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Impaired iloprost-induced platelet inhibition and phosphoproteome changes in patients with confirmed pseudohypoparathyroidism type Ia, linked to genetic mutations in GNAS.

ABSTRACT: Patients diagnosed with pseudohypoparathyroidism type Ia (PHP Ia) suffer from hormonal resistance and abnormal postural features, in a condition classified as Albright hereditary osteodystrophy (AHO) syndrome. This syndrome is linked to a maternally inherited mutation in the GNAS complex locus, encoding for the GTPase subunit Gs?. Here, we investigated how platelet phenotype and omics analysis can assist in the often difficult diagnosis. By coupling to the IP receptor, Gs? induces platelet inhibition via adenylyl cyclase and cAMP-dependent protein kinase A (PKA). In platelets from seven patients with suspected AHO, one of the largest cohorts examined, we studied the PKA-induced phenotypic changes. Five patients with a confirmed GNAS mutation, displayed impairments in Gs?-dependent VASP phosphorylation, aggregation, and microfluidic thrombus formation. Analysis of the platelet phosphoproteome revealed 2,516 phosphorylation sites, of which 453 were regulated by Gs?-PKA. Common changes in the patients were: (1) a joint panel of upregulated and downregulated phosphopeptides; (2) overall PKA dependency of the upregulated phosphopeptides; (3) links to key platelet function pathways. In one patient with GNAS mutation, diagnosed as non-AHO, the changes in platelet phosphoproteome were reversed. This combined approach thus revealed multiple phenotypic and molecular biomarkers to assist in the diagnosis of suspected PHP Ia.

SUBMITTER: Swieringa F

PROVIDER: S-EPMC7347634 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Impaired iloprost-induced platelet inhibition and phosphoproteome changes in patients with confirmed pseudohypoparathyroidism type Ia, linked to genetic mutations in GNAS.

Swieringa Frauke F Solari Fiorella A FA Pagel Oliver O Beck Florian F Huang Jingnan J Feijge Marion A H MAH Jurk Kerstin K Körver-Keularts Irene M L W IMLW Mattheij Nadine J A NJA Faber Jörg J Pohlenz Joachim J Russo Alexandra A Stumpel Connie T R M CTRM Schrander Dirk E DE Zieger Barbara B van der Meijden Paola E J PEJ Zahedi René P RP Sickmann Albert A Heemskerk Johan W M JWM

Scientific reports 20200709 1

Patients diagnosed with pseudohypoparathyroidism type Ia (PHP Ia) suffer from hormonal resistance and abnormal postural features, in a condition classified as Albright hereditary osteodystrophy (AHO) syndrome. This syndrome is linked to a maternally inherited mutation in the GNAS complex locus, encoding for the GTPase subunit Gsα. Here, we investigated how platelet phenotype and omics analysis can assist in the often difficult diagnosis. By coupling to the IP receptor, Gsα induces platelet inhib ...[more]

PMID: 32647264

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Project description:Patients diagnosed with pseudohypoparathyroidism type Ia (PHP Ia) suffer from hormonal resistance. This is often accompanied by abnormal postural and facial features, brachydactyly and dermal calcifications, a condition classified as Albright hereditary osteodystrophy (AHO) syndrome. Typically, this is the result of maternal inheritance of a mutation (or epigenetic defect) in the GNAS complex locus, encoding for the GTPase subunit Gsα. However, accurate diagnosis is often difficult. In blood platelets, Gsα couples to receptors for prostaglandin E1 and iloprost, and provides a master signal for platelet inhibition via adenylyl cyclase and cAMP-dependent protein kinase A (PKA). Here, we evaluated the iloprost-induced functional changes and phosphoproteome in platelets from eight patients with confirmed or suspected PHP Ia, one of the largest cohorts examined. Our aim was to asses how current proteomics techniques can help to find phosphorylation aberrations in these patients, and hence to improve future diagnosis Platelets from six out of eight patients (4 families), with confirmed GNAS mutations, displayed impairments in Gsα-dependent functional responses, i.e. VASP phosphorylation, aggregation, and microfluidic thrombus formation. Detailed analysis of platelet phosphoproteome revealed a consistent set of 2,516 protein phosphorylation sites, of which 453 were recognised as regulated by iloprost-Gsα, and 263 were upregulated. In five patients with AHO, we detected impairments in the iloprost-induced platelet phosphoproteome that were linked to a dysregulated platelet inhibition. The changes in these patients concerned: (i) both upregulated and downregulated phosphopeptides; (ii) a high Gsα and PKA dependency of the upregulated phosphopeptides; (iii) multiple phosphoproteins implicated in key platelet functions and biological pathways. Confirmation of these changes in iloprost-induced phosphoproteome was obtained using a panel of 14 targeted phosphopeptide assays. In contrast, or one patient with GNAS mutation diagnosed as non-AHO, we noticed reversed changes in the iloprost phosphoproteome. This combination of phosphoproteomic approaches can be a powerful tool to assist in future molecular diagnosis of patients with suspected PHP Ia.

Dataset Information

Impaired iloprost-induced platelet inhibition and phosphoproteome changes in patients with confirmed pseudohypoparathyroidism type Ia, linked to genetic mutations in GNAS.

Publications

Impaired iloprost-induced platelet inhibition and phosphoproteome changes in patients with confirmed pseudohypoparathyroidism type Ia, linked to genetic mutations in GNAS.

Similar Datasets

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