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GNAS Defects Identified by Stimulatory G Protein -Subunit Signalling Studies in Platelets

Center for Molecular and Vascular Biology (K.F., B.I., V.L., C.T., C.W., C.V.G.), Department of Pediatrics (V.L., M.V.H., W.P., F.d.Z., J.J., C.V.G.), and Department of Endocrinology (Internal Medicine) (M.B., R.B.), University Hospital Gasthuisberg, University of Leuven, 3000 Leuven, Belgium; and Department of Pediatrics (N.G.), Université Catholique de Louvain Medical School, Saint-Luc Academic Hospital, 1000 Brussels, Belgium

Address all correspondence and requests for reprints to: Kathleen Freson, Center for Molecular and Vascular Biology, University of Leuven, Herestraat 49, B-3000 Leuven, Belgium. E-mail: Kathleen.freson{at}med.kuleuven.be.

Context: GNAS is an imprinted region that gives rise to several transcripts, antisense transcripts, and noncoding RNAs, including transcription of RNA encoding the -subunit of the stimulatory G protein (Gs). The complexity of the GNAS cluster results in ubiquitous genomic imprints, tissue-specific Gs 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 Gs 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 stimulation.

Results: Platelets are easily accessible, and platelet aggregation responses were found to reflect Gs signaling defects in patients, in concordance with the patient’s phenotype and genotype. Gs hypofunction in PHPIa and PPHP patients with GNAS mutations was clearly detected by this method. Mildly decreased or normal Gs function was detected in patients with PHPIb with either an overall or exon 1A-only epigenetic defect, respectively. Platelet Gs expression was reduced in both PHPIb patient groups, whereas XLs 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 Gs defects, which may otherwise be quite challenging.