Mutations in tropomyosin 4 underlie a rare form of human macrothrombocytopenia
AuthorPleines, I; Woods, J; Chappaz, S; Kew, V; Foad, N; Ballester-Beltran, J; Aurbach, K; Lincetto, C; Lane, RM; Schevzov, G; ...
Source TitleJournal of Clinical Investigation
PublisherAMER SOC CLINICAL INVESTIGATION INC
University of Melbourne Author/sKile, Benjamin; Alexander, Warren; Hilton, Douglas; Chappaz, Stephanie
AffiliationMedical Biology (W.E.H.I.)
School of BioSciences
Document TypeJournal Article
CitationsPleines, I., Woods, J., Chappaz, S., Kew, V., Foad, N., Ballester-Beltran, J., 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., Collins, P. W. ,... Kile, B. T. (2017). Mutations in tropomyosin 4 underlie a rare form of human macrothrombocytopenia. JOURNAL OF CLINICAL INVESTIGATION, 127 (3), pp.814-829. https://doi.org/10.1172/JCI86154.
Access StatusOpen Access
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.
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