Mutations in tropomyosin 4 underlie a rare form of human macrothrombocytopenia.Report as inadecuate

Mutations in tropomyosin 4 underlie a rare form of human macrothrombocytopenia.

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Publication Date: 2017-03

Journal Title: The Journal of clinical investigation

ISSN: 0021-9738

Publisher: American Society for Clinical Investigation

Volume: 127

Issue: 3

Pages: 814-829

Language: English

Type: Article

This Version: VoR

Physical Medium: Print-Electronic

Metadata: Show full item record

Citation: Pleines, I., Woods, J., Chappaz, S., Kew, V., Foad, N., Ballester-Beltrán, J., Aurbach, K., et al. (2017). Mutations in tropomyosin 4 underlie a rare form of human macrothrombocytopenia

The Journal of clinical investigation, 127 (3), 814-829.

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 $\textit{TPM4}$ variant that causes truncation of the TPM4 protein and segregates with macrothrombocytopenia, a disorder characterized by low platelet count. $\textit{N-Ethyl-N}$-nitrosourea–induced (ENU-induced) missense mutations in $\textit{Tpm4}$ or targeted inactivation of the $\textit{Tpm4}$ locus led to gene dosage–dependent macrothrombocytopenia in mice. All other blood cell counts in $\textit{Tpm4}$-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 $\textit{TPM4}$ in platelet biogenesis in humans and mice and reveal that truncating variants in $\textit{TPM4}$ cause a previously undescribed dominant Mendelian platelet disorder.

Sponsorship: The research participants were enrolled in the Biomedical Research Centres/Units Inherited Diseases Genetic Evaluation (BRIDGE) Bleeding and Platelet Disorders (BPD) study (UK REC10/H0304/66). We are grateful to all the donors who allowed us to use their samples for this study. We thank Sofia Papadia from the NIHR BioResource for organizing the recalls of BRIDGE-BPD participants. The genome sequencing of the BRIDGE-BPD participants was supported by the NIHR BioResource–Rare Diseases (to ET, KD, and WHO). The NIHR BioResource–Rare Diseases is responsible for the delivery of the rare diseases pilot phase of the 100,000 Genomes Project and is funded by the National Institute for Health Research (NIHR; Research in the Ouwehand laboratory also receives funding support from the European Commission, NIHR, Wellcome Trust, Medical Research Council (MRC), and British Heart Foundation under numbers RP-PG-0310-1002 and RG/09/12/28096. SKW is supported by an MRC Clinical Training Fellowship (MR/K023489/1). ADM receives support from the Bristol NIHR Biomedical Research Unit for Cardiovascular Disease. This work was supported by a Project Grant (no. 575535), a Program Grant (no. 1016647), a Fellowship (1063008 to BTK and 1058344 to WSA), Project Grants (to PWG and ECH), and an Independent Research Institutes Infrastructure Support Scheme Grant (no. 361646) from the Australian National Health and Medical Research Council; a fellowship from the Sylvia and Charles Viertel Foundation (to BTK); a start-up grant, a fellowship, and a grant from the German Research Foundation (SFB 688, PL707/1-1 and PL707/2-1 to IP); the Kids’ Cancer Project (to PWG); a Fellowship from the European Hematology Association (to MRT) and the British Heart Foundation (PG/13/77/30375 to MRT); NHS Blood and Transplant (to WHO and MRT); the Australian Cancer Research Fund; and a Victorian State Government Operational Infrastructure Support Grant.

Embargo Lift Date: 2100-01-01


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Author: Pleines, IrinaWoods, JoanneChappaz, StephaneKew, VerityFoad, NicolaBallester-Beltrán, JoséAurbach, KatjaLincetto, ChiaraLane, Ra



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