The imprinting box of the Prader-Willi/Angelman syndrome domain

A subset of mammalian genes is monoallelically expressed in a parent-of-ori gin manner. These genes are subject to an imprinting process that epigeneti cally marks alleles according to their parental origin during gametogenesis . Imprinted genes can be organized in clusters as exemplified by the 2-Mb d omain on human chromosome 15q11-q13 and its mouse orthologue on chromosome 7c (ref. 1). Loss of this 2-Mb domain on the paternal or maternal allele re sults in two neurogenetic disorders, Prader-Willi syndrome (PWS) or Angelma n syndrome (AS), respectively. Microdeletions on the paternal allele share a 4.3-kb short region of overlap (SRO), which includes the SNRPN promoter/e xon1. cause PWS and silence paternally expressed genes(2). Microdeletions o n the maternal allele share a 0.88-kb SRO located 35 kb upstream to the SNR PN promoter(3), cause AS and alleviate repression of genes on the maternal allele(4). Individuals carrying both AS and PWS deletions on the paternal a llele show a PWS phenotype and genotype. These observations suggest that ci s elements within the AS-SRO and PWS-SRO constitute an imprinting box that regulates the entire domain on both chromosomes. Here we show that a minitr ansgene composed of a 200-bp Snrpn promoter/exon1 and a 1-kb sequence locat ed approximately 35 kb upstream to the SNRPN promoter confer imprinting as judged by differential methylation, parent-of-origin-specific transcription and asynchronous replication.