PXD016534

PXD016534 is an original dataset announced via ProteomeXchange.

Title	Impaired iloprost-induced platelet inhibition and phosphoproteome changes in patients with confirmed pseudohypoparathyroidism type Ia, linked to genetic mutations in GNAS
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.
HostingRepository	PRIDE
AnnounceDate	2024-10-22
AnnouncementXML	Submission_2024-10-22_05:26:50.693.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Fiorella Andrea Solari
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	TMT6plex-127 reporter+balance reagent acylated N-terminal; phosphorylated residue; iTRAQ8plex-116 reporter+balance reagent acylated residue; monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Fusion Lumos; Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2019-11-29 08:16:36	ID requested
1	2021-09-08 14:54:08	announced
⏵ 2	2024-10-22 05:26:54	announced	2024-10-22: Updated project metadata.

Huang J, Swieringa F, Solari FA, Provenzale I, Grassi L, De Simone I, Baaten CCFMJ, Cavill R, Sickmann A, Frontini M, Heemskerk JWM, Assessment of a complete and classified platelet proteome from genome-wide transcripts of human platelets and megakaryocytes covering platelet functions. Sci Rep, 11(1):12358(2021) [pubmed]

10.1038/s41598-021-91661-x;

submitter keyword: Human platelets, phosphoproteome, TMT, iTRAQ, proteome,Albright hereditary osteodystrophy

Prof. Albert Sickmann
contact affiliation	Leibniz-Institut für Analytische Wissenschaften – ISAS – e.V.
contact email	albert.sickmann@isas.de
lab head
Fiorella Andrea Solari
contact affiliation	Leibniz-Institut für Analytische Wissenschaften – ISAS – e.V.
contact email	fiorella.solari@isas.de
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD016534
     1. Label: PRIDE project
     2. Name: Impaired iloprost-induced platelet inhibition and phosphoproteome changes in patients with confirmed pseudohypoparathyroidism type Ia, linked to genetic mutations in GNAS