Paternal deletion from Snrpn to Ube3a in the mouse causes hypotonia, growth retardation and partial lethality and provides evidence for a gene contributing to Prader-Willi syndrome

Prader-Willi syndrome (PWS) is caused by paternal deficiency of human chrom osome 15q11-q13, There is conflicting evidence from human translocations re garding the direct involvement of SNRPN in the pathogenesis of PWS and it i s not known if the phenotypic features result from the loss of expression o f a single imprinted gene or multiple genes. In an attempt to dissect genot ype/phenotype correlations for the homologous region of mouse chromosome 7C , we prepared three mutant genotypes: (i) mice with a deletion of Snrpn exo n 2, which removes a portion of a small, upstream open reading frame (ORF); (ii) mice with double targeting for Snrpn exon 2 and Ube3a; (iii) mice del eted from Snrpn to Ube3a, removing coding exons for both loci and interveni ng genes. Mice deleted for Snrpn exon 2 have no obvious phenotypic abnormal ities and switching of the genomic imprint for the region is conserved. Mic e carrying the Snrpn-Ube3a deletion on the paternal chromosome showed sever e growth retardation, hypotonia and similar to 80% lethality before weaning . The surviving mice were fertile and were not obese up to 14 months of age , The deletion was transmitted for multiple generations and continued to ca use partial lethality when inherited paternally, but not when inherited mat ernally. The normal imprinted expression and methylation patterns of necdin , a gene outside the deletion region, indicate that the deletion is not an imprinting mutation. The data suggest the presence of a paternally expresse d structural gene between Snrpn and Ipw whose deficiency causes lethality, although other possibilities exist, including position effects on expressio n of imprinted genes or that simultaneous deficiency of both ORFs of Snrpn causes lethality.