Bernhard Horsthemke
Institut fur Humangenetik; Universitatsklinikum Essen
Human chromosome 15 harbors an imprinted domain of 2-3 Mbp, which is controlled by an imprinting center (IC). To date, five imprinted genes (ZNF127, NDN, SNRPN, IPW and UBE3A) and a non-imprinted testis-specific gene (Farber et al., unpublished) have been identified within this domain. Based on the identification of inherited microdeletions in several Prader-Willi (PWS) and Angelman syndrome (AS) patients with an imprinting defect, the IC has been mapped to a 100 kb region including the SNRPN gene and appears to have a bipartite structure. Mutations of the proximal part of the IC block the paternal to maternal imprint switch during female gametogenesis. The critical region has been narrowed down to 880 bp and contains an alternative 5' exon of SNRPN. Mutations of the distal part of the IC block the maternal to paternal imprint switch during male gametogenesis. The critical region has been narrowed down to 4.3 kb and spans SNRPN exon 1. In several other AS and PWS patients with an imprinting defect, no mutation was found. In each IC deletion and non-deletion patient with PWS, the aberrantly imprinted chromosome region was inherited from the paternal grandmother. This suggests that the grandmatemal imprint was not erased in the father's germline. In AS patients with an IC deletion, the aberrantly imprinted chromosome region was inherited from the maternal grandfather. In IC non-deletion patients, however, the chromosome was from either the paternal or the maternal grandmother. The latter finding suggests that a paternal imprint developed in the maternal germline or postzygotically, and that this is the default imprint. Recently, we have studied a family in which the father of a PWS patient is mosaic for an IC deletion on his paternal chromosome. Unexpectedly we have found that the deletion chromosome has a maternal methylation imprint in both the father and the patient, suggesting a postzygotic imprint switch in early embryonic cells in the father. This finding demonstrates that the SNRPN exon 1 region is not only required for paternal imprinting in the germline, but also for the postzygotic maintenance of the paternal imprint.