Understanding the pathogenesis of Angelman syndrome through animal models

Abstract

Angelman syndrome (AS) is a neurodevelopmental disorder characterized by severe mental retardation, lack of speech, ataxia, susceptibility to seizures, and unique behavioral features such as easily provoked smiling and laughter and autistic features. The disease is primarily caused by deletion or loss-of-function mutations of the maternally inherited UBE3A gene located within chromosome 15q11-q13. The UBE3A gene encodes a 100 kDa protein that functions as ubiquitin ligase and transcriptional coactivator. Emerging evidence now indicates that UBE3A plays a very important role in synaptic function and in regulation of activity-dependent synaptic plasticity. A number of animal models for AS have been generated to understand the disease pathogenesis. The most widely used model is the UBE3A-maternal-deficient mouse that recapitulates most of the essential features of AS including cognitive and motor abnormalities. This paper mainly discusses various animal models of AS and how these models provide fundamental insight into understanding the disease biology for potential therapeutic intervention.

Figure 1

Imprinting map of the human chromosome 15q11-13 region around AS imprinting centre (AS-IC). Paternal and maternal chromosome 15q11-13 regions around AS-IC and PWS-IC are represented in (a) and (b), respectively. Paternally expressed genes (gray boxes), maternally expressed genes (black boxes), maternally repressed genes (white boxes), and biallelically expressed genes (dark gray boxes) are represented with arrows marking transcription start sites. Right arrow indicates gene transcription on “+” strand, whereas left arrow indicates gene transcription on “−” strand. AS-IC (triangle) and PWS-IC (ellipse) are shaded depending on histone modification in the area. AS-IC is dormant (gray triangle) on paternal chromosome, whereas on the maternal chromosome it is acetylated and methylated at H3-lys4 (green triangle), thus active. PWS-IC is active on paternal chromosome (green ellipse) since it is also acetylated and methylated at H3-lys4. However, PWS-IC at the maternal chromosome is methylated at H3-lys9 and repressed (red ellipse). Differentially CpG methylated region (DMR1) in SNRPN exon 1 overlaps with PWS-IC partially. Note that DMR1 on maternal but not paternal chromosome is methylated (black pin). UBE3A-ATS (antisense transcript) originating upstream of SNRPN can either be a degradable complex with UBE3A transcript or prevent the extension of UBE3A transcript (collision or upstream histone modifications represented by “X”).