INHERITED MICRODELETIONS IN THE ANGELMAN AND PRADER-WILLI SYNDROMES DEFINE AN IMPRINTING CENTER ON HUMAN-CHROMOSOME-15

A subset of patients with Angelman and Prader-Willi syndrome have appa rently normal chromosomes of biparental origin, but abnormal DNA methy lation at several loci within chromosome 15q11-13, and probably have a defect in imprinting. Using probes from a newly established 160-kb co ntig including D15S63 (PW71) and SNRPN, we have identified inherited m icrodeletions in two AS families and three PWS families. The deletions probably affect a single genetic element that we term the 15q11-13 im printing centre (IC). In our model, the IC regulates the chromatin str ucture, DNA methylation and gene expression in cis throughout 15q11-13 . Mutations of the imprinting centre can be transmitted silently throu gh the germline of one sex, but appear to block the resetting of the i mprint in the germline of the opposite sex.