A transgene insertion creating a heritable chromosome deletion mouse modelof Prader-Willi and Angelman syndromes

Prader-Willi syndrome (PWS) and Angelman syndrome (AS) result from the loss of function of imprinted genes in human chromosome 15q11-q13, The central part of mouse chromosome 7 is homologous to human 15q11-q13, with conservat ion of both gene order and imprinted features. We report here the character ization of a transgene insertion (Epstein-Barr virus Latent Membrane Protei n 2A, LMP2A) into mouse chromosome 7C, which has resulted in mouse models f or PWS and AS dependent on the sex of the transmitting parent. Epigenotype (allelic expression and DNA methylation) and fluorescence in situ hybridiza tion analyses indicate that the transgene-induced mutation has generated a complete deletion of the PWS/AS-homologous region but has not deleted flank ing loci. Because the intact chromosome 7, opposite the deleted homolog, ma intains the correct imprint in somatic cells of PWS and AS mice and establi shes the correct imprint in male and female germ cells of AS mice, homologo us association and replication asynchrony are not part of the imprinting me chanism. This heritable-deletion mouse model will be particularly useful fo r the identification of the etiological genes and mechanisms, phenotypic ba sis, and investigation of therapeutic approaches for PWS.