MINIMAL DEFINITION OF THE IMPRINTING CENTER AND FIXATION OF A CHROMOSOME 15Q11-Q13 EPIGENOTYPE BY IMPRINTING MUTATIONS

Patients with disorders involving imprinted genes such as Angelman syn drome (AS) and Prader-Willi syndrome (PWS) can have a mutation in the imprinting mechanism. Previously, we identified an imprinting center ( IC) within chromosome 15q11-q13 and proposed that IC mutations block r esetting of the imprint, fixing on that chromosome the parental imprin t (epigenotype) on which the mutation arose. We now describe four new microdeletions of the IC, the smallest (6 kb) of which currently defin es the minimal region sufficient to confer an AS imprinting mutation. The AS deletions all overlap this minimal region, centromeric to the P WS microdeletions, which include the first exon of the SNRPN gene. Non e of five genes or transcripts in the 1.0 Mb vicinity of the IC (ZNF12 7, SNRPN, PAR-5, IPW, and PAR-1), each normally expressed only from th e paternal allele, was expressed in cells from PWS imprinting mutation patients. In contrast, AS imprinting mutation patients show biparenta l expression of SNRPN and IPW but must lack expression of the putative AS gene 250-1000 kb distal of the IC. These data strongly support a m odel in which the paternal chromosome of these PWS patients carries an ancestral maternal epigenotype, and the maternal chromosome of these AS patients carries an ancestral paternal epigenotype. The IC therefor e functions to reset the maternal and paternal imprints throughout a 2 -Mb imprinted domain within human chromosome 15q11-q13 during gametoge nesis.