Angelman syndrome: insights into genomic imprinting and neurodevelopmental phenotypes

Abstract

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.

Figure 1

Possible mechanisms for UBE3A imprinting in the brain. a. A map of the maternal (MAT) and paternal (PAT) human chromosome region 15q11-q13 containing UBE3A, adapted from Lalande and Calciano [27]. Maternally expressed genes are depicted in red and paternally expressed genes are depicted in blue. Non-imprinted genes are represented in green. Top: Methylation at the maternal PWS imprinting center (PWS-IC, black circle) globally represses expression of surrounding genes (gray boxes), including the UBE3A antisense (UBE3A–ATS) transcript. However, the maternal copy of UBE3A is expressed (red arrow). Bottom: On the paternal chromosome, the PWS-IC contains a cluster of CpG sites that are unmethylated (open circle), permitting paternal gene expression (blue boxes), including the UBE3A–ATS transcript (blue arrow). The UBE3A–ATS (0.5–1.0 Mb in length) overlaps the paternal UBE3A locus, resulting in transcriptional silencing of UBE3A (red arrow fading to white). Open triangles represent the AS imprinting center (AS-IC). Neighboring genes upstream of UBE3A include: NDN (necdin) and genes encoding snoRNAs [SNRPN PAR5 (Prader-Willi Angelman Syndrome region 5), HBII-85₂₇ HBII-52₄₇ and IPW (Imprinted in Prader-Willi syndrome)]. Neighboring genes downstream of UBE3A include: ATP10A, the GABA_A receptor β3, α5 and γ2 subunits (GABRB3, GABRA5, GABRG3), OCA2 (Oculocutaneous albinism II) and HERC2 (Hect domain and RDL 2). b. Zoomed in region from a depicting a cutoff (dashed vertical blue line) beyond which the silencing of UBE3A transcription by the UBE3A–ATS is incomplete [33]. Left of the line, the UBE3A–ATS transcript (dark blue shading) competes with the sense transcript (light red shading), resulting in silencing of full-length UBE3A sense transcripts. In contrast, to the right of the line, truncated paternal 5’ segments of the UBE3A sense transcripts (red) are produced [33]. c. Hypothetical mechanisms of UBE3A–ATS/sense competition at the paternal allele. Top: Collision model [42]. If transcription can only occur in one direction at a single time, RNA polymerases (RNAPII) transcribing the UBE3A sense strand (red) are competed off of their templates by oncoming complexes engaged in transcription of the UBE3A–ATS strand (blue). Bottom: RNA-DNA interaction model [42]. Production of the UBE3A–ATS induces histone modifications (HM) that modify chromatin architecture along the UBE3A locus. Transcriptional elongation of UBE3A is prematurely aborted at these regions, yielding truncated UBE3A sense transcripts (red). Note that similar models of RNA regulation have been described for genomic imprinting at other loci, such as Xist, a non-coding RNA (ncRNA) that contributes to X chromosome inactivation and Air, a paternally expressed ncRNA that leads to silencing of paternal insulin-like growth factor 2 receptor (Igf2r) [100].

Figure 2

Schematic model illustrating the potential contribution of UBE3A to neuronal morphology and developing neural circuits. a. During synaptogenesis, UBE3A ubiquitinates and promotes the degradation of the RhoA-GEF Ephexin-5 by the UPS [67] leading to inactivation of RhoA and facilitates formation of dendritic spines (highlighted in blue). UBE3A also ubiquitinates and promotes the degradation of Arc [66], an immediate early gene that facilitates the experience-dependent remodeling of pre-existing synapses by mediating AMPA receptor (AMPAR) endocytosis [87, 88]. This remodeling allows functional neural circuits to arise during development. Red circles, synapse elimination; yellow circles, growth of new spines. bUBE3A deficiency results in the accumulation of Ephexin-5 and Arc, as observed in the Ube3a^m−/p+ mice [66, 67]. Increased Ephexin-5 levels lead to an enhancement in active RhoA levels, which results in deficits in excitatory synapse formation [67]. Inappropriately high accumulation of Arc leads to excessive endocytosis of GluA1-containing AMPARs from glutamatergic synaptic sites [66], hence reducing excitatory synaptic transmission. This also increases the number of silent (AMPAR-lacking) synapses, which may subsequently be eliminated during experience-dependent synapse remodeling. The resulting synaptic and circuit dysfunction may underlie various AS phenotypes, including learning deficits, ataxia, seizures and impaired social/communication skills.