IMPRINTING MUTATIONS SUGGESTED BY ABNORMAL DNA METHYLATION PATTERNS IN FAMILIAL ANGELMAN AND PRADER-WILLI SYNDROMES

The D15S9 and D15S63 Loci in the Prader-Willi/Angelman syndrome region on chromosome 15 are subject to parent-of-origin-specific DNA methyla tion. We have found two Prader-Willi syndrome families in which the pa tients carry a maternal methylation imprint on the paternal chromosome . In one of these families, the patients have a small deletion encompa ssing the gene for the small nuclear ribonucleoprotein polypeptide N, which maps 130 kb telomeric to D15S63. Furthermore, we have identified a pair of nondeletion Angelman syndrome sibs and two isolated Angelma n syndrome patients who carry a paternal methylation imprint on the ma ternal chromosome, These Angelman and Prader-Willi syndrome patients m ay have a defect in the imprinting process in 15q11-13. We propose a m odel in which a cis-acting mutation prevents the resetting of the impr inting signal in the germ line and thus disturbs the expression of imp rinted genes in this region.