title: Imprinting-mutation mechanisms in Prader-Willi syndrome.
abstract: Microdeletions of a region termed the "imprinting center" (IC) in chromosome 15q11-q13 have been identified in several families with Prader-Willi syndrome (PWS) or Angelman syndrome who show epigenetic inheritance for this region that is consistent with a mutation in the imprinting process. The IC controls resetting of parental imprints in 15q11-q13 during gametogenesis. We have identified a larger series of cases of familial PWS, including one case 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 transcription-factor binding sites is consistent with this region defining the SNRPN gene promoter. These findings suggest that promoter elements at SNRPN play a key role in the initiation of imprint switching during spermatogenesis. We also identified three patients with sporadic PWS who have an imprinting mutation (IM) and no detectable mutation in the IC. An inherited 15q11-q13 mutation or a trans-factor gene mutation are unlikely; thus, the disease 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 disease, since the epigenetic effect of an IM in the parental germ line determines the phenotypic effect in the patient.
authors.affiliation: Department of Genetics, Case Western Reserve University School of Medicine, and Center for Human Genetics, University Hospitals of Cleveland, OH 44106-4955, USA.
authors.forename: T
authors.initials: T
authors.lastname: Ohta
authors.forename: T A
authors.initials: TA
authors.lastname: Gray
authors.forename: P K
authors.initials: PK
authors.lastname: Rogan
authors.forename: K
authors.initials: K
authors.lastname: Buiting
authors.forename: J M
authors.initials: JM
authors.lastname: Gabriel
authors.forename: S
authors.initials: S
authors.lastname: Saitoh
authors.forename: B
authors.initials: B
authors.lastname: Muralidhar
authors.forename: B
authors.initials: B
authors.lastname: Bilienska
authors.forename: M
authors.initials: M
authors.lastname: Krajewska-Walasek
authors.forename: D J
authors.initials: DJ
authors.lastname: Driscoll
authors.forename: B
authors.initials: B
authors.lastname: Horsthemke
authors.forename: M G
authors.initials: MG
authors.lastname: Butler
authors.forename: R D
authors.initials: RD
authors.lastname: Nicholls
mesh_terms: D000328:Adult; D000818:Animals; D001324:Autoantigens; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D002884:Chromosomes, Human, Pair 15; D019175:DNA Methylation; D003850:Deoxyribonuclease I; D019143:Evolution, Molecular; D005260:Female; D015870:Gene Expression; D005819:Genetic Markers; D018392:Genomic Imprinting; D006801:Humans; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D011218:Prader-Willi Syndrome / Q000235:genetics*; D017411:Ribonucleoproteins, Small Nuclear; D055517:snRNP Core Proteins