill
United States
Zip Code
Huang, Hsien-Sung; Yoon, Bong-June; Brooks, Sherian et al. (2014) Snx14 regulates neuronal excitability, promotes synaptic transmission, and is imprinted in the brain of mice. PLoS One 9:e98383
Mabb, Angela M; Kullmann, Paul H M; Twomey, Margaret A et al. (2014) Topoisomerase 1 inhibition reversibly impairs synaptic function. Proc Natl Acad Sci U S A 111:17290-5
Judson, Matthew C; Sosa-Pagan, Jason O; Del Cid, Wilmer A et al. (2014) Allelic specificity of Ube3a expression in the mouse brain during postnatal development. J Comp Neurol 522:1874-96
Huang, Hsien-Sung; Burns, Andrew J; Nonneman, Randal J et al. (2013) Behavioral deficits in an Angelman syndrome model: effects of genetic background and age. Behav Brain Res 243:79-90
King, Ian F; Yandava, Chandri N; Mabb, Angela M et al. (2013) Topoisomerases facilitate transcription of long genes linked to autism. Nature 501:58-62
Huang, Hsien-Sung; Allen, John A; Mabb, Angela M et al. (2012) Topoisomerase inhibitors unsilence the dormant allele of Ube3a in neurons. Nature 481:185-9