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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2025,4,22]]},"abstract":"<jats:p>\n                    Pseudohypoparathyroidism type 1B (PHP1B) is a multihormone resistance disorder caused by aberrant\n                    <jats:italic>GNAS<\/jats:italic>\n                    methylation. Characteristic epigenetic changes at\n                    <jats:italic>GNAS<\/jats:italic>\n                    differentially methylated regions (DMRs), i.e., NESP, AS1, AS2, XL, and A\/B, are associated with specific structural defects in different autosomal dominant PHP1B (AD-PHP1B) subtypes. However, mechanisms underlying abnormal\n                    <jats:italic>GNAS<\/jats:italic>\n                    methylation remain incompletely defined, largely because viable PHP1B mouse models are lacking. Using lymphoblastoid cells and induced pluripotent stem cells, we show that various\n                    <jats:italic>GNAS<\/jats:italic>\n                    methylation patterns in PHP1B reflect differential disruption of sense and antisense\n                    <jats:italic>GNAS<\/jats:italic>\n                    transcripts. In cases with broad\n                    <jats:italic>GNAS<\/jats:italic>\n                    methylation changes, loss of the maternal, sense-transcribed exon H\/AS region impairs methylation of the AS1 DMR, which results in biallelic expression of an antisense transcript,\n                    <jats:italic>GNAS-AS1<\/jats:italic>\n                    , and NESP hypermethylation. In contrast, cases with normal AS1 methylation, including\n                    <jats:italic>STX16<\/jats:italic>\n                    deletions, show monoallelic\n                    <jats:italic>GNAS-AS1<\/jats:italic>\n                    expression and normal NESP methylation. The roles of these\n                    <jats:italic>GNAS<\/jats:italic>\n                    transcripts were confirmed by a retrotransposon in\n                    <jats:italic>GNAS-AS1<\/jats:italic>\n                    intron 1, identified in an AD-PHP1B family. This insertion impaired exon H\/AS transcription when located on the maternal allele, thus preventing the complete establishment of methylation at all maternal\n                    <jats:italic>GNAS<\/jats:italic>\n                    DMRs, leading to biallelic\n                    <jats:italic>GNAS-AS1<\/jats:italic>\n                    transcription. However, maternal\n                    <jats:italic>GNAS-AS1<\/jats:italic>\n                    transcription was profoundly attenuated, thus allowing only a small gain-of-methylation at NESP. Likewise, on the paternal allele, the retrotransposon attenuated\n                    <jats:italic>GNAS-AS1<\/jats:italic>\n                    transcription, thus preventing complete NESP methylation. Our findings support a model of bidirectional transcription-mediated regulation of methylation at\n                    <jats:italic>GNAS<\/jats:italic>\n                    DMRs and will help to refine systematic approaches for establishing molecular defects underlying different PHP1B subtypes.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2423271122","type":"journal-article","created":{"date-parts":[[2025,4,18]],"date-time":"2025-04-18T13:45:16Z","timestamp":1744983916000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":5,"title":["Bidirectional disruption of\n                    <i>GNAS<\/i>\n                    transcripts causes broad methylation defects in pseudohypoparathyroidism type 1B"],"prefix":"10.1073","volume":"122","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9787-7922","authenticated-orcid":false,"given":"Yorihiro","family":"Iwasaki","sequence":"first","affiliation":[{"name":"Endocrine Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School","place":["Boston"]},{"name":"Division of Endocrinology, Metabolism & Nephrology, Tazuke Kofukai Medical Research Institute, Kitano Hospital","place":["Osaka, Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monica","family":"Reyes","sequence":"additional","affiliation":[{"name":"Endocrine Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School","place":["Boston"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7851-4069","authenticated-orcid":false,"given":"Anna","family":"Ryabets-Lienhard","sequence":"additional","affiliation":[{"name":"Center for Endocrinology, Diabetes, and Metabolism, Children\u2019s Hospital Los Angeles, University of Southern California Keck School of Medicine","place":["Los Angeles"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Barbara","family":"Gales","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Pediatric Nephrology, University of California, Los Angeles, Geffen School of Medicine","place":["Los Angeles"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3455-002X","authenticated-orcid":false,"given":"Agn\u00e8s","family":"Linglart","sequence":"additional","affiliation":[{"name":"Universit\u00e9 Paris-Saclay, INSERM, Physiologie et Physiopathologie Endocriniennes","place":["Le Kremlin-Bic\u00eatre, France"]},{"name":"Assistance Publique-H\u00f4pitaux de Paris, Centre de R\u00e9f\u00e9rence des Maladies du M\u00e9tabolisme du Calcium et du Phosphate and Service d\u2019Endocrinologie d\u2019Endocrinologie et Diab\u00e8te de l\u2019enfant, H\u00f4pital Bic\u00eatre","place":["Le Kremlin-Bic\u00eatre, France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6096-8601","authenticated-orcid":false,"given":"Danny E.","family":"Miller","sequence":"additional","affiliation":[{"name":"Division of Genetic Medicine, Department of Pediatrics, University of Washington and Seattle Children\u2019s Hospital","place":["Seattle"]},{"name":"Department of Laboratory Medicine and Pathology, University of Washington","place":["Seattle"]},{"name":"Brotman Baty Institute for Precision Medicine, University of Washington","place":["Seattle"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isidro B.","family":"Salusky","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Division of Pediatric Nephrology, University of California, Los Angeles, Geffen School of Medicine","place":["Los Angeles"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2643-3504","authenticated-orcid":false,"given":"Murat","family":"Bastepe","sequence":"additional","affiliation":[{"name":"Endocrine Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School","place":["Boston"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7491-0515","authenticated-orcid":false,"given":"Harald","family":"J\u00fcppner","sequence":"additional","affiliation":[{"name":"Endocrine Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School","place":["Boston"]},{"name":"Pediatric Nephrology Unit, Massachusetts General Hospital and Harvard Medical 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Albright, C. Burnett, P. Smith, W. Parson, Pseudohypoparathyroidism\u2014An example of \u2018Seabright-Bantam syndrome\u2019 report of three cases. Endocrinology 30, 922\u2013932 (1942).","journal-title":"Endocrinology"},{"key":"e_1_3_4_4_2","first-page":"337","article-title":"Pseudo-pseudohypoparathyroidism","volume":"65","author":"Albright F.","year":"1952","unstructured":"F. Albright, A. P. Forbes, H. Henneman, Pseudo-pseudohypoparathyroidism. Trans. Assoc. Am. Phys. 65, 337\u2013350 (1952).","journal-title":"Trans. Assoc. Am. 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