期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2012
卷号：109
期号：17
页码：6638-6643
DOI：10.1073/pnas.1117608109
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Maternal deletion of the NESP55 differentially methylated region (DMR) (delNESP55/ASdel3-4m, delNASm) from the GNAS locus in humans causes autosomal dominant pseudohypoparathyroidism type Ib (AD-PHP-IbdelNASm), a disorder of proximal tubular parathyroid hormone (PTH) resistance associated with loss of maternal GNAS methylation imprints. Mice carrying a similar, maternally inherited deletion of the Nesp55 DMR ({Delta}Nesp55m) replicate these Gnas epigenetic abnormalities and show evidence for PTH resistance, yet these mice demonstrate 100% mortality during the early postnatal period. We investigated whether the loss of extralarge s (XLs) imprinting and the resultant biallelic expression of XLs are responsible for the early postnatal lethality in{Delta} Nesp55m mice. First, we found that{Delta} Nesp55m mice are hypoglycemic and have reduced stomach-to-body weight ratio. We then generated mice having the same epigenetic abnormalities as the{Delta} Nesp55m mice but with normalized XLs expression due to the paternal disruption of the exon giving rise to this Gnas product. These mice ({Delta}Nesp55m/Gnasxlm+/p-) showed nearly 100% survival up to postnatal day 10, and a substantial number of them lived to adulthood. The hypoglycemia and reduced stomach-to-body weight ratio observed in 2-d-old{Delta} Nesp55m mice were rescued in the{Delta} Nesp55m/Gnasxlm+/p- mice. Surviving double-mutant animals had significantly reduced Gs mRNA levels and showed hypocalcemia, hyperphosphatemia, and elevated PTH levels, thus providing a viable model of human AD-PHP-Ib. Our findings show that the hypoglycemia and early postnatal lethality caused by the maternal deletion of the Nesp55 DMR result from biallelic XLs expression. The double-mutant mice will help elucidate the pathophysiological mechanisms underlying AD-PHP-Ib.
关键词：stimulatory G protein | renal proximal tubule | cyclic AMP
