Imprinting mechanisms and genes involved in Prader-Willi and Angelman syndromes

Abstract

Prader-Willi (PWS) and Angelman (AS) syndromes illustrate a disease paradigm of genomic imprinting, an epigenetic modification of DNA that results in parent-of-origin specific expression during embryogenesis and in the adult. From genetic data, at least two imprinted genes may be required for the classical PWS phenotype, whereas AS probably involves a single imprinted gene, and rare familial forms of both disorders involve imprinting mutations. In addition, the nonimprinted P gene is associated with pigmentation disorders in PWS, AS and oculocutaneous albinism. Identification of new genes, delineation of small deletions in unique patients, and direct screening for imprinted sequences, should soon identify candidate genes for PWS and AS. The mechanism of imprinting involves DNA methylation and replication timing, and appears to include multiple imprinted genes within a large imprinted domain. Imprinting of these genes may be regulated in cis, by an imprinting control element (ICE). Future studies can be expected to unravel the gene identities and imprinting mechanisms involved in these fascinating disorders; ultimately it may be possible to reactivate imprinted gene expression as a therapeutic approach.