Review
Angelman syndrome: insights into genomic imprinting and neurodevelopmental phenotypes

https://doi.org/10.1016/j.tins.2011.04.001Get rights and content

Angelman syndrome (AS) is a severe genetic disorder caused by mutations or deletions of the maternally inherited UBE3A gene. UBE3A encodes an E3 ubiquitin ligase that is expressed biallelically in most tissues but is maternally expressed in almost all neurons. In this review, we describe recent advances in understanding the expression and function of UBE3A in the brain and the etiology of AS. We highlight current AS model systems, epigenetic mechanisms of UBE3A regulation, and the identification of potential UBE3A substrates in the brain. In the process, we identify major gaps in our knowledge that, if bridged, could move us closer to identifying treatments for this debilitating neurodevelopmental disorder.

Section snippets

Introduction to Angelman syndrome

Angelman Syndrome (AS) was originally described by Harry Angelman in 1965 and occurs in approximately one out of every 12,000 births 1, 2. Patients with AS exhibit developmental delay, speech impairments, intellectual disability, epilepsy, abnormal EEGs (electroencephalograms), puppet-like ataxic movements, prognathism, tongue protrusion, paroxysms of laughter, abnormal sleep patterns, and hyperactivity [3]. Moreover, patients with AS often exhibit socialization and communication deficits that

Monitoring neuronal UBE3A imprinting

The genomic region spanning UBE3A, the UBE3A antisense transcript (UBE3A-ATS), and the spliceosomal protein SNRPN (small nuclear ribonucleoprotein polypeptide N) [27] contains a large number of imprinted genes that are either paternally or maternally expressed in the human brain [27]. Mice possess a chromosomal region that is syntenic to human 15q11-q13 in which orthologous genes, including Ube3a, are also imprinted 28, 29, 30. UBE3A is expressed from the maternal allele in most neurons, while

AS mouse models recapitulate many AS patient phenotypes

To date, three AS mouse models have been engineered with targeted mutations that mimic de novo chromosomal abnormalities underlying AS (Table 1). Because brain-specific paternal imprinting of Ube3a also occurs in mice, all three models are based on the maternal inheritance of a chromosomal deletion that includes Ube3a. Importantly, these models recapitulate the loss of UBE3A in neurons in the central nervous system (CNS) 45, 46, 47 and display several AS-relevant phenotypes 48, 49, 50.

Changes in neuronal morphology in AS mouse models

To help understand the profound neurological deficits underlying AS, researchers have explored neuroanatomical correlates of abnormal connectivity and synaptic development in Ube3am−/p+ mice. These studies have almost exclusively focused on measuring dendritic spines at the single-cell level owing to the fact that in vivo, UBE3A is localized to postsynaptic compartments in addition to the nucleus [44]. Dendritic spine density (∼15-20%) and length (∼10-15%) are reduced in post-adolescent Ube3a

Changes in synaptic plasticity in AS mouse models

Early investigations of altered synaptic plasticity in Ube3am−/p+ mice were inspired by findings of impaired contextual fear conditioning, which led to studies of whether long-term potentiation (LTP) of Schaffer collateral synapses in the CA1 hippocampal region was impaired. Standard high-frequency stimulation protocols evoke only a transient potentiation of these synapses in hippocampal slices from Ube3am−/p+ mice [48]. However, sustained LTP, similar to what was observed typically in

Identification of brain substrates for UBE3A

UBE3A is a HECT E3 ubiquitin ligase that ubiquitinates protein substrates, leading to their degradation by the ubiquitin proteasome system (UPS) 74, 75. Multiple mutations in UBE3A have been attributed to defective UBE3A stability or catalytic function 23, 76. The ubiquitination and degradation of p53, the first identified substrate of UBE3A 77, 78, require not only UBE3A, but a viral cofactor E6, hence the initial naming of UBE3A as an E6-associated protein (E6-AP) 77, 78, 79, 80. Notably, E6

Conclusions and future directions

Although research is beginning to unveil the connections between UBE3A function and AS, there are still fundamental questions that remain to be answered (Box 1). For instance, does the UBE3A antisense mechanism fully account for why UBE3A is epigenetically silenced in the brain but not other tissues? If yes, can expression of the functionally intact, but epigenetically silenced, paternal UBE3A allele be upregulated by pharmacological means or by genetically manipulating UBE3A-ATS transcription?

Acknowledgements

We would like to thank Kathryn Condon, Yong-hui Jiang, Ian King, Anne West, and Jason Yi for critical reading of the manuscript. B.D.P. is supported by the Angelman Syndrome Foundation and the National Eye Institute (R01EY018323), and B.D.P. and M.J.Z. are supported by the Simons Foundation. Work in M.J.Z.’s laboratory is supported by the National Institute of Neurological Disorders and Stroke (NINDS) (R01NS060725, R01NS067688). A.M.M. is supported by a Ruth L. Kirschtein National Research

Glossary

Allele
One of two or more forms of a given DNA sequence of a gene.
Genomic Imprinting
A genetic process whereby genes are differentially expressed depending on their parent-of-origin inheritance.
Context-dependent fear conditioning
A behavioral paradigm where animals learn to fear a neutral stimulus when paired with a noxious or painful stimulus. Brain regions involved include the amygdala and, when cued by spatial context, the hippocampus.
Epigenetic
Heritable and reversible modifications to

References (104)

  • S. Saitoh et al.

    Parent-of-origin specific histone acetylation and reactivation of a key imprinted gene locus in Prader-Willi syndrome

    Am. J. Hum. Genet.

    (2000)
  • R.M. Gustin

    Tissue-specific variation of Ube3a protein expression in rodents and in a mouse model of Angelman syndrome

    Neurobiol. Dis.

    (2010)
  • Y.H. Jiang

    Mutation of the Angelman ubiquitin ligase in mice causes increased cytoplasmic p53 and deficits of contextual learning and long-term potentiation

    Neuron

    (1998)
  • K. Miura

    Neurobehavioral and electroencephalographic abnormalities in Ube3a maternal-deficient mice

    Neurobiol. Dis.

    (2002)
  • S.A. Mulherkar et al.

    Loss of dopaminergic neurons and resulting behavioural deficits in mouse model of Angelman syndrome

    Neurobiol. Dis.

    (2010)
  • G. Cheron

    Fast cerebellar oscillation associated with ataxia in a mouse model of Angelman syndrome

    Neuroscience

    (2005)
  • S. Arber

    ETS gene Er81 controls the formation of functional connections between group Ia sensory afferents and motor neurons

    Cell

    (2000)
  • D. Colas

    Sleep disturbances in Ube3a maternal-deficient mice modeling Angelman syndrome

    Neurobiol. Dis.

    (2005)
  • O. Bruni

    Sleep disturbances in Angelman syndrome: a questionnaire study

    Brain Dev.

    (2004)
  • S. Miano

    Sleep polygraphy in Angelman syndrome

    Clin. Neurophysiol.

    (2004)
  • P.L. Greer

    The Angelman Syndrome protein Ube3A regulates synapse development by ubiquitinating arc

    Cell

    (2010)
  • S.S. Margolis

    EphB-mediated degradation of the RhoA GEF Ephexin5 relieves a developmental brake on excitatory synapse formation

    Cell

    (2010)
  • E.M. Cooper

    Biochemical analysis of Angelman syndrome-associated mutations in the E3 ubiquitin ligase E6-associated protein

    J. Biol. Chem.

    (2004)
  • M. Scheffner

    The HPV-16 E6 and E6-AP complex functions as a ubiquitin-protein ligase in the ubiquitination of p53

    Cell

    (1993)
  • A. Mishra

    E6-AP promotes misfolded polyglutamine proteins for proteasomal degradation and suppresses polyglutamine protein aggregation and toxicity

    J. Biol. Chem.

    (2008)
  • S. Kumar

    Identification of HHR23A as a substrate for E6-associated protein-mediated ubiquitination

    J. Biol. Chem.

    (1999)
  • A. Mishra

    UBE3A/E6-AP regulates cell proliferation by promoting proteasomal degradation of p27

    Neurobiol. Dis.

    (2009)
  • G.L. Lyford

    Arc, a growth factor and activity-regulated gene, encodes a novel cytoskeleton-associated protein that is enriched in neuronal dendrites

    Neuron

    (1995)
  • S. Chowdhury

    Arc/Arg3.1 interacts with the endocytic machinery to regulate AMPA receptor trafficking

    Neuron

    (2006)
  • M.W. Waung

    Rapid translation of Arc/Arg3.1 selectively mediates mGluR-dependent LTD through persistent increases in AMPAR endocytosis rate

    Neuron

    (2008)
  • O. Steward

    Synaptic activation causes the mRNA for the IEG Arc to localize selectively near activated postsynaptic sites on dendrites

    Neuron

    (1998)
  • N. Plath

    Arc/Arg3.1 is essential for the consolidation of synaptic plasticity and memories

    Neuron

    (2006)
  • J.D. Shepherd

    Arc/Arg3.1 mediates homeostatic synaptic scaling of AMPA receptors

    Neuron

    (2006)
  • Y. Yamamoto

    The human E6-AP gene (UBE3A) encodes three potential protein isoforms generated by differential splicing

    Genomics

    (1997)
  • T.C. Scanlon

    Isolation of human proteasomes and putative proteasome-interacting proteins using a novel affinity chromatography method

    Exp. Cell Res.

    (2009)
  • X. Wang et al.

    Identifying dynamic interactors of protein complexes by quantitative mass spectrometry

    Mol. Cell. Proteomics

    (2008)
  • B.D. Bower et al.

    The “happy puppet” syndrome

    Arch. Dis. Child.

    (1967)
  • C.A. Williams

    Angelman syndrome 2005: updated consensus for diagnostic criteria

    Am. J. Med. Genet. A

    (2006)
  • S.U. Peters

    Autism in Angelman syndrome: implications for autism research

    Clin. Genet.

    (2004)
  • Trillingsgaard, A. and Ostergaard, J.R., (2004). Autism in Angelman syndrome: an exploration of comorbidity. Autism 8:...
  • T. Kishino

    UBE3A/E6-AP mutations cause Angelman syndrome

    Nat. Genet.

    (1997)
  • J.S. Sutcliffe

    The E6-AP ubiquitin-protein ligase (UBE3A) gene is localized within a narrowed Angelman syndrome critical region

    Genome Res.

    (1997)
  • T. Matsuura

    De novo truncating mutations in E6-AP ubiquitin-protein ligase gene (UBE3A) in Angelman syndrome

    Nat. Genet.

    (1997)
  • M. Landers

    Regulation of the large (approximately 1000 kb) imprinted murine Ube3a antisense transcript by alternative exons upstream of Snurf/Snrpn

    Nucleic Acids Res.

    (2004)
  • C. Rougeulle

    An imprinted antisense RNA overlaps UBE3A and a second maternally expressed transcript

    Nat. Genet.

    (1998)
  • M. Runte

    The IC-SNURF-SNRPN transcript serves as a host for multiple small nucleolar RNA species and as an antisense RNA for UBE3A

    Hum. Mol. Genet.

    (2001)
  • M. Runte

    SNURF-SNRPN and UBE3A transcript levels in patients with Angelman syndrome

    Hum. Genet.

    (2004)
  • K. Yamasaki

    Neurons but not glial cells show reciprocal imprinting of sense and antisense transcripts of Ube3a

    Hum. Mol. Genet.

    (2003)
  • U. Albrecht

    Imprinted expression of the murine Angelman syndrome gene, Ube3a, in hippocampal and Purkinje neurons

    Nat. Genet.

    (1997)
  • A.C. Lossie

    Distinct phenotypes distinguish the molecular classes of Angelman syndrome

    J. Med. Genet.

    (2001)
  • Cited by (203)

    • Neurogenetic motor disorders

      2023, Handbook of Clinical Neurology
    • CRISPR technology and its potential role in treating rare imprinting diseases

      2023, Principles of Gender-Specific Medicine: Sex and Gender-Specific Biology in the Postgenomic Era
    View all citing articles on Scopus
    *

    These authors contributed equally to this work.

    View full text