AbstractPrader‐Willi syndrome (PWS) and Angelman syndrome (AS) are neurobehavioral disorders resulting from deficiency of imprinted gene expression from paternal or maternal chromosome 15q11‐15q13, respectively. In humans, expression of the imprinted genes is under control of a bipartite cis‐acting imprinting center (IC). Families with deletions causing PWS imprinting defects localize the PWS‐IC to 4.3 kb overlapping with SNRPN exon 1. Families with deletions causing AS imprinting defects localize the AS‐IC to 880 bp 35 kb upstream of the PWS‐IC. We report two mouse mutations resulting in defects similar to that seen in AS patients with deletion of the AS‐IC. An insertion/duplication mutation 13 kb upstream of Snrpn exon 1 resulted in lack of methylation at the maternal Snrpn promoter, activation of maternally repressed genes, and decreased expression of paternally repressed genes. The acquisition of a paternal epigenotype on the maternal chromosome in the mutant mice was demonstrated by the ability to rescue the lethality and growth retardation in a mouse model of a PWS imprinting defect. A second mutation, an 80‐kb deletion extending upstream of the first mutation, caused a similar imprinting defect with variable penetrance. These results suggest that there is a mouse functional equivalent to the human AS‐IC. genesis 44:12–22, 2006. © 2006 Wiley‐Liss, Inc.