Abstract
Prader-Willi syndrome (PWS) is a neurogenetic disease characterized by infantile hypotonia, gonadal hypoplasia, obsessive behaviour and neonatal feeding difficulties followed by hyperphagia, leading to profound obesity1. PWS is due to a lack of paternal genetic information at 15q11–q13 (ref. 2). Five 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 well as two poorly characterized framents designated PAR-1 and PAR-5 (ref. 10). 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 paternal imprint in the male germ line and leads to PWS. Here we report a PWS family in which the father is mosaic for an IC deletion on his paternal chromosome. The deletion chromosome has acquired a maternal methylation imprint in his somatic cells. We have made identical findings in chimaeric mice generated from two independent embryonic stem (ES) cell lines harbouring a similar deletion. Our studies demonstrate that the PWS IC element is not only required for the establishment of the paternal imprint, but also for its postzygotic maintenance.
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Acknowledgements
We thank M.A. Handel for consulting on the interpretation of testis histology; C. Lich for technical assistance; E. Michaud for the agouti probe; F. Muscatelli for the NDN probe; D. Lohmann for the Rbe7 probe; T. Gridley for the CJ.7 ES line; the Jaenisch lab for the J4 ES line; and C. Färber, M. Zeschnigk and G. Gillessen-Kaesbach for helpful discussion. This work was supported, in part, by a grant from the National Institutes of Health (GM55272 to C.I.B.) and a grant from the Deutsche Forschungsgemeinschaft (Ho 949/12-2 to B.H.). S.M.B. was supported by an NIH training grant (T32 CA09126).
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Bielinska, B., Blaydes, S., Buiting, K. et al. De novo deletions of SNRPN exon 1 in early human and mouse embryos result in a paternal to maternal imprint switch. Nat Genet 25, 74–78 (2000). https://doi.org/10.1038/75629
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DOI: https://doi.org/10.1038/75629
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