{"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":1791092510666,"version":"4.1.0"},"reference-count":45,"publisher":"The Endocrine Society","issue":"12","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2008,12,1]]},"abstract":"<jats:p>Context: GNAS is an imprinted region that gives rise to several transcripts, antisense transcripts, and noncoding RNAs, including transcription of RNA encoding the \u03b1-subunit of the stimulatory G protein (Gs\u03b1). The complexity of the GNAS cluster results in ubiquitous genomic imprints, tissue-specific Gs\u03b1 expression, and multiple genotype-phenotype relationships. Phenotypes resulting from genetic and epigenetic abnormalities of the GNAS region include Albright\u2019s hereditary osteodystrophy, pseudohypoparathyroidism types Ia (PHPIa) and Ib (PHPIb), and pseudopseudohypoparathyroidism (PPHP).<\/jats:p>\n                  <jats:p>Objective: The aim was to study the complex GNAS pathology by a functional test as an alternative to the generally used but labor-intensive erythrocyte complementation assay.<\/jats:p>\n                  <jats:p>Design and Patients: We report the first platelet-based diagnostic test for Gs\u03b1 hypofunction, supported by clinical, biochemical, and molecular data for six patients with PHPIa or PPHP and nine patients with PHPIb. The platelet test is based on the inhibition of platelet aggregation by cAMP, produced after Gs\u03b1 stimulation.<\/jats:p>\n                  <jats:p>Results: Platelets are easily accessible, and platelet aggregation responses were found to reflect Gs\u03b1 signaling defects in patients, in concordance with the patient\u2019s phenotype and genotype. Gs\u03b1 hypofunction in PHPIa and PPHP patients with GNAS mutations was clearly detected by this method. Mildly decreased or normal Gs\u03b1 function was detected in patients with PHPIb with either an overall or exon 1A-only epigenetic defect, respectively. Platelet Gs\u03b1 expression was reduced in both PHPIb patient groups, whereas XL\u03b1s was up-regulated only in PHPIb patients with the broad epigenetic defect.<\/jats:p>\n                  <jats:p>Conclusion: The platelet-based test is a novel tool for establishing the diagnosis of Gs\u03b1 defects, which may otherwise be quite challenging.<\/jats:p>","DOI":"10.1210\/jc.2008-0883","type":"journal-article","created":{"date-parts":[[2008,9,23]],"date-time":"2008-09-23T21:07:06Z","timestamp":1222204026000},"page":"4851-4859","source":"Crossref","is-referenced-by-count":34,"title":["GNAS Defects Identified by Stimulatory G Protein \u03b1-Subunit Signalling Studies in Platelets"],"prefix":"10.1210","volume":"93","author":[{"given":"Kathleen","family":"Freson","sequence":"first","affiliation":[{"name":"Center for Molecular and Vascular Biology (K.F., B.I., V.L., C.T., C.W., C.V.G.), University Hospital Gasthuisberg, University of Leuven, 3000 Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benedetta","family":"Izzi","sequence":"additional","affiliation":[{"name":"Center for Molecular and Vascular Biology (K.F., B.I., V.L., C.T., C.W., C.V.G.), University Hospital Gasthuisberg, University of Leuven, 3000 Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Veerle","family":"Labarque","sequence":"additional","affiliation":[{"name":"Center for Molecular and Vascular Biology (K.F., B.I., V.L., C.T., C.W., C.V.G.), University Hospital Gasthuisberg, University of Leuven, 3000 Leuven, Belgium"},{"name":"Department of Pediatrics (V.L., M.V.H., W.P., F.d.Z., J.J., C.V.G.), University Hospital Gasthuisberg, University of Leuven, 3000 Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monique","family":"Van Helvoirt","sequence":"additional","affiliation":[{"name":"Department of Pediatrics (V.L., M.V.H., W.P., F.d.Z., J.J., C.V.G.), University Hospital Gasthuisberg, University of Leuven, 3000 Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chantal","family":"Thys","sequence":"additional","affiliation":[{"name":"Center for Molecular and Vascular Biology (K.F., B.I., V.L., C.T., C.W., C.V.G.), University Hospital Gasthuisberg, University of Leuven, 3000 Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christine","family":"Wittevrongel","sequence":"additional","affiliation":[{"name":"Center for Molecular and Vascular Biology (K.F., B.I., V.L., C.T., C.W., C.V.G.), University Hospital Gasthuisberg, University of Leuven, 3000 Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie","family":"Bex","sequence":"additional","affiliation":[{"name":"Department of Endocrinology (Internal Medicine) (M.B., R.B.), University Hospital Gasthuisberg, University of Leuven, 3000 Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roger","family":"Bouillon","sequence":"additional","affiliation":[{"name":"Department of Endocrinology (Internal Medicine) (M.B., R.B.), University Hospital Gasthuisberg, University of Leuven, 3000 Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathalie","family":"Godefroid","sequence":"additional","affiliation":[{"name":"Department of Pediatrics (N.G.), Universite\u0301 Catholique de Louvain Medical School, Saint-Luc Academic Hospital, 1000 Brussels, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Willem","family":"Proesmans","sequence":"additional","affiliation":[{"name":"Department of Pediatrics (V.L., M.V.H., W.P., F.d.Z., J.J., C.V.G.), University Hospital Gasthuisberg, University of Leuven, 3000 Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francis","family":"de Zegher","sequence":"additional","affiliation":[{"name":"Department of Pediatrics (V.L., M.V.H., W.P., F.d.Z., J.J., C.V.G.), University Hospital Gasthuisberg, University of Leuven, 3000 Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jaak","family":"Jaeken","sequence":"additional","affiliation":[{"name":"Department of Pediatrics (V.L., M.V.H., W.P., F.d.Z., J.J., C.V.G.), University Hospital Gasthuisberg, University of Leuven, 3000 Leuven, Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chris","family":"Van Geet","sequence":"additional","affiliation":[{"name":"Center for Molecular and Vascular Biology (K.F., B.I., V.L., C.T., C.W., C.V.G.), University Hospital Gasthuisberg, University of Leuven, 3000 Leuven, Belgium"},{"name":"Department of Pediatrics (V.L., M.V.H., W.P., F.d.Z., J.J., C.V.G.), University Hospital Gasthuisberg, University of Leuven, 3000 Leuven, 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upstream of the GNAS locus.","volume":"1068","author":"Juppner","year":"2006","journal-title":"Ann NY Acad Sci"},{"key":"2020071613381843100_R23","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1093\/hmg\/ddi009","article-title":"Distinct patterns of abnormal GNAS imprinting in familial and sporadic pseudohypoparathyroidism type IB.","volume":"14","author":"Liu","year":"2005","journal-title":"Hum Mol Genet"},{"key":"2020071613381843100_R24","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1046\/j.1365-2265.1997.1100922.x-i1","article-title":"GNAS mutational analysis in pseudohypoparathyroidism.","volume":"49","author":"Ahmed","year":"1998","journal-title":"Clin Endocrinol (Oxf)"},{"key":"2020071613381843100_R25","first-page":"4630","article-title":"Analysis of the GNAS gene in Albright\u2019s hereditary osteodystrophy.","volume":"86","author":"Ahrens","year":"2001","journal-title":"J Clin Endocrinol Metab"},{"key":"2020071613381843100_R26","doi-asserted-by":"crossref","first-page":"120","DOI":"10.1159\/000185501","article-title":"Clinical and biological heterogeneity in pseudohypoparathyroidism syndrome. Results of a multicenter study.","volume":"48","author":"Marguet","year":"1997","journal-title":"Horm Res"},{"key":"2020071613381843100_R27","doi-asserted-by":"crossref","first-page":"647","DOI":"10.1515\/JPEM.2006.19.S2.647","article-title":"Determination of Gs \u03b1 protein activity in Albright\u2019s hereditary osteodystrophy.","volume":"19","author":"Ahrens","year":"2006","journal-title":"J Pediatr Endocrinol Metab"},{"key":"2020071613381843100_R28","doi-asserted-by":"crossref","first-page":"1319","DOI":"10.1016\/0006-291X(80)90563-X","article-title":"Deficient activity of guanine nucleotide regulatory protein in erythrocytes from patients with pseudohypoparathyroidism.","volume":"94","author":"Levine","year":"1980","journal-title":"Biochem Biophys Res Commun"},{"key":"2020071613381843100_R29","doi-asserted-by":"crossref","first-page":"733","DOI":"10.1055\/s-0037-1616126","article-title":"Genetic variation of the extra-large stimulatory G protein \u03b1-subunit leads to Gs hyperfunction in platelets and is a risk factor for bleeding.","volume":"86","author":"Freson","year":"2000","journal-title":"Thromb Haemost"},{"key":"2020071613381843100_R30","doi-asserted-by":"crossref","first-page":"2741","DOI":"10.1093\/hmg\/11.22.2741","article-title":"Pseudohypoparathyroidism type Ib with disturbed imprinting in the GNAS cluster and Gs\u03b1 deficiency in platelets.","volume":"11","author":"Freson","year":"2002","journal-title":"Hum Mol Genet"},{"key":"2020071613381843100_R31","doi-asserted-by":"crossref","first-page":"1255","DOI":"10.1172\/JCI19159","article-title":"Autosomal dominant pseudohypoparathyroidism type Ib is associated with a heterozygous microdeletion that likely disrupts a putative imprinting control element of GNAS.","volume":"112","author":"Bastepe","year":"2003","journal-title":"J Clin Invest"},{"key":"2020071613381843100_R32","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1038\/ng1487","article-title":"Deletion of the NESP55 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