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

Frauke Swieringa, Fiorella A. Solari, Oliver Pagel, Florian Beck, Jingnan Huang, Marion A. H. Feijge, Kerstin Jurk, Irene M. L. W. Koerver-Keularts, Nadine J. A. Mattheij, Joerg Faber, Joachim Pohlenz, Alexandra Russo, Connie T. R. M. Stumpel, Dirk E. Schrander, Barbara Zieger, Paola E. J. van Der Meijden, Rene P. Zahedi, Albert Sickmann, Johan W. M. Heemskerk*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

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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 alpha. Here, we investigated how platelet phenotype and omics analysis can assist in the often difficult diagnosis. By coupling to the IP receptor, Gs alpha 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 alpha -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 alpha -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.

Original languageEnglish
Article number11389
Number of pages16
JournalScientific Reports
Volume10
Issue number1
DOIs
Publication statusPublished - 9 Jul 2020

Keywords

  • STIMULATORY G-PROTEIN
  • THROMBUS FORMATION
  • HEREDITARY OSTEODYSTROPHY
  • PROCOAGULANT ACTIVITY
  • PHOSPHORYLATION
  • REVEALS
  • ROLES
  • QUANTIFICATION
  • COMBINATION
  • ACTIVATION

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