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 infantile hypotonia, gonadal hypoplasia, obsessive behaviour and neonatal feeding difficulties followed by hyperphagia, leading to profound obesity. 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.
Bielinska
B
B
Department of Genetics, The Children's Memorial Health Institute, Warsaw, Poland.
Blaydes
S M
SM
Buiting
K
K
Yang
T
T
Krajewska-Walasek
M
M
Horsthemke
B
B
Brannan
C I
CI
D000328:Adult; D000818:Animals; D001324:Autoantigens / Q000235:genetics* / Q000378:metabolism; D015139:Blotting, Southern; D002460:Cell Line; D002675:Child, Preschool; D019175:DNA Methylation; D004622:Embryo, Mammalian / Q000502:physiology*; D005091:Exons / Q000235:genetics*; D005260:Female; D018392:Genomic Imprinting / Q000235:genetics*; D006801:Humans; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010375:Pedigree; D011218:Prader-Willi Syndrome / Q000235:genetics; D017411:Ribonucleoproteins, Small Nuclear / Q000235:genetics*; D017384:Sequence Deletion; D055517:snRNP Core Proteins
D001324:Autoantigens; D017411:Ribonucleoproteins, Small Nuclear; C526417:SNRPN protein, human; D055517:snRNP Core Proteins