False deletion of the D15S986 maternal allele in a suspected case of Angelman syndrome

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.

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Angelman syndrome imprinting center encodes a transcriptional promoter

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1411261111 ◽

2014 ◽

Vol 112 (22) ◽

pp. 6871-6875 ◽

Cited By ~ 27

Author(s):

Michael W. Lewis ◽

Jason O. Brant ◽

Joseph M. Kramer ◽

James I. Moss ◽

Thomas P. Yang ◽

...

Keyword(s):

Dna Sequences ◽

Angelman Syndrome ◽

Paternal Allele ◽

Specific Gene ◽

Prader Willi Syndrome ◽

Maternal Allele ◽

Expression Of Genes ◽

Imprinting Center ◽

Maternal Contribution ◽

Parent Of Origin

Clusters of imprinted genes are often controlled by an imprinting center that is necessary for allele-specific gene expression and to reprogram parent-of-origin information between generations. An imprinted domain at 15q11–q13 is responsible for both Angelman syndrome (AS) and Prader–Willi syndrome (PWS), two clinically distinct neurodevelopmental disorders. Angelman syndrome arises from the lack of maternal contribution from the locus, whereas Prader–Willi syndrome results from the absence of paternally expressed genes. In some rare cases of PWS and AS, small deletions may lead to incorrect parent-of-origin allele identity. DNA sequences common to these deletions define a bipartite imprinting center for the AS–PWS locus. The PWS–smallest region of deletion overlap (SRO) element of the imprinting center activates expression of genes from the paternal allele. The AS–SRO element generates maternal allele identity by epigenetically inactivating the PWS–SRO in oocytes so that paternal genes are silenced on the future maternal allele. Here we have investigated functional activities of the AS–SRO, the element necessary for maternal allele identity. We find that, in humans, the AS–SRO is an oocyte-specific promoter that generates transcripts that transit the PWS–SRO. Similar upstream promoters were detected in bovine oocytes. This result is consistent with a model in which imprinting centers become DNA methylated and acquire maternal allele identity in oocytes in response to transiting transcription.

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Molecular Analysis of an Extra inv dup(15)(q13) Chromosome in Two Patients with Angelman Syndrome

Acta geneticae medicae et gemellologiae twin research ◽

10.1017/s0001566000001331 ◽

1996 ◽

Vol 45 (1-2) ◽

pp. 217-220 ◽

Cited By ~ 2

Author(s):

T. Buchholz ◽

S. Schuffenhauer ◽

K. Evans ◽

L. Robson ◽

B. Appleton ◽

...

Keyword(s):

Molecular Analysis ◽

Angelman Syndrome ◽

Uniparental Disomy ◽

Molecular Data ◽

Monoallelic Expression ◽

Chromosome 15 ◽

Prader Willi Syndrome ◽

Loss Of Function ◽

Maternal Allele ◽

Molecular Defects

Angelman syndrome (AS) is caused by the loss of function of yet unidentified gene(s) which map within 15q 11-13 and show monoallelic expression from the maternal allele. Lack of the maternal allele(s), due to either a deletion on the maternal chromosome 15 (about 70% of AS patients) or a paternal uniparental disomy (UPD)15 (<5%), are the most common molecular defects in AS. Prader-Willi syndrome (PWS) also maps to proximal 15q, but is caused by the loss of function of paternally expressed gen(s) [1]. Here we describe clinical, cytogenetic and molecular data for two non-related patients with AS who carry a nonmosaic extra cromosome inv dup(15).

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Angelman Syndrome: Identification and Management

Neonatal Network The Journal of Neonatal Nursing ◽

10.1891/0730-0832.36.3.142 ◽

2017 ◽

Vol 36 (3) ◽

pp. 142-151 ◽

Cited By ~ 2

Author(s):

Daniela Bonello ◽

Francesca Camilleri ◽

Jean Calleja-Agius

Keyword(s):

Ubiquitin Ligase ◽

Angelman Syndrome ◽

Chromosomal Region ◽

Motor Pattern ◽

E3 Ubiquitin Ligase ◽

Genetic Mutations ◽

Maternal Allele ◽

Ube3a Gene ◽

Severe Clinical Picture ◽

Genetically Determined

AbstractAngelman syndrome (AS) is a neurobehavioral and genetically determined condition, which affects approximately 1 in 15,000 individuals. It is caused by various genetic mutations and deletions of the maternally-inherited UBE3A gene, on the 15q11-13 chromosomal region. The UBE3A gene, which encodes E3 ubiquitin ligase, shows tissue-specific imprinting, being expressed entirely from the maternal allele.The diagnosis of AS is confirmed either by methylation test or by mutation analysis. A more severe clinical picture is linked with the deletion phenotype.Patients with AS have a behavioral and motor pattern defined as “happy puppet” because it is characterized by puppet-like ataxic jerky movements; a happy, sociable disposition; and paroxysms of laughter.There is currently no cure for AS, and management is mainly symptomatic. Novel therapeutic options are directed toward the possibility of activating the silenced paternal copy of the UBE3A gene.

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AAC Considerations for Individuals With Angelman Syndrome

Perspectives on Augmentative and Alternative Communication ◽

10.1044/aac24.3.106 ◽

2015 ◽

Vol 24 (3) ◽

pp. 106-113 ◽

Cited By ~ 1

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.

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