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 (Delta Nesp55(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 as (XL alpha s) imprinting and the resultant biallelic expression of XLas are responsible for the early postnatal lethality in Delta Nesp55(m) mice. First, we found that Delta Nesp55(m) mice are hypoglycemic and have reduced stomach-to-body weight ratio. We then generated mice having the same epigenetic abnormalities as the Delta Nesp55(m) mice but with normalized XLas expression due to the paternal disruption of the exon giving rise to this Gnas product. These mice (Delta Nesp55(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 Delta Nesp55(m) mice were rescued in the Delta Nesp55(m)/Gnasxl(m+/p-) mice. Surviving double-mutant animals had significantly reduced Gas 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 XLas expression. The double-mutant mice will help elucidate the pathophysiological mechanisms underlying AD-PHP-Ib.