Evidence for genetic modifiers of postnatal lethality in PWS-IC deletion mice

Prader–Willi syndrome (PWS), most notably characterized by infantile hypotonia, short stature and morbidobesity, results from deficiencies in multiple genes that are subject to genomic imprinting. The usefulnessof current mouse models of PWS has been limited by postnatal lethality in affected mice. Here, we reportthe survival of the PWS-imprinting center (IC) deletion mice on a variety of strain backgrounds.Expression analyses of the genes affected in the PWS region suggest that while there is low-level expressionfrom both parental alleles in PWS-IC deletion pups, this expression does not explain their survival on certainstrain backgrounds. Rather, the data provide evidence for strain-specific modifier genes that support thesurvival of PWS-IC deletion mice.INTRODUCTIONPrader–Willi syndrome (PWS) is characterized by infantilehypotonia, gonadal hypoplasia, a moderate delay in physicaland mental development, short stature, obsessive/compulsivebehavior and neonatal feeding difficulties, later followed byhyperphagia which contributes to profound obesity (1). PWSis an imprinting disorder caused by loss of paternal geneexpression from chromosome 15q11–q13. The predominantcauses are paternal inheritance of a 4 Mb deletion of15q11–q13 or maternal uniparental disomy (UPD) forchromosome 15 (2). A second neurobehavioral disorder,Angelman syndrome (AS), also maps to 15q11–q13 but iscaused by the loss of maternal contribution (3). A smallnumber of cases of both PWS and AS are due to imprintingdefects. These can be caused by microdeletions involvingthe imprinting center (IC), which regulates imprinting acrossan 2 Mb region (4). The IC has a bipartite structure, com-prising the PWS-IC, located around exon 1 of SNRPN (5),and the AS-IC, located 35 kb upstream of SNRPN (6). Nocase of PWS has been attributed to a single gene defect,strongly suggesting that it is a contiguous gene syndrome (7).A number of paternally expressed PWS candidate geneshave been identified, including MKRN3 (8), MAGEL2 (9),NDN (10), SNRPN (11,12), IPW (13), a number of snoRNAs(HBII-436, HBII-13, HBII-437, HBII-438A, HBII-85, HBII-52 and HBII-438B) (14,15) and an antisense transcriptto the UBE3A gene (16). Recent evidence suggests thatSNRPN, the snoRNAs and the UBE3A antisense are productsof a single transcriptional unit (17).Both gene content and imprinting are conserved in a regionof mouse chromosome 7C. The first mouse model of PWS tobe reported was a model for UPD (18). Mice with maternalduplication of a region of chromosome 7 show poor feeding,failure to thrive and die between 2 and 8 days after birth. Amodel for PWS deletions arose fortuitously as a transgene-induced deletion of the PWS/AS orthologous region in mice(19). These mice are reported to have failure to thrive,feeding difficulties, reduced movement, irregular respirationand all die within 1 week of birth. We previously generateda model for PWS-IC deletions by targeted deletion of 35 kb(originally reported to be 42 kb) including 16 kb upstream ofSnrpn and exons 1–6 (PWS-IC