Mutations in tropomyosin 4 underlie a rare form of human macrothrombocytopenia

Irina Pleines, Joanne Woods, Stephane Chappaz, Verity Kew, Nicola Foad, Katja Aurbach, Chiara Lincetto, Rachael M Lane, Galina Schevzov, Warren S Alexander, Douglas J Hilton, William J Astle, Kate Downes, Paquita Nurden, Sarah K Westbury, Andrew D Mumford, Samya G Obaji, Fabien Delerue, Lars M Ittner, Nicole S BryceMira Holliday, Christine A Lucas, Edna C Hardeman, Willem H Ouwehand, Peter W Gunning, Ernest Turro, Marloes R Tijssen, Benjamin T Kile

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Abstract

Platelets are anuclear cells that are essential for blood clotting. They are produced by large polyploid precursor cells called megakaryocytes. Previous genome-wide association studies in nearly 70,000 individuals indicated that single nucleotide variants (SNVs) in the gene encoding the actin cytoskeletal regulator tropomyosin 4 (TPM4) exert an effect on the count and volume of platelets. Platelet number and volume are independent risk factors for heart attack and stroke. Here, we have 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, a disorder characterized by low platelet count. N-Ethyl-N-nitrosourea–induced (ENU-induced) missense mutations in Tpm4 or targeted inactivation of the Tpm4 locus led to gene dosage–dependent macrothrombocytopenia in mice. All other blood cell counts in Tpm4-deficient mice were normal. Insufficient TPM4 expression in human and mouse megakaryocytes resulted in a defect in the terminal stages of platelet production and had a mild effect on platelet function. Together, our findings demonstrate a nonredundant role for TPM4 in platelet biogenesis in humans and mice and reveal that truncating variants in TPM4 cause a previously undescribed dominant Mendelian platelet disorder.
Original languageEnglish
Pages (from-to)814-829
Number of pages16
JournalJournal of Clinical Investigation
Volume127
Issue number3
Early online date30 Jan 2017
DOIs
Publication statusPublished - 1 Mar 2017

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Pleines, I., Woods, J., Chappaz, S., Kew, V., Foad, N., Aurbach, K., Lincetto, C., Lane, R. M., Schevzov, G., Alexander, W. S., Hilton, D. J., Astle, W. J., Downes, K., Nurden, P., Westbury, S. K., Mumford, A. D., Obaji, S. G., Delerue, F., Ittner, L. M., ... Kile, B. T. (2017). Mutations in tropomyosin 4 underlie a rare form of human macrothrombocytopenia. Journal of Clinical Investigation, 127(3), 814-829. https://doi.org/10.1172/JCI86154