UBE3A: An E3 Ubiquitin Ligase With Genome-Wide Impact in Neurodevelopmental Disease - PubMed (original) (raw)

Review

UBE3A: An E3 Ubiquitin Ligase With Genome-Wide Impact in Neurodevelopmental Disease

Simon Jesse Lopez et al. Front Mol Neurosci. 2019.

Abstract

UBE3A is an E3 ubiquitin ligase encoded by an imprinted gene whose maternal deletion or duplication leads to distinct neurodevelopment disorders Angelman and Dup15q syndromes. Despite the known genetic basis of disease, how changes in copy number of a ubiquitin ligase gene can have widespread impact in early brain development is poorly understood. Previous studies have identified a wide array of UBE3A functions, interaction partners, and ubiquitin targets, but no central pathway fully explains its critical role in neurodevelopment. Here, we review recent UBE3A studies that have begun to investigate mechanistic, cellular pathways and the genome-wide impacts of alterations in UBE3A expression levels to gain broader insight into how UBE3A affects the developing brain. These studies have revealed that UBE3A is a multifunctional protein with important nuclear and cytoplasmic regulatory functions that impact proteasome function, Wnt signaling, circadian rhythms, imprinted gene networks, and chromatin. Synaptic functions of UBE3A interact with light exposures and mTOR signaling and are most critical in GABAergic neurons. Understanding the genome-wide influences of UBE3A will help uncover its role in early brain development and ultimately lead to identification of key therapeutic targets for UBE3A-related neurodevelopmental disorders.

Keywords: Angelman syndrome; autism (ASD); human genetics and genomics; neurodevelopment; parental imprinting; synapse.

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Figures

Figure 1

Figure 1

UBE3A transcriptional regulation and key related pathways. (A) The diagrams outline the expression and imprinting status of UBE3A. Maternal-specific methylation of the imprinting control region (ICR) upstream of SNRPN is represented by filled circles. Paternal-specific expression and transcriptional elongation through the locus results in the expression of the UBE3A antisense transcript (UBE3A-ATS) that is responsible for UBE3A imprinting. In neurons, paternal expression of SNRPN through UBE3A leads to transcription of the SNORD116 and SNORD115 clusters and induces UBE3A silencing via the UBE3A-ATS. In non-neurons, paternal SNRPN transcription does not progress to transcribe the UBE3A-ATS and UBE3A is expressed biallelically (note that non-neuronal transcription of paternal SNRPN stops upstream of SNORD116 in mice but stops just downstream of SNORD116 in human). White circles indicate unmethylated ICR, black circles indicate methylated ICR, green boxes indicate location of CpG islands, and gray fill indicates unexpressed genes. (B) The major processes affected by altered UBE3A levels in neurons discussed in this review. UBE3A has diverse functions and no single mechanism explains the phenotypes observed in UBE3A-related disorders. Understanding how these processes are connected via UBE3A my be key for therapeutic intervention.

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