Angelman syndrome, a genomic imprinting disorder of the brain.

Introduction Harry Angelman, an English pediatrician, reported three cases of “Puppet Children” in 1965 (Angelman, 1965). These individuals displayed severe intellectual disability, ataxia, absent speech, jerky arm movements and bouts of inappropriate laughter. More cases were described as “Happy Puppet” syndrome (Bower and Jeavons, 1967), and additional consensus diagnostic criteria for what is now recognized as Angelman syndrome (AS) include microcephaly, seizures, EEG abnormalities, and hyperactivity (Williams et al., 2006). The current understanding of the clinical characteristics of AS children and adults has been summarized previously (Clayton-Smith and Laan, 2003; Dan, 2009; Van Buggenhout and Fryns, 2009). Mapping of the AS genetic locus to the long arm of chromosome 15 between bands q11 and q13 (15q11-q13) was first reported in 1987 (Magenis et al., 1987) and confirmed in additional patients displaying chromosome 15q11-q13 deletions (Knoll et al., 1989). AS was only observed when the deletion occurred on the copy of chromosome 15 that was inherited from the mother (Knoll et al., 1989). This observation was remarkable because it had been previously found that a deletion of 15q11-q13 of the chromosome inherited from the father causes Prader-Willi syndrome (PWS), a disorder characterized by hyperphagia and obesity (Butler and Palmer, 1983). The intriguing observation that the 15q11-q13 deletion caused an entirely different disease depending on whether it was transmitted by the mother or the father was explained the discovery in 1989 that chromosome 15q11q13 is subject to genomic imprinting (Nicholls et al., 1989), an epigenetic process whereby expression is allele-specific, i.e., one of the two parental copies of a gene is silenced. The specific gene in 15q11-q13 that causes AS encodes ubiquitin protein ligase E3A (UBE3A). UBE3A is also known as E6-associated protein (E6-AP) because it was originally discovered as a binding partner of the E6 protein of the human papilloma virus (Huibregtse et al., 1991, 1993). The relationship between genomic imprinting and UBE3A is illustrated in Figure 1. In non-neuronal tissues of normal individuals, UBE3A is expressed from both the chromosome 15 that is inherited from the father (blue) and the chromosome inherited from the mother (magenta). In neurons, the paternal copy (allele) of UBE3A is silenced by the process of genomic imprinting. As a result, only the maternal UBE3A allele is expressed in neurons from normal individuals (Albrecht et al., 1997; Rougeulle et al., 1997; Vu and Hoffman, 1997) (Fig. 1). In AS, the maternal UBE3A allele is absent or inactivated and, as a result, there is no active copy of UBE3A in neurons. Loss of the active maternal UBE3A allele in AS is caused, in the majority of cases ( 75%), by maternal deletion of the chromosome 15q11-q13 region that contains UBE3A (Lossie et al., 2001). Another 20% of AS cases result from mutations of the maternal UBE3A allele (Kishino et al., 1997; Matsuura et al., 1997). The remainder result from uniparental disomy (the inheritance of two paternal and no maternal chromosomes 15) or from imprinting defects (see below). There are also cases of AS for which no molecular abnormality has been detected.