Mutations in tropomyosin 4 underlie a rare form of human macrothrombocytopenia

Pleines, I; Woods, J; Chappaz, S; Kew, V; Foad, N; Ballester-Beltran, 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

Author(s): Pleines, I; Woods, J; Chappaz, S; Kew, V; Foad, N; Ballester-Beltran, 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;
Details: Publication Year 2017-03-01,Volume 127,Issue #3,Page 814-829
Journal Title: J Clin Invest
Publication Type: Journal Article
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.
Research Division(s): Cancer And Haematology; Molecular Medicine; Chemical Biology
Link To PubMed Central Version: https://www-ncbi-nlm-nih-gov/pmc/articles/PMC5330761/
Publisher's Version: https://doi.org/10.1172/JCI86154
NHMRC Grants: NHMRC/1063008, NHMRC/1058344, NHMRC/575535, NHMRC/1016647,
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2017-05-15 01:16:28

Last Modified: 2017-05-15 02:55:50