{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T11:54:24Z","timestamp":1791287664365,"version":"4.1.0"},"reference-count":56,"publisher":"National Academy of Sciences","issue":"17","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2012,4,24]]},"abstract":"<jats:p>\n                    Maternal deletion of the NESP55 differentially methylated region (DMR) (delNESP55\/ASdel3-4\n                    <jats:sup>m<\/jats:sup>\n                    , delNAS\n                    <jats:sup>m<\/jats:sup>\n                    ) from the\n                    <jats:italic>GNAS<\/jats:italic>\n                    locus in humans causes autosomal dominant pseudohypoparathyroidism type Ib (AD-PHP-Ib\n                    <jats:sup>delNASm<\/jats:sup>\n                    ), a disorder of proximal tubular parathyroid hormone (PTH) resistance associated with loss of maternal\n                    <jats:italic>GNAS<\/jats:italic>\n                    methylation imprints. Mice carrying a similar, maternally inherited deletion of the Nesp55 DMR (\n                    <jats:italic>\u0394Nesp55<\/jats:italic>\n                    <jats:sup>m<\/jats:sup>\n                    ) replicate these\n                    <jats:italic>Gnas<\/jats:italic>\n                    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 \u03b1s (XL\u03b1s) imprinting and the resultant biallelic expression of XL\u03b1s are responsible for the early postnatal lethality in\n                    <jats:italic>\u0394Nesp55<\/jats:italic>\n                    <jats:sup>m<\/jats:sup>\n                    mice. First, we found that\n                    <jats:italic>\u0394Nesp55<\/jats:italic>\n                    <jats:sup>m<\/jats:sup>\n                    mice are hypoglycemic and have reduced stomach-to-body weight ratio. We then generated mice having the same epigenetic abnormalities as the\n                    <jats:italic>\u0394Nesp55<\/jats:italic>\n                    <jats:sup>m<\/jats:sup>\n                    mice but with normalized XL\u03b1s expression due to the paternal disruption of the exon giving rise to this\n                    <jats:italic>Gnas<\/jats:italic>\n                    product. These mice (\n                    <jats:italic>\u0394Nesp55<\/jats:italic>\n                    <jats:sup>m<\/jats:sup>\n                    \/\n                    <jats:italic>Gnasxl<\/jats:italic>\n                    <jats:sup>m+\/p\u2212<\/jats:sup>\n                    ) 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\n                    <jats:italic>\u0394Nesp55<\/jats:italic>\n                    <jats:sup>m<\/jats:sup>\n                    mice were rescued in the\n                    <jats:italic>\u0394Nesp55<\/jats:italic>\n                    <jats:sup>m<\/jats:sup>\n                    \/\n                    <jats:italic>Gnasxl<\/jats:italic>\n                    <jats:sup>m+\/p\u2212<\/jats:sup>\n                    mice. Surviving double-mutant animals had significantly reduced G\u03b1s 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 XL\u03b1s expression. The double-mutant mice will help elucidate the pathophysiological mechanisms underlying AD-PHP-Ib.\n                  <\/jats:p>","DOI":"10.1073\/pnas.1117608109","type":"journal-article","created":{"date-parts":[[2012,4,10]],"date-time":"2012-04-10T23:55:20Z","timestamp":1334102120000},"page":"6638-6643","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":21,"title":["Loss of XL\u03b1s (extra-large \u03b1s) imprinting results in early postnatal hypoglycemia and lethality in a mouse model of pseudohypoparathyroidism Ib"],"prefix":"10.1073","volume":"109","author":[{"given":"Eduardo","family":"Fern\u00e1ndez-Rebollo","sequence":"first","affiliation":[{"name":"Endocrine Unit, Department of Medicine, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akira","family":"Maeda","sequence":"additional","affiliation":[{"name":"Endocrine Unit, Department of Medicine, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monica","family":"Reyes","sequence":"additional","affiliation":[{"name":"Endocrine Unit, Department of Medicine, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Serap","family":"Turan","sequence":"additional","affiliation":[{"name":"Endocrine Unit, Department of Medicine, and"},{"name":"Pediatric Endocrinology, Marmara University School of Medicine, Istanbul 34899, Turkey;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leopold F.","family":"Fr\u00f6hlich","sequence":"additional","affiliation":[{"name":"Endocrine Unit, Department of Medicine, and"},{"name":"Institute of Pathology, Medical University of Graz, 8036 Graz, Austria;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonius","family":"Plagge","sequence":"additional","affiliation":[{"name":"Cellular and Molecular Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool L69 3BX, United Kingdom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gavin","family":"Kelsey","sequence":"additional","affiliation":[{"name":"Epigenetics Programme, The Babraham Institute, Cambridge CB22 3AT, United Kingdom; 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