Dataset Information

Functional class assignment of the complete platelet proteome and transcriptome

ABSTRACT: Advances in platelet transcriptomics allow prediction of the full human platelet proteome. We integrated proteomes from six cohorts, encompassing 5.2k unique proteins (3.5k with copy numbers), with novel genome-wide platelet and megakaryocyte transcriptomes (Blueprint).

INSTRUMENT(S): Q Exactive HF

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Platelet

SUBMITTER: Fiorella Andrea Solari

LAB HEAD: Albert Sickmann

PROVIDER: PXD022011 | Pride | 2021-09-09

REPOSITORIES: Pride

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Publications

Assessment of a complete and classified platelet proteome from genome-wide transcripts of human platelets and megakaryocytes covering platelet functions.

Huang Jingnan J Swieringa Frauke F Solari Fiorella A FA Provenzale Isabella I Grassi Luigi L De Simone Ilaria I Baaten Constance C F M J CCFMJ Cavill Rachel R Sickmann Albert A Frontini Mattia M Heemskerk Johan W M JWM

Scientific reports 20210611 1

Novel platelet and megakaryocyte transcriptome analysis allows prediction of the full or theoretical proteome of a representative human platelet. Here, we integrated the established platelet proteomes from six cohorts of healthy subjects, encompassing 5.2 k proteins, with two novel genome-wide transcriptomes (57.8 k mRNAs). For 14.8 k protein-coding transcripts, we assigned the proteins to 21 UniProt-based classes, based on their preferential intracellular localization and presumed function. Thi ...[more]

PMID: 34117303

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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.

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	qExHF01_09184.raw	Raw
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