{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T21:00:23Z","timestamp":1791406823245,"version":"4.3.3"},"reference-count":34,"publisher":"National Academy of Sciences","issue":"20","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2010,5,18]]},"abstract":"<jats:p>\n                    Approximately 100 genes undergo genomic imprinting. Mutations in fewer than 10 imprinted genetic loci, including\n                    <jats:italic>GNAS,<\/jats:italic>\n                    are associated with complex human diseases that differ phenotypically based on the parent transmitting the mutation. Besides the ubiquitously expressed Gs\u03b1, which is of broad biological importance,\n                    <jats:italic>GNAS<\/jats:italic>\n                    gives rise to an antisense transcript and to several Gs\u03b1 variants that are transcribed from the nonmethylated parental allele. We previously identified two almost identical\n                    <jats:italic>GNAS<\/jats:italic>\n                    microdeletions extending from exon NESP55 to antisense (AS) exon 3 (delNESP55\/delAS3-4). When inherited maternally, both deletions are associated with erasure of all maternal\n                    <jats:italic>GNAS<\/jats:italic>\n                    methylation imprints and autosomal-dominant pseudohypoparathyroidism type Ib, a disorder characterized by parathyroid hormone\u2013resistant hypocalcemia and hyperphosphatemia. As for other imprinting disorders, the mechanisms resulting in abnormal\n                    <jats:italic>GNAS<\/jats:italic>\n                    methylation are largely unknown, in part because of a paucity of suitable animal models. We now showed in mice that deletion of the region equivalent to delNESP55\/delAS3-4 on the paternal allele (\u0394Nesp55\n                    <jats:sup>p<\/jats:sup>\n                    ) leads to healthy animals without\n                    <jats:italic>Gnas<\/jats:italic>\n                    methylation changes. In contrast, mice carrying the deletion on the maternal allele (\u0394Nesp55\n                    <jats:sup>m<\/jats:sup>\n                    ) showed loss of all maternal\n                    <jats:italic>Gnas<\/jats:italic>\n                    methylation imprints, leading in kidney to increased 1A transcription and decreased Gs\u03b1 mRNA levels, and to associated hypocalcemia, hyperphosphatemia, and secondary hyperparathyroidism. Besides representing a murine autosomal-dominant pseudohypoparathyroidism type Ib model and one of only few animal models for imprinted human disorders, our findings suggest that the Nesp55 differentially methylated region is an additional principal imprinting control region, which directs\n                    <jats:italic>Gnas<\/jats:italic>\n                    methylation and thereby affects expression of all maternal\n                    <jats:italic>Gnas<\/jats:italic>\n                    -derived transcripts.\n                  <\/jats:p>","DOI":"10.1073\/pnas.0910224107","type":"journal-article","created":{"date-parts":[[2010,4,28]],"date-time":"2010-04-28T23:16:27Z","timestamp":1272496587000},"page":"9275-9280","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":58,"title":["Targeted deletion of the Nesp55 DMR defines another\n                    <i>Gnas<\/i>\n                    imprinting control region and provides a mouse model of autosomal dominant PHP-Ib"],"prefix":"10.1073","volume":"107","author":[{"given":"Leopold F.","family":"Fr\u00f6hlich","sequence":"first","affiliation":[{"name":"Endocrine Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114;"},{"name":"Institute of Pathophysiology, University of Veterinary Medicine, 1210 Vienna, Austria;"},{"name":"Institute of Pathology, Medical University of Graz, 8036 Graz, Austria;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Mrakovcic","sequence":"additional","affiliation":[{"name":"Institute of Pathophysiology, University of Veterinary Medicine, 1210 Vienna, Austria;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ralf","family":"Steinborn","sequence":"additional","affiliation":[{"name":"VetOMICS Center, University of Veterinary Medicine, 1210 Vienna, Austria;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ung-Il","family":"Chung","sequence":"additional","affiliation":[{"name":"Endocrine Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114;"},{"name":"Department of Bioengineering, University of Tokyo Graduate Schools of Engineering and Medicine, Tokyo 113-0033, Japan; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Murat","family":"Bastepe","sequence":"additional","affiliation":[{"name":"Endocrine Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harald","family":"J\u00fcppner","sequence":"additional","affiliation":[{"name":"Endocrine Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114;"},{"name":"Pediatric Nephrology Unit, Department of Pediatrics, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2010,4,28]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.tig.2005.06.008"},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-genom-082908-150026"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1138\/20050188"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.med.55.091902.103843"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.pharmthera.2007.03.013"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1677\/JOE-07-0544"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.95.17.10038"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.95.26.15475"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.96.7.3830"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.97.7.3342"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/9.5.835"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1159\/000090832"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2006-2287"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2007-0927"},{"key":"e_1_3_3_15_2","first-page":"65","article-title":"GNAS locus and pseudohypoparathyroidism","volume":"63","author":"Bastepe M","year":"2005","unstructured":"M Bastepe, H J\u00fcppner, GNAS locus and pseudohypoparathyroidism. 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