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Specific proteome changes in platelets from individuals with GATA1-, GFI1B- and RUNX1-linked bleeding disorders

ABSTRACT: Mutations in the transcription factors GATA1, GFI1B and RUNX1 (GATA Binding Factor 1, Growth Factor Independence 1B, Runt-related transcription factor 1) cause familial platelet and bleeding disorders. Mutant platelets exhibit common abnormalities including an α-granule reduction. This suggests that similar pathways are deregulated by different transcription factor mutations. To identify common factors, full platelet proteomes from individuals with mutant GATA1R216Q, GFI1BQ287*, RUNX1TD2-6, or RUNX1Q154Rfs, and healthy controls were examined by label free quantitative mass spectrometry. Unsupervised clustering analysis of 2823 reliably quantified proteins revealed profound differences between cases and controls. Among cases, 82 of 174 significantly downregulated proteins were assigned to platelet function, hemostasis and granule biology, in line with platelet dysfunction and bleedings. Remarkably, only two of these proteins were diminished in all affected cases. This indicates that transcription factor mutations alter platelet proteomes in distinct largely non-overlapping manners. In contrast to the two common diminished proteins, 46 proteins were overrepresented in all affected cases compared to controls. These proteins converged to mitochondrial, metabolic and other biological processes. This work provides the quantitative landscape of proteins that affect platelet function when deregulated by mutated transcription factors in inherited bleeding disorders.

INSTRUMENT(S): Orbitrap Fusion

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Blood Platelet, Platelet

DISEASE(S): Bleeding

SUBMITTER: Floris van Alphen

LAB HEAD: Bert A. van der Reijden

PROVIDER: PXD020343 | Pride | 2022-02-22

REPOSITORIES: Pride

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			Action	DRS
	BDN001_1.raw	Raw
	BDN001_2.raw	Raw
	BDN001_3.raw	Raw
	BDN010_1.raw	Raw
	BDN010_2.raw	Raw

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