Abstract
Angelman syndrome (AS) is a severe neurodevelopmental disorder caused by maternal deficiency of the imprinted gene UBE3A. Individuals with AS suffer from intellectual disability, speech impairment, and motor dysfunction. Currently there is no cure for the disease. Here, we evaluated the phenotypic effect of activating the silenced paternal allele of Ube3a by depleting its antisense RNA Ube3a-ATS in mice. Premature termination of Ube3a-ATS by poly(A) cassette insertion activates expression of Ube3a from the paternal chromosome, and ameliorates many disease-related symptoms in the AS mouse model, including motor coordination defects, cognitive deficit, and impaired long-term potentiation. Studies on the imprinting mechanism of Ube3a revealed a pattern of biallelic transcription initiation with suppressed elongation of paternal Ube3a, implicating transcriptional collision between sense and antisense polymerases. These studies demonstrate the feasibility and utility of unsilencing the paternal copy of Ube3a via targeting Ube3a-ATS as a treatment for Angelman syndrome.
Highlights
Angelman syndrome (AS) is clinically manifested by features of intellectual and developmental disability, absence of speech, ataxic movement, epilepsy, and unique behaviors such as frequent laughter and fascination with water [1,2]
It is characterized by absence of speech, ataxia, intellectual disability, epilepsy, and a characteristic behavior of frequent laughter and smiling
The disease is caused by loss of the maternal allele of UBE3A, which is preferentially silenced on the paternal chromosome and expressed on the maternal chromosome in neurons due to genomic imprinting
Summary
Angelman syndrome (AS) is clinically manifested by features of intellectual and developmental disability, absence of speech, ataxic movement, epilepsy, and unique behaviors such as frequent laughter and fascination with water [1,2]. The disease is caused by deficiency of an E3 ubiquitin ligase termed UBE3A, which participates in many important neuronal functions such as synaptic development, signal transduction, and plasticity [3]. The gene encoding UBE3A is among a handful of human genes that are subject to genomic imprinting. In neuronal cells, it is highly expressed from the maternal allele, but silenced on the paternal allele. Disruption of the maternal allele, through genomic deletion, paternal uniparental disomy, imprinting defects, or point mutations, leads to the absence of UBE3A expression in neuronal tissues and Angelman syndrome. One could speculate that by correcting the expression level of UBE3A via activating the silenced paternal allele, the disease might be treated
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