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Type: Journal article
Title: Mutations in tropomyosin 4 underlie a rare form of human macrothrombocytopenia
Author: Pleines, I.
Woods, J.
Chappaz, S.
Kew, V.
Foad, N.
Ballester-Beltrán, J.
Aurbach, K.
Lincetto, C.
Lane, R.
Schevzov, G.
Alexander, W.
Hilton, D.
Astle, W.
Downes, K.
Nurden, P.
Westbury, S.
Mumford, A.
Obaji, S.
Collins, P.
BioResource, N.
et al.
Citation: Journal of Clinical Investigation, 2017; 127(3):814-829
Publisher: American Society for Clinical Investigation
Issue Date: 2017
ISSN: 0021-9738
Statement of
Irina Pleines ... Benjamin T. Kile
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.
Keywords: Blood Platelets
Rights: This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit
DOI: 10.1172/JCI86154
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