Angelman and Prader-Willi syndromes

Abstract

Angelman and Prader-Willi syndromes (AS and PWS) have very different phenotypes but are considered together, as the genes responsible map to the chromosome region 15q11-13 and are subject to genomic imprinting, whereby gene expression is dependent on the parent of origin. In PWS, the gene(s) responsible are expressed only on the paternal chromosome and the maternal copy is silenced, whereas in AS the maternal copy is active and the paternal copy silenced. Hence, a child inheriting a deletion of the critical region of the paternally derived chromosome 15 will develop PWS and a child inheriting a similar deletion of the maternally derived 15 will develop AS. Similarly, a child inheriting two copies of maternally derived chromosome 15 instead of one paternal and one maternal copy (a phenomenon known as uniparental disomy or UPD) develops PWS as there are no active (i.e. paternal) copies of the Prader-Willi gene(s) present. A child with paternal UPD for chromosome 15 has AS. Only a fraction of human genes are imprinted and imprinted genes tend to be clustered. Within the PWS/AS cluster, some genes are not imprinted. Among these is the P gene involved in melanin biosynthesis; deletion of an allele at this locus might account for the fair hair and blue eyes of many PWS and AS children. A small region regulates the imprinting process and mutations in this 'imprinting centre' can alter the pattern of methylation at adjacent loci and be another cause of PWS or AS. Imprinting is probably mediated by an interplay of events including differential methylation. The differential methylation of the DNA in the PWS/AS