Untersuchungen zur Rolle von Tropomyosin 4 und Tropomyosin 1 in der Hämatopoese, Thrombozytenproduktion und Thrombozytenfunktion

• Antragstellerin: Dr. Irina Pleines
• Fachliche Zuordnung: Hämatologie, Onkologie ; Zellbiologie
• Förderung: Förderung von 2016 bis 2019
• Projektkennung: Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 315312020

• Erstellungsjahr: 2019

Zusammenfassung der Projektergebnisse

Inherited platelet disorders are characterized by defects in megakaryocyte maturation, platelet production or platelet function, and are often associated with an increased bleeding risk. A large GWAS meta-analysis indicated that single nucleotide variants (SNVs) in the genes encoding the actin cytoskeletal regulators tropomyosin 4 (TPM4) and tropomyosin 1 (TPM1) have an effect on the count and volume of platelets. We isolated a mouse line with an ENU-induced missense mutation in Tpm4. Mice carrying this mutation exhibited dose-dependent macrothrombocytopenia, while all other blood cell counts were normal. In addition, we identified 2 unrelated families in the BRIDGE Bleeding and Platelet Disorders (BPD) collection who carry a TPM4 variant that causes truncation of the TPM4 protein and segregates with macrothrombocytopenia. Insufficient TPM4 expression in human and mouse megakaryocytes resulted in a defect in the terminal stages of platelet production and mildly affected platelet function. Our results indicate that TPM4 regulates the interaction of actin filaments with several cytoskeletal regulators of known importance in platelet production, including n-cofilin, NMM-IIa, Filamin A and Actinin 1. In contrast, the analysis of mice lacking Tpm1 in megakaryocytes and platelets revealed that TPM1 is largely dispensable for platelet production and function. Similarly, Tpm1/Tpm4 double-mutant mice exhibited a macrothrombocytopenia, which was only very moderately aggravated as compared to Tpm4 mutant mice and no dramatic platelet function defects were observed. Together, our findings demonstrate largely non-redundant roles for TPM4 and TPM1 in platelet biogenesis reveal that variants affecting TPM4 expression cause a previously undescribed dominant Mendelian platelet disorder.

Projektbezogene Publikationen (Auswahl)

• A Cdc42/RhoA regulatory circuit downstream of glycoprotein Ib guides transendothelial platelet biogenesis. Nat Commun. 2017;8:15838
  Dütting S, Gaits-Iacovoni F, Stegner D, Popp M, Antkowiak A, van Eeuwijk JMM, Nurden P, Stritt S, Heib T, Aurbach K, Angay O, Cherpokova D, Heinz N, Baig AA, Gorelashvili MG, Gerner F, Heinze KG, Ware J, Krohne G, Ruggeri ZM, Nurden AT, Schulze H, Modlich U, Pleines I, Brakebusch C, Nieswandt B
  
• Mutations in tropomyosin 4 underlie a rare form of human macrothrombocytopenia. J Clin Invest. 2017;127:814-829
  Pleines I, Woods J, Chappaz S, Kew V, Foad N, Ballester-Beltrán J, Aurbach K, Lincetto C, Lane RM, Schevzov G, Alexander WS, Hilton DJ, Astle WJ, Downes K, Nurden P, Westbury SK, Mumford AD, Obaji SG, Collins PW, Delerue F, Ittner LM, Bryce NS, Holliday M, Lucas CA, Hardeman EC, Ouwehand WH, Gunning PW, Turro E, Tijssen MR, Kile BT
  
• Rho GTPases and their downstream effectors in megakaryocyte biology. Platelets. 2019;30:9-16
  Pleines I, Cherpokova D, Bender M