Elucidation of imprinting mechanisms and phenotypes in Prader-Willi syndrome mice

Genomic imprinting is an epigenetic phenomenon in which genes are expressed exclusively from one parental allele or the other. Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are human genetic disorders resulting from the absence of genes that are subject to genomic imprinting. PWS is a contiguous gene syndrome that results from the absence of two or more paternally expressed genes, while AS is a disorder that can result from the absence of a single maternally expressed gene, UBE3A, which lies in the same region.; This study uses a mouse model for PWS in which paternal transmission of a PWS imprinting center (PWS-IC) mutation results in complete loss of local paternal gene expression. This targeted mutation accurately models both the molecular and phenotypic aspects of PWS, and it has been applied to both of these aspects in this study.; It has first been shown that imprinted expression of Ube3a, most likely results from the regulation of a paternally expressed transcript that is antisense to the Ube3a gene, suggesting an interesting model for the regulation of gene expression in this imprinted region. The minimum sequence that is sufficient to confer proper imprinted expression of the paternally expressed genes to transgenes in vivo was then identified. This provides a stringent assay that can be used to test the proposed model of imprinted gene expression.; Transgenic rescue of the PWS mouse was also used in our mouse model to correlate specific attributes of the PWS phenotype to specific gene products. A transgene that shows expression of a single small nucleolar RNA (snoRNA) cluster rescues the small stature phenotype of PWS mice, while three other genes were found to have no obvious effect on the PWS phenotype in mice. We have also found that the PWS phenotype is less severe on certain strain backgrounds, suggesting the presence of modifier genes that may ameliorate the PWS phenotype. These modifier genes may help to identify gene pathways involved in PWS as well as future targets for gene therapy that may ultimately help the PWS patient.