title: Lack of Pwcr1/MBII-85 snoRNA is critical for neonatal lethality in Prader-Willi syndrome mouse models.
abstract: Prader-Willi syndrome (PWS) is a neurobehavioral disorder caused by the lack of paternal expression of imprinted genes in the human chromosome region 15q11-13. Recent studies of rare human translocation patients narrowed the PWS critical genes to a 121-kb region containing PWCR1/HBII-85 and HBII-438 snoRNA genes. The existing mouse models of PWS that lack the expression of multiple genes, including Snrpn, Ube3a, and many intronic snoRNA genes, are characterized by 80%-100% neonatal lethality. To define the candidate region for PWS-like phenotypes in mice, we analyzed the expression of several genetic elements in mice carrying the large radiation-induced p(30PUb) deletion that includes the p locus. Mice having inherited this deletion from either parent develop normally into adulthood. By Northern blot and RT-PCR assays of brain tissue, we found that Pwcr1/MBII-85 snoRNAs are expressed normally, while MBII-52 snoRNAs are not expressed when the deletion is paternally inherited. Mapping of the distal deletion breakpoint indicated that the p30PUb deletion includes the entire MBII-52 snoRNA gene cluster and three previously unmapped EST sequences. The lack of expression of these elements in mice with a paternal p30PUb deletion indicates that they are not critical for the neonatal lethality observed in PWS mouse models. In addition, we identified MBII-436, the mouse homolog of the HBII-436 snoRNA, confirmed its imprinting status, and mapped it outside of the p30PUb deletion. Taking together all available data, we conclude that the lack of Pwcr1/MBII-85 snoRNA expression is the most likely cause for the neonatal lethality in PWS model mice.
authors.affiliation: Department of Genetics, Stanford University, Stanford, California 94305, USA.
authors.forename: Feng
authors.initials: F
authors.lastname: Ding
authors.forename: Yelena
authors.initials: Y
authors.lastname: Prints
authors.forename: Madhu S
authors.initials: MS
authors.lastname: Dhar
authors.forename: Dabney K
authors.initials: DK
authors.lastname: Johnson
authors.forename: Carmen
authors.initials: C
authors.lastname: Garnacho-Montero
authors.forename: Robert D
authors.initials: RD
authors.lastname: Nicholls
authors.forename: Uta
authors.initials: U
authors.lastname: Francke
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001483:Base Sequence; D001921:Brain / Q000378:metabolism; D002872:Chromosome Deletion; D004195:Disease Models, Animal; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D011218:Prader-Willi Syndrome / Q000150:complications / Q000235:genetics* / Q000503:physiopathology*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020537:RNA, Small Nucleolar / Q000235:genetics* / Q000378:metabolism*; D016415:Sequence Alignment; D015996:Survival Rate
chemical_list: D012333:RNA, Messenger; D020537:RNA, Small Nucleolar