scholarly journals CRISPR/Cas9 directed to the Ube3a antisense transcript improves Angelman syndrome phenotype in mice

2021 ◽  
Author(s):  
Ralf S. Schmid ◽  
Xuefeng Deng ◽  
Priyalakshmi Panikker ◽  
Msema Msackyi ◽  
Camilo Breton ◽  
...  
Keyword(s):  
Angelman Syndrome ◽  
Antisense Transcript ◽  
Ube3a Antisense

scholarly journals BIOLOGICAL SCIENCES: Genetics

2018 ◽  
Author(s):  
Jack S. Hsiao ◽  
Noelle D. Germain ◽  
Andrea Wilderman ◽  
Christopher Stoddard ◽  
Luke A. Wojenski ◽  
...  
Keyword(s):  
Boundary Element ◽  
Angelman Syndrome ◽  
Antisense Transcript ◽  
Neurodevelopmental Disorder ◽  
Boundary Function ◽  
Paternal Allele ◽  
Loss Of Function ◽  
Maternal Allele ◽  
Specific Expression ◽  
Human Neurons

ABSTRACTAngelman syndrome (AS) is a severe neurodevelopmental disorder caused by the loss of function from the maternal allele of UBE3A, a gene encoding an E3 ubiquitin ligase. UBE3A is only expressed from the maternally-inherited allele in mature human neurons due to tissue-specific genomic imprinting. Imprinted expression of UBE3A is restricted to neurons by expression of UBE3A antisense transcript (UBE3A-ATS) from the paternally-inherited allele, which silences the paternal allele of UBE3A in cis. However, the mechanism restricting UBE3A-ATS expression and UBE3A imprinting to neurons is not understood. We used CRISPR/Cas9-mediated genome editing to functionally define a bipartite boundary element critical for neuron-specific expression of UBE3A-ATS in humans. Removal of this element led to upregulation of UBE3A-ATS without repressing paternal UBE3A. However, increasing expression of UBE3A-ATS in the absence of the boundary element resulted in full repression of paternal UBE3A, demonstrating that UBE3A imprinting requires both the loss of function from the boundary element as well as upregulation of UBE3A-ATS. These results suggest that manipulation of the competition between UBE3A-ATS and UBE3A may provide a potential therapeutic approach for AS.SIGNIFICANCE STATEMENTAngelman syndrome is a neurodevelopmental disorder caused by loss of function from the maternal allele of UBE3A, an imprinted gene. The paternal allele of UBE3A is silenced by a long, non-coding antisense transcript in mature neurons. We have identified a boundary element that stops the transcription of the antisense transcript in human pluripotent stem cells, and thus restricts UBE3A imprinted expression to neurons. We further determined that UBE3A imprinting requires both the loss of the boundary function and sufficient expression of the antisense transcript to silence paternal UBE3A. These findings provide essential details about the mechanisms of UBE3A imprinting that may suggest additional therapeutic approaches for Angelman syndrome.

scholarly journals A bipartite boundary element restrictsUBE3Aimprinting to mature neurons

2019 ◽  
Vol 116 (6) ◽  
pp. 2181-2186 ◽  
Author(s):  
Jack S. Hsiao ◽  
Noelle D. Germain ◽  
Andrea Wilderman ◽  
Christopher Stoddard ◽  
Luke A. Wojenski ◽  
...  
Keyword(s):  
Boundary Element ◽  
Antisense Transcript ◽  
Neurodevelopmental Disorder ◽  
Paternal Allele ◽  
Loss Of Function ◽  
Gene Encoding ◽  
Specific Expression ◽  
Human Neurons ◽  
Mature Neurons ◽  
Ube3a Antisense

Angelman syndrome (AS) is a severe neurodevelopmental disorder caused by the loss of function from the maternal allele ofUBE3A, a gene encoding an E3 ubiquitin ligase.UBE3Ais only expressed from the maternally inherited allele in mature human neurons due to tissue-specific genomic imprinting. Imprinted expression ofUBE3Ais restricted to neurons by expression ofUBE3A antisense transcript(UBE3A-ATS) from the paternally inherited allele, which silences the paternal allele ofUBE3Aincis. However, the mechanism restrictingUBE3A-ATSexpression andUBE3Aimprinting to neurons is not understood. We used CRISPR/Cas9-mediated genome editing to functionally define a bipartite boundary element critical for neuron-specific expression ofUBE3A-ATSin humans. Removal of this element led to up-regulation ofUBE3A-ATSwithout repressing paternalUBE3A. However, increasing expression ofUBE3A-ATSin the absence of the boundary element resulted in full repression of paternalUBE3A, demonstrating thatUBE3Aimprinting requires both the loss of function from the boundary element as well as the up-regulation ofUBE3A-ATS. These results suggest that manipulation of the competition betweenUBE3A-ATSandUBE3Amay provide a potential therapeutic approach for AS.

scholarly journals A placebo-controlled trial of folic acid and betaine in identical twins with Angelman syndrome

2019 ◽  
Vol 14 (1) ◽  
Author(s):  
Julia Han ◽  
Terry Jo Bichell ◽  
Stephanie Golden ◽  
Irina Anselm ◽  
Susan Waisbren ◽  
...  
Keyword(s):  
Folic Acid ◽  
Angelman Syndrome ◽  
Antisense Transcript ◽  
Controlled Trial ◽  
Neurodevelopmental Disorder ◽  
Uniparental Disomy ◽  
Identical Twins ◽  
Clinical Phenotypes ◽  
Severe Intellectual Disability ◽  
The Brain

Abstract Background Angelman syndrome (AS) is a neurodevelopmental disorder that is caused by maternal genetic deficiency of a gene that encodes E6-AP ubiquitin-protein ligase (gene symbol UBE3A) mapping to chromosome 15q11-q13. AS leads to stiff and jerky gait, excess laughter, seizures, and severe intellectual disability. In some parts of the brain, the paternally inherited UBE3A gene is subject to genomic imprinting by the action of the UBE3A-antisense transcript (UBE3A-ATS) on the paternally inherited allele. Consequently, only the maternally inherited UBE3A gene is expressed in mature neurons. AS occurs due to deletions of the maternal 15q11 − 13 region, paternal uniparental disomy (UPD), imprinting center defects, mutations in the maternal UBE3A gene, or other unknown genetic malfunctions that result in a silenced maternal UBE3A gene in the specific imprinted regions of the brain. Results A potential treatment strategy for AS is to increase methylation of UBE3A-ATS to promote expression of the paternal UBE3A gene and thus ameliorate the clinical phenotypes of AS. We treated two sets of male identical twins with class I deletions with a 1 year treatment trial of either betaine and folic acid versus placebo. We found no statistically significant changes in the clinical parameters tested at the end of the 1 year trial, nor did we find any significant adverse events. Conclusions This study tested the hypothesis that by increasing the methylation of the UBE3A-antisense transcript in Angelman syndrome to promote expression of the silenced paternal UBE3A gene we may ameliorate the clinical phenotypes of AS. We treated two sets of identical twins with placebo versus betaine and folic acid. Although this study represented a novel approach to treating Angelman syndrome, the differences in the developmental testing results was not significant. This paper also discusses the value of monozygotic twin studies in minimizing confounding variables and its utility in conducting small treatment studies. Trial registration NCT00348933. Registered 6 July 2006.

AAC Considerations for Individuals With Angelman Syndrome

2015 ◽  
Vol 24 (3) ◽  
pp. 106-113 ◽  
Author(s):  
Stephen N. Calculator
Keyword(s):  
Angelman Syndrome ◽  
Augmentative And Alternative Communication ◽  
High Tech ◽  
Alternative Communication ◽  
Design And Implementation

Purpose To provide an overview of communication characteristics exhibited by individuals with Angelman Syndrome (AS) and special considerations associated with the design and implementation of augmentative and alternative communication (AAC) programs. Method Results of recent studies exploring individuals' uses of AAC are reviewed, with particular emphasis on factors related to individuals' acceptance and successful uses of AAC systems. Results Not applicable Conclusion Despite their inconsistent access to practices previously found to foster individuals' acceptance of AAC systems, individuals with AS demonstrate the ability to use AAC systems, including high-tech AAC devices, successfully.

Behavioral Intervention to Reduce Sleep Problems in Children With Angelman Syndrome

2013 ◽  
Author(s):  
Keith D. Allen ◽  
Brett R. Kuhn ◽  
Kristi Dehaai ◽  
Dustin P. Wallace
Keyword(s):  
Behavioral Intervention ◽  
Angelman Syndrome ◽  
Sleep Problems
Sign in / Sign up

Export Citation Format

Share Document