{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,4]],"date-time":"2026-10-04T05:41:50Z","timestamp":1791092510671,"version":"4.1.0"},"reference-count":32,"publisher":"Oxford University Press (OUP)","issue":"8","license":[{"start":{"date-parts":[[2011,2,23]],"date-time":"2011-02-23T00:00:00Z","timestamp":1298419200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2011,8,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>In pseudohypoparathyroidism (PHP), PTH resistance results from impairment of signal transduction of G protein\u2013coupled receptors caused by a deficiency of the Gs\u03b1-cAMP signaling cascade due to diminished Gs\u03b1 activity in maternally imprinted tissues. In PHP-Ia, inactivating mutations of the GNAS gene lead to haploinsufficiency in some tissues with biallelic expression, so in addition to PHP, Albright's hereditary osteodystrophy (AHO) is also present. In PHP-Ib, caused by methylation defects at the GNAS locus, diminished Gs\u03b1 activity was thought to be limited to maternally imprinted tissues, such as the renal proximal tubule and the thyroid, leading to a lack of AHO. Recently, we demonstrated methylation defects in patients with AHO signs, indicating a connection between epigenetic changes and AHO. Our objective was to determine Gs\u03b1 activity in erythrocyte membranes in patients with epigenetic defects at the GNAS locus compared to normal controls and patients with inactivating GNAS mutations. Gs\u03b1 activity and expression, mutation of the GNAS locus, and methylation status were studied in patients with PHP and mild signs of AHO (PHP-Ia: 12; PHP-Ib: 17, of which 8 had some features of AHO). Then, we statistically compared the Gs\u03b1 activity of the different PHP subtypes. Patients with methylation defects at the GNAS locus show a significant decrease in erythrocyte Gs\u03b1 activity compared to normal controls (PHP-Ib versus controls, p\u2009&amp;lt;\u2009.001). This was significantly lower in patients with AHO signs (PHP-Ib\u2009+\u2009mild-AHO versus PHP-Ib, p\u2009&amp;lt;\u2009.05). Our research shows that PHP-Ia and PHP-Ib classification is not only overlapped genetically, as reported, but also in terms of Gs\u03b1 activity. Reduced expression of GNAS due to methylation defects could downregulate Gs\u03b1 activity in other tissues beyond those described and could also be causative of AHO. \u00a9 2011 American Society for Bone and Mineral Research<\/jats:p>","DOI":"10.1002\/jbmr.369","type":"journal-article","created":{"date-parts":[[2011,2,26]],"date-time":"2011-02-26T01:54:18Z","timestamp":1298685258000},"page":"1864-1870","source":"Crossref","is-referenced-by-count":45,"title":["Gs\u03b1 activity is reduced in erythrocyte membranes of patients with psedohypoparathyroidism due to epigenetic alterations at the <i>GNAS<\/i> locus"],"prefix":"10.1093","volume":"26","author":[{"given":"Celia","family":"Zazo","sequence":"first","affiliation":[{"name":"Molecular Genetics Laboratory, Research Unit, Hospital Txagorritxu, Vitoria-Gasteiz, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susanne","family":"Thiele","sequence":"additional","affiliation":[{"name":"Department of Pediatric and Adolescent Medicine, University of L\u00fcbeck, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cesar","family":"Mart\u00edn","sequence":"additional","affiliation":[{"name":"Unidad de Biof\u00edsica, Departamento de Bioqu\u00edmica, Universidad del Pa\u00eds Vasco, Centro Mixto CSIC-UPV\/EHU, Bilbao, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eduardo","family":"Fernandez-Rebollo","sequence":"additional","affiliation":[{"name":"Endocrine Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lorea","family":"Martinez-Indart","sequence":"additional","affiliation":[{"name":"Clinical Epidemiology Unit, Research Unit, CAIBER-Hospital de Cruces, Barakaldo-Bizkaia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ralf","family":"Werner","sequence":"additional","affiliation":[{"name":"Department of Pediatric and Adolescent Medicine, University of L\u00fcbeck, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Intza","family":"Garin","sequence":"additional","affiliation":[{"name":"Molecular Genetics Laboratory, Research Unit, Hospital Txagorritxu, Vitoria-Gasteiz, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Spanish PHP","family":"Group","sequence":"additional","affiliation":[{"name":"Molecular Genetics Laboratory, Research Unit, Hospital Txagorritxu, Vitoria-Gasteiz, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olaf","family":"Hiort","sequence":"additional","affiliation":[{"name":"Department of Pediatric and Adolescent Medicine, University of L\u00fcbeck, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guiomar","family":"Perez de Nanclares","sequence":"additional","affiliation":[{"name":"Molecular Genetics Laboratory, Research Unit, Hospital Txagorritxu, Vitoria-Gasteiz, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2011,2,23]]},"reference":[{"key":"2024020318011101600_bib1","doi-asserted-by":"crossref","first-page":"1159","DOI":"10.1152\/physrev.00003.2005","article-title":"Mammalian G proteins and their cell type specific functions","volume":"85","author":"Wettschureck","year":"2005","journal-title":"Physiol Rev."},{"key":"2024020318011101600_bib2","first-page":"675","article-title":"Endocrine manifestations of stimulatory G protein alpha-subunit mutations and the role of genomic imprinting","volume":"22","author":"Weinstein","year":"2001","journal-title":"Endocr Rev."},{"key":"2024020318011101600_bib3","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1007\/978-0-387-77576-0_3","article-title":"The GNAS locus and pseudohypoparathyroidism","volume":"626","author":"Bastepe","year":"2008","journal-title":"Adv Exp Med 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