{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,7]],"date-time":"2026-10-07T11:06:26Z","timestamp":1791371186420,"version":"4.3.1"},"reference-count":112,"publisher":"Bioscientifica","issue":"1","content-domain":{"domain":["journals.bioscientifica.com"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2024,1,1]]},"abstract":"<jats:p>Several human disorders are caused by genetic or epigenetic changes involving the GNAS locus on chromosome 20q13.3 that encodes the alpha-subunit of the stimulatory G protein (Gs\u03b1) and several splice variants thereof. Thus, pseudohypoparathyroidism type Ia (PHP1A) is caused by heterozygous inactivating mutations involving the maternal GNAS exons 1\u201313 resulting in characteristic abnormalities referred to as Albright\u2019s hereditary osteodystrophy (AHO) that are associated with resistance to several agonist ligands, particularly to parathyroid hormone (PTH), thereby leading to hypocalcemia and hyperphosphatemia. GNAS mutations involving the paternal Gs\u03b1 exons also cause most of these AHO features, but without evidence for hormonal resistance, hence the term pseudopseudohypoparathyroidism (PPHP). Autosomal dominant pseudohypoparathyroidism type Ib (PHP1B) due to maternal GNAS or STX16 mutations (deletions, duplications, insertions, and inversions) is associated with epigenetic changes at one or several differentially methylated regions (DMRs) within GNAS. Unlike the inactivating Gs\u03b1 mutations that cause PHP1A and PPHP, hormonal resistance is caused in all PHP1B variants by impaired Gs\u03b1 expression due to loss of methylation at GNAS exon A\/B, which can be associated in some familial cases with epigenetic changes at the other maternal GNAS DMRs. The genetic defect(s) responsible for sporadic PHP1B, the most frequent variant of this disorder, remain(s) unknown for the majority of patients. However, characteristic epigenetic GNAS changes can be readily detected that include a gain of methylation at the neuroendocrine secretory protein (NESP) DMR. Multiple genetic or epigenetic GNAS abnormalities can thus impair Gs\u03b1 function or expression, consequently leading to inadequate cAMP-dependent signaling events downstream of various Gs\u03b1-coupled receptors.<\/jats:p>","DOI":"10.1530\/jme-23-0104","type":"journal-article","created":{"date-parts":[[2023,11,15]],"date-time":"2023-11-15T06:43:00Z","timestamp":1700030580000},"update-policy":"https:\/\/doi.org\/10.1530\/crossmarkpolicy-6","source":"Crossref","is-referenced-by-count":7,"title":["Pseudohypoparathyroidism: complex disease variants with unfortunate names"],"prefix":"10.1530","volume":"72","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7491-0515","authenticated-orcid":true,"given":"Harald","family":"J\u00fcppner","sequence":"first","affiliation":[{"name":"Endocrine Unit 1","department":["Department of Medicine and Pediatric Nephrology Unit, Department of Pediatrics, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"416","published-online":{"date-parts":[[2023,11,15]]},"reference":[{"key":"2026070811322086000_bib1","doi-asserted-by":"crossref","first-page":"8366","DOI":"10.1073\/pnas.0308758101","article-title":"XLalphas, the extra-long form of the alpha-subunit of the Gs G protein, is significantly longer than suspected, and so is its companion Alex","volume":"101","author":"Abramowitz","year":"2004","journal-title":"PNAS"},{"key":"2026070811322086000_bib2","first-page":"922","article-title":"Pseudohypoparathyroidism - an example of \u201cSeabright-Bantam syndrome\u201d","volume":"30","author":"Albright","year":"1942","journal-title":"Endocrinology"},{"key":"2026070811322086000_bib3","first-page":"337","article-title":"Pseudo-pseudohypoparathyroidism","volume":"65","author":"Albright","year":"1952","journal-title":"Transactions of the Association of American Physicians"},{"key":"2026070811322086000_bib4","doi-asserted-by":"crossref","DOI":"10.3390\/genes12081214","article-title":"DNA methylation dynamics in the female germline and maternal-effect mutations that disrupt genomic imprinting","volume":"12","author":"Anvar","year":"2021","journal-title":"Genes"},{"key":"2026070811322086000_bib5","article-title":"Pseudohypoparathyroidism, Albright's hereditary osteodystrophy, and progressive osseous heteroplasia: disorders caused by inactivating GNAS mutations that reduce Gs\u03b1 activity","author":"Bastepe","year":"2023","journal-title":"Endocrinology"},{"key":"2026070811322086000_bib6","doi-asserted-by":"crossref","first-page":"1283","DOI":"10.1086\/320117","article-title":"Paternal uniparental isodisomy of chromosome 20q (patUPD20q) - and the resulting changes in GNAS1 methylation - as a plausible cause of pseudohypoparathyroidism","volume":"68","author":"Bastepe","year":"2001","journal-title":"American Journal of Human Genetics"},{"key":"2026070811322086000_bib7","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1038\/ng1487","article-title":"Deletion of the NESP55 differentially methylated region causes loss of maternal GNAS imprints and pseudohypoparathyroidism type Ib","volume":"37","author":"Bastepe","year":"2005","journal-title":"Nature Genetics"},{"key":"2026070811322086000_bib8","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1016\/j.bone.2010.10.168","article-title":"Paternal uniparental isodisomy of the entire chromosome 20 as a molecular cause of pseudohypoparathyroidism type Ib (PHP-Ib)","volume":"48","author":"Bastepe","year":"2011","journal-title":"Bone"},{"key":"2026070811322086000_bib9","doi-asserted-by":"crossref","first-page":"8893","DOI":"10.1073\/pnas.83.23.8893","article-title":"Human cDNA clones for four species of G alpha s signal transduction protein","volume":"83","author":"Bray","year":"1986","journal-title":"PNAS"},{"key":"2026070811322086000_bib10","doi-asserted-by":"crossref","first-page":"E623","DOI":"10.1210\/jc.2014-4047","article-title":"Loss of methylation at GNAS exon A\/B is associated with increased intrauterine growth","volume":"100","author":"Br\u00e9hin","year":"2015","journal-title":"Journal of Clinical Endocrinology and Metabolism"},{"key":"2026070811322086000_bib11","doi-asserted-by":"crossref","first-page":"1244","DOI":"10.1016\/S0021-9258(18)60316-3","article-title":"Adenosine 3',5'-phosphate in biological materials. 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