title: Loss of XLαs (extra-large αs) imprinting results in early postnatal hypoglycemia and lethality in a mouse model of pseudohypoparathyroidism Ib.
abstract: 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 (ΔNesp55(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 αs (XLαs) imprinting and the resultant biallelic expression of XLαs are responsible for the early postnatal lethality in ΔNesp55(m) mice. First, we found that ΔNesp55(m) mice are hypoglycemic and have reduced stomach-to-body weight ratio. We then generated mice having the same epigenetic abnormalities as the ΔNesp55(m) mice but with normalized XLαs expression due to the paternal disruption of the exon giving rise to this Gnas product. These mice (ΔNesp55(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 ΔNesp55(m) mice were rescued in the ΔNesp55(m)/Gnasxl(m+/p-) mice. Surviving double-mutant animals had significantly reduced Gαs 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 XLαs expression. The double-mutant mice will help elucidate the pathophysiological mechanisms underlying AD-PHP-Ib.
authors.affiliation: Endocrine Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Fernández-Rebollo
authors.forename: Akira
authors.initials: A
authors.lastname: Maeda
authors.forename: Monica
authors.initials: M
authors.lastname: Reyes
authors.forename: Serap
authors.initials: S
authors.lastname: Turan
authors.forename: Leopold F
authors.initials: LF
authors.lastname: Fröhlich
authors.forename: Antonius
authors.initials: A
authors.lastname: Plagge
authors.forename: Gavin
authors.initials: G
authors.lastname: Kelsey
authors.forename: Harald
authors.initials: H
authors.lastname: Jüppner
authors.forename: Murat
authors.initials: M
authors.lastname: Bastepe
mesh_terms: D000818:Animals; D001835:Body Weight; D002864:Chromogranins; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000235:genetics*; D005804:Genes, Lethal; D018392:Genomic Imprinting; D007003:Hypoglycemia / Q000150:complications / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D009929:Organ Size; D011547:Pseudohypoparathyroidism / Q000150:complications / Q000235:genetics*; D013270:Stomach / Q000473:pathology
chemical_list: D002864:Chromogranins; C498642:Gnas protein, mouse; D019205:GTP-Binding Protein alpha Subunits, Gs