TY - JOUR
T1 - Proteomic landscapes of inherited platelet disorders with different etiologies
AU - Kreft, Iris C.
AU - Huisman, Elise J.
AU - Cnossen, Marjon H.
AU - van Alphen, Floris P. J.
AU - van der Zwaan, Carmen
AU - van Leeuwen, Karin
AU - van Spaendonk, Rosalina
AU - Porcelijn, Leendert
AU - Veen, Caroline S. B.
AU - van den Biggelaar, Maartje
AU - de Haas, Masja
AU - Meijer, Alexander B.
AU - Hoogendijk, Arie J.
N1 - Funding Information: The work presented here was supported by the Landsteiner Foundation for Blood Transfusion Research [LSBR-1517 to M.v.d.B., LSBR-1923 to M.v.d.B. and A.J.H]. We acknowledge all the patients and family members who contributed to this research. The authors would like to thank the people from the research facility of Sanquin for helping with isolation of platelets. Publisher Copyright: © 2022 International Society on Thrombosis and Haemostasis
PY - 2023/2/1
Y1 - 2023/2/1
N2 - BACKGROUND: Inherited platelet disorders (IPDs) are a heterogeneous group of rare diseases that are caused by the defects in early megakaryopoiesis, proplatelet formation, and/or mature platelet function. Although genomic sequencing is increasingly used to identify genetic variants underlying IPD, this technique does not disclose resulting molecular changes that impact platelet function. Proteins are the functional units that shape platelet function; however, insights into how variants that cause IPDs impact platelet proteomes are limited. OBJECTIVES: The objective of this study was to profile the platelet proteomics signatures of IPDs. METHODS: We performed unbiased label-free quantitative mass spectrometry (MS)-based proteome profiling on platelets of 34 patients with IPDs with variants in 13 ISTH TIER1 genes that affect different stages of platelet development. RESULTS: In line with the phenotypical heterogeneity between IPDs, proteomes were diverse between IPDs. We observed extensive proteomic alterations in patients with a GFI1B variant and for genetic variants in genes encoding proteins that impact cytoskeletal processes (MYH9, TUBB1, and WAS). Using the diversity between IPDs, we clustered protein dynamics, revealing disrupted protein-protein complexes. This analysis furthermore grouped proteins with similar cellular function and location, classifying mitochondrial protein constituents and identifying both known and putative novel alpha granule associated proteins. CONCLUSIONS: With this study, we demonstrate a MS-based proteomics perspective to IPDs. By integrating the effects of IPDs that impact different aspects of platelet function, we dissected the biological contexts of protein alterations to gain further insights into the biology of platelet (dys)function.
AB - BACKGROUND: Inherited platelet disorders (IPDs) are a heterogeneous group of rare diseases that are caused by the defects in early megakaryopoiesis, proplatelet formation, and/or mature platelet function. Although genomic sequencing is increasingly used to identify genetic variants underlying IPD, this technique does not disclose resulting molecular changes that impact platelet function. Proteins are the functional units that shape platelet function; however, insights into how variants that cause IPDs impact platelet proteomes are limited. OBJECTIVES: The objective of this study was to profile the platelet proteomics signatures of IPDs. METHODS: We performed unbiased label-free quantitative mass spectrometry (MS)-based proteome profiling on platelets of 34 patients with IPDs with variants in 13 ISTH TIER1 genes that affect different stages of platelet development. RESULTS: In line with the phenotypical heterogeneity between IPDs, proteomes were diverse between IPDs. We observed extensive proteomic alterations in patients with a GFI1B variant and for genetic variants in genes encoding proteins that impact cytoskeletal processes (MYH9, TUBB1, and WAS). Using the diversity between IPDs, we clustered protein dynamics, revealing disrupted protein-protein complexes. This analysis furthermore grouped proteins with similar cellular function and location, classifying mitochondrial protein constituents and identifying both known and putative novel alpha granule associated proteins. CONCLUSIONS: With this study, we demonstrate a MS-based proteomics perspective to IPDs. By integrating the effects of IPDs that impact different aspects of platelet function, we dissected the biological contexts of protein alterations to gain further insights into the biology of platelet (dys)function.
KW - blood platelets
KW - inherited blood coagulation disorders
KW - mass spectrometry
KW - multiprotein complexes
KW - proteomics
UR - http://www.scopus.com/inward/record.url?scp=85147893788&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/j.jtha.2022.11.021
DO - https://doi.org/10.1016/j.jtha.2022.11.021
M3 - Article
C2 - 36700500
SN - 1538-7933
VL - 21
SP - 359-372.e3
JO - Journal of thrombosis and haemostasis : JTH
JF - Journal of thrombosis and haemostasis : JTH
IS - 2
ER -