Molecular epigenetics of Angelman syndrome

Abstract

Angelman syndrome (AS) is a neurogenetic disorder characterized by severe mental retardation, ataxia, seizures, EEG abnormalities and bouts of inappropriate laughter. AS individuals fail to inherit a normal active maternal copy of ubiquitin protein ligase E3A (UBE3A). UBE3A is subject to genomic imprinting, with predominant transcription of the maternal allele in brain. The known genetic causes of AS are maternal deletion of chromosome 15q11-q13, paternal chromosome 15 uniparental disomy, UBE3A mutation and an abnormality of the imprinting process, termed imprinting defect. There remain major questions concerning the molecular pathogenesis of AS, including: 1) the mechanisms underlying the imprinting defect class of AS, 2) the identity of proteins targeted by UBE3A, 3) the role of a noncoding antisense transcript in regulating UBE3A imprinting and 4) the contribution of other genes such as methyl-binding CpG-binding protein 2 and gamma-aminobutyric acid A receptor, subunit beta3 to the AS phenotype.

Angelman Syndrome, a Genomic Imprinting Disorder of the Brain

“…2B) has led to the hypothesis that the paternal UBE3A allele is silenced by this cisacting antisense transcript (Rougeulle et al, 1998;Chamberlain and Brannan, 2001;Runte et al, 2001;Yamasaki et al, 2003). The hypothesis that UBE3A imprinting is regulated by an antisense transcript is consistent with the finding that the imprinting of several other genes is mediated by antisense transcription (Lalande and Calciano, 2007).…”

“…There are several proposed mechanisms by which UBE3A-ATS could mediate the epigenetic silencing of UBE3A in neurons (Rougeulle and Heard, 2002;Shibata and Lee, 2004;Lalande and Calciano, 2007). These include transcriptional interference resulting from the simultaneous occupancy of RNA polymerase complexes on the positive and negative strands, and RNA interference induced by double-stranded RNA formed between sense and antisense RNAs.…”

Genetic architecture, epigenetic influence and environment exposure in the pathogenesis of Autism

“…Altered DNA methylation has been found during brain development in several neuropsychiatric diseases [37][38][39][40]. MECP2, a well-known epigenetic regulation gene, has been reported to be truncated or aberrantly methylated in Rett syndrome and autism [41,42].…”

The molecular basis of cognitive deficits in pervasive developmental disorders: Table 1.

“…Disruption of each of these three processes has been implicated in the pathophysiology of human diseases, but only the UPS has been shown thus far to be affected in PDD (Tai and Schuman 2008;Betancur 2011). The prime example of a PDD caused by disruption of the UPS is Angelman syndrome (AS), which most often occurs when the UPS executor protein ubiquitin ligase E6-AP, also known as UBE3A, is absent due to mutations in the maternal copy of the UBE3A gene (Lalande and Calciano 2007).…”