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dc.contributor.authorPleines, Irinaen
dc.contributor.authorWoods, Joanneen
dc.contributor.authorChappaz, Stephaneen
dc.contributor.authorKew, Verityen
dc.contributor.authorFoad, Nicolaen
dc.contributor.authorBallester-Beltrán, Joséen
dc.contributor.authorAurbach, Katjaen
dc.contributor.authorLincetto, Chiaraen
dc.contributor.authorLane, Rachael Men
dc.contributor.authorSchevzov, Galinaen
dc.contributor.authorAlexander, Warren Sen
dc.contributor.authorHilton, Douglas Jen
dc.contributor.authorAstle, Williamen
dc.contributor.authorDownes, Kateen
dc.contributor.authorNurden, Paquitaen
dc.contributor.authorWestbury, Sarah Ken
dc.contributor.authorMumford, Andrew Den
dc.contributor.authorObaji, Samya Gen
dc.contributor.authorCollins, Peter Wen
dc.contributor.authorDelerue, Fabienen
dc.contributor.authorIttner, Lars Men
dc.contributor.authorBryce, Nicole Sen
dc.contributor.authorHolliday, Miraen
dc.contributor.authorLucas, Christine Aen
dc.contributor.authorHardeman, Edna Cen
dc.contributor.authorOuwehand, Willemen
dc.contributor.authorGunning, Peter Wen
dc.contributor.authorTurro Bassols, Ernesten
dc.contributor.authorTijssen, Marloesen
dc.contributor.authorKile, Benjamin Ten
dc.description.abstractPlatelets 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.
dc.description.sponsorshipThe 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.
dc.publisherAmerican Society for Clinical Investigation
dc.rightsAttribution 4.0 Internationalen
dc.rightsAttribution 4.0 Internationalen
dc.rightsAttribution 4.0 Internationalen
dc.rightsAttribution 4.0 Internationalen
dc.subjectBlood Plateletsen
dc.subjectMice, Inbred BALB Cen
dc.subjectMice, Mutant Strainsen
dc.subjectGenetic Diseases, Inbornen
dc.subjectGenes, Dominanten
dc.subjectMutation, Missenseen
dc.subjectGenome-Wide Association Studyen
dc.titleMutations in tropomyosin 4 underlie a rare form of human macrothrombocytopenia.en
prism.publicationNameThe Journal of clinical investigationen
dc.contributor.orcidAstle, William [0000-0001-8866-6672]
dc.contributor.orcidDownes, Kate [0000-0003-0366-1579]
dc.contributor.orcidOuwehand, Willem [0000-0002-7744-1790]
dc.contributor.orcidTurro Bassols, Ernest [0000-0002-1820-6563]
rioxxterms.typeJournal Article/Reviewen
pubs.funder-project-idMRC (MR/L003120/1)
pubs.funder-project-idBritish Heart Foundation (RG/09/012/28096)
pubs.funder-project-idBritish Heart Foundation (RG/08/014/24067)
pubs.funder-project-idBritish Heart Foundation (PG/13/77/30375)
cam.orpheus.successThu Jan 30 12:56:37 GMT 2020 - The item has an open VoR version.*

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Attribution 4.0 International
Except where otherwise noted, this item's licence is described as Attribution 4.0 International