CONTEXT: GNAS is an imprinted region that gives rise to several transcripts, antisense transcripts, and noncoding RNAs, including transcription of RNA encoding the alpha-subunit of the stimulatory G protein (Gsalpha). The complexity of the GNAS cluster results in ubiquitous genomic imprints, tissue-specific Gsalpha expression, and multiple genotype-phenotype relationships. Phenotypes resulting from genetic and epigenetic abnormalities of the GNAS region include Albright's hereditary osteodystrophy, pseudohypoparathyroidism types Ia (PHPIa) and Ib (PHPIb), and pseudopseudohypoparathyroidism (PPHP). 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. DESIGN AND PATIENTS: We report the first platelet-based diagnostic test for Gsalpha 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 Gsalpha stimulation. RESULTS: Platelets are easily accessible, and platelet aggregation responses were found to reflect Gsalpha signaling defects in patients, in concordance with the patient's phenotype and genotype. Gsalpha hypofunction in PHPIa and PPHP patients with GNAS mutations was clearly detected by this method. Mildly decreased or normal Gsalpha function was detected in patients with PHPIb with either an overall or exon 1A-only epigenetic defect, respectively. Platelet Gsalpha expression was reduced in both PHPIb patient groups, whereas XLalphas was up-regulated only in PHPIb patients with the broad epigenetic defect. CONCLUSION: The platelet-based test is a novel tool for establishing the diagnosis of Gsalpha defects, which may otherwise be quite challenging.
CONTEXT: GNAS is an imprinted region that gives rise to several transcripts, antisense transcripts, and noncoding RNAs, including transcription of RNA encoding the alpha-subunit of the stimulatory G protein (Gsalpha). The complexity of the GNAS cluster results in ubiquitous genomic imprints, tissue-specific Gsalpha expression, and multiple genotype-phenotype relationships. Phenotypes resulting from genetic and epigenetic abnormalities of the GNAS region include Albright's hereditary osteodystrophy, pseudohypoparathyroidism types Ia (PHPIa) and Ib (PHPIb), and pseudopseudohypoparathyroidism (PPHP). 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. DESIGN AND PATIENTS: We report the first platelet-based diagnostic test for Gsalpha 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 Gsalpha stimulation. RESULTS: Platelets are easily accessible, and platelet aggregation responses were found to reflect Gsalpha signaling defects in patients, in concordance with the patient's phenotype and genotype. Gsalpha hypofunction in PHPIa and PPHP patients with GNAS mutations was clearly detected by this method. Mildly decreased or normal Gsalpha function was detected in patients with PHPIb with either an overall or exon 1A-only epigenetic defect, respectively. Platelet Gsalpha expression was reduced in both PHPIb patient groups, whereas XLalphas was up-regulated only in PHPIb patients with the broad epigenetic defect. CONCLUSION: The platelet-based test is a novel tool for establishing the diagnosis of Gsalpha defects, which may otherwise be quite challenging.
Authors: Qing He; Richard Bouley; Zun Liu; Marc N Wein; Yan Zhu; Jordan M Spatz; Chia-Yu Wang; Paola Divieti Pajevic; Antonius Plagge; Jodie L Babitt; Murat Bastepe Journal: Proc Natl Acad Sci U S A Date: 2017-10-23 Impact factor: 11.205
Authors: Serap Turan; Jaakko Ignatius; Jukka S Moilanen; Outi Kuismin; Helen Stewart; Nicholas P Mann; Agnès Linglart; Murat Bastepe; Harald Jüppner Journal: J Clin Endocrinol Metab Date: 2012-10-18 Impact factor: 5.958
Authors: Benedetta Izzi; Inge Francois; Veerle Labarque; Chantal Thys; Christine Wittevrongel; Koen Devriendt; Eric Legius; Annick Van den Bruel; Marc D'Hooghe; Diether Lambrechts; Francis de Zegher; Chris Van Geet; Kathleen Freson Journal: PLoS One Date: 2012-06-05 Impact factor: 3.240
Authors: Xuechun Bai; Tianfu Yang; Austin M Putz; Zhiquan Wang; Changxi Li; Frédéric Fortin; John C S Harding; Michael K Dyck; Jack C M Dekkers; Catherine J Field; Graham S Plastow Journal: BMC Genomics Date: 2021-07-13 Impact factor: 3.969