title: A transgene insertion creating a heritable chromosome deletion mouse model of Prader-Willi and angelman syndromes.
abstract: 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 conservation of both gene order and imprinted features. We report here the characterization of a transgene insertion (Epstein-Barr virus Latent Membrane Protein 2A, LMP2A) into mouse chromosome 7C, which has resulted in mouse models for PWS and AS dependent on the sex of the transmitting parent. Epigenotype (allelic expression and DNA methylation) and fluorescence in situ hybridization analyses indicate that the transgene-induced mutation has generated a complete deletion of the PWS/AS-homologous region but has not deleted flanking loci. Because the intact chromosome 7, opposite the deleted homolog, maintains the correct imprint in somatic cells of PWS and AS mice and establishes the correct imprint in male and female germ cells of AS mice, homologous association and replication asynchrony are not part of the imprinting mechanism. This heritable-deletion mouse model will be particularly useful for the identification of the etiological genes and mechanisms, phenotypic basis, and investigation of therapeutic approaches for PWS.
authors.affiliation: Department of Genetics, Case Western Reserve University School of Medicine and Center for Human Genetics, University Hospitals of Cleveland, 10900 Euclid Avenue, Cleveland, OH 44106-4955, USA.
authors.forename: J M
authors.initials: JM
authors.lastname: Gabriel
authors.forename: M
authors.initials: M
authors.lastname: Merchant
authors.forename: T
authors.initials: T
authors.lastname: Ohta
authors.forename: Y
authors.initials: Y
authors.lastname: Ji
authors.forename: R G
authors.initials: RG
authors.lastname: Caldwell
authors.forename: M J
authors.initials: MJ
authors.lastname: Ramsey
authors.forename: J D
authors.initials: JD
authors.lastname: Tucker
authors.forename: R
authors.initials: R
authors.lastname: Longnecker
authors.forename: R D
authors.initials: RD
authors.lastname: Nicholls
mesh_terms: D017204:Angelman Syndrome / Q000235:genetics*; D000818:Animals; D002872:Chromosome Deletion; D002874:Chromosome Mapping; D002884:Chromosomes, Human, Pair 15; D019175:DNA Methylation; D005260:Female; D018392:Genomic Imprinting; D004854:Herpesvirus 4, Human / Q000235:genetics; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D010375:Pedigree; D011218:Prader-Willi Syndrome / Q000235:genetics*; D014763:Viral Matrix Proteins / Q000235:genetics
chemical_list: C037662:EBV-associated membrane antigen, Epstein-Barr virus; D014763:Viral Matrix Proteins