De novo deletions of SNRPN exon 1 in early human and mouse embryos result in a paternal to maternal imprint switch

Prader-Willi syndrome (PWS) is a neurogenetic disease characterized by infa ntile hypotonia, gonadal hypoplasia, obsessive behaviour and neonatal feedi ng difficulties followed by hyperphagia, leading to profound obesity(1). PW S is due to a lack of paternal genetic information at 15q11-q13 (ref. 2). F ive imprinted, paternally expressed genes map to the PWS region, MKRN3 (ref . 3), NDN (ref. 4), NDNL1 (ref. 5), SNRPN (refs 6-8) and IPW (ref. 9), as w ell as two poorly characterized framents designated PAR-1 and PAR-5 (ref. 1 0). Imprinting of this region involves a bipartite 'imprinting centre' (IC) , which overlaps SNRPN (refs 10,11). Deletion of the SNRPN promoter/exon 1 region (the PWS IC element) appears to impair the establishment of the pate rnal imprint in the male germ line and leads to PWS. Here we report a PWS f amily in which the father is mosaic for an IC deletion on his paternal chro mosome. The deletion chromosome has acquired a maternal methylation imprint in his somatic cells. We have made identical findings in chimaeric mice ge nerated from two independent embryonic stem (ES) cell lines harbouring a si milar deletion. Our studies demonstrate that the PWS IC element is not only required for the establishment of the paternal imprint, but also for its p ostzygotic maintenance.