Imprinting-mutation mechanisms in Prader-Willi syndrome

Microdeletions of a region termed the "imprinting center" (IC) in chromosom e 15q11-q13 have been identified in several families with Prader-Willi synd rome (PWS) or Angelman syndrome who show epigenetic inheritance for this re gion that is consistent with a mutation in the imprinting process. The IC c ontrols resetting of parental imprints in 15q11-q13 during gametogenesis. W e have identified a larger series of cases of familial PWS, including one c ase with a deletion of only 7.5 kb, that narrows the PWS critical region to <4.3 kb spanning the SNRPN gene CpG island and exon 1. Identification of a strong DNase I hypersensitive site, specific for the paternal allele, and six evolutionarily conserved (human-mouse) sequences that are potential tra nscription-factor binding sites is consistent with this region defining the SNRPN gene promoter. These findings suggest that promoter elements at SNRP N play a key role in the initiation of imprint switching during spermatogen esis. We also identified three patients with sporadic PWS who have an impri nting mutation (IM) and no detectable mutation in the IC. An inherited 15q1 1-q13 mutation or a trans-factor gene mutation are unlikely; thus, the dise ase in these patients may arise from a developmental or stochastic failure to switch the maternal-to-paternal imprint during parental spermatogenesis. These studies allow a better understanding of a novel mechanism of human d isease, since the epigenetic effect of an IM in the parental germ line dete rmines the phenotypic effect in the patient.