Minimal sequence of the murine Prader-Willi imprinting center and affected genes.

摘要

Prader-Willi syndrome (PWS) and Angelman syndrome (AS) are genetic disorders that can result from a loss of a cluster of oppositely imprinted genes. The orthologous region has been found in mouse, and mouse models have been used to examine imprinting in the PWS/AS region. The PWS/AS region is controlled by a bipartite imprinting center consisting of the PWS imprinting center (PWS-IC) and the AS imprinting center (AS-IC).;Atp10a is located close to the PWS/AS region and there is some data to support the idea that Atp10a may also be imprinted and regulated as a part of the PWS/AS cluster of genes. Atp10a encodes a putative phospholipid translocase and is thought to possibly contribute to the AS phenotype. We investigated the imprinting status of Atp10a in mouse by examining differences in allelic gene expression using a single nucleotide polymorphism between mouse strains. We found that Atp10a is not imprinted in all examined regions of the mouse brain and the PWS-IC has no effect on Atp10a imprinting. We also examined CpG methylation in a CpG island associated with Atp10a and found no differential methylation supporting our result that Atp10a is not imprinted.;Although the human PWS-IC has been narrowed down to 4.3 kb including Snrpn exon 1 by mapping microdeletions found in patients with PWS, the smallest region known to cause a complete imprinting defect in mouse is 35 kb. We have created a new mouse model that defines the limits of the PWS-IC to 6 kb, and allows for selective deletion of the PWS-IC using cre/loxp technology. Using crosses between this new mouse model, PWS-IC^delta6kb, and a ubiquitouslyexpressing transgenic cre mouse line, CMV-cre, we were able to create mice with a paternally derived widespread deletion of the PWS-IC. These mice show a postnatal lethality phenotype and lack expression of normally paternally expressed PWS genes similar to what is observed in the 35 kb PWS-IC deletion mice. This new mouse model narrows the known boundaries of the mouse PWS-IC and opens up novel avenues for research on PWS and imprinting.