| First Author | Fernández-Rebollo E | Year | 2012 |
| Journal | Proc Natl Acad Sci U S A | Volume | 109 |
| Issue | 17 | Pages | 6638-43 |
| PubMed ID | 22496590 | Mgi Jnum | J:183830 |
| Mgi Id | MGI:5319408 | Doi | 10.1073/pnas.1117608109 |
| Citation | Fernandez-Rebollo E, et al. (2012) Loss of XLalphas (extra-large alphas) imprinting results in early postnatal hypoglycemia and lethality in a mouse model of pseudohypoparathyroidism Ib. Proc Natl Acad Sci U S A 109(17):6638-43 |
| abstractText | Maternal deletion of the NESP55 differentially methylated region (DMR) (delNESP55/ASdel3-4(m), delNAS(m)) from the GNAS locus in humans causes autosomal dominant pseudohypoparathyroidism type Ib (AD-PHP-Ib(delNASm)), 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 (DeltaNesp55(m)) 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 alphas (XLalphas) imprinting and the resultant biallelic expression of XLalphas are responsible for the early postnatal lethality in DeltaNesp55(m) mice. First, we found that DeltaNesp55(m) mice are hypoglycemic and have reduced stomach-to-body weight ratio. We then generated mice having the same epigenetic abnormalities as the DeltaNesp55(m) mice but with normalized XLalphas expression due to the paternal disruption of the exon giving rise to this Gnas product. These mice (DeltaNesp55(m)/Gnasxl(m+/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 DeltaNesp55(m) mice were rescued in the DeltaNesp55(m)/Gnasxl(m+/p-) mice. Surviving double-mutant animals had significantly reduced Galphas 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 XLalphas expression. The double-mutant mice will help elucidate the pathophysiological mechanisms underlying AD-PHP-Ib. |
