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Mutations in tropomyosin 4 underlie a rare form of human macrothrombocytopenia

Research output: Contribution to journalArticle

  • Irina Pleines
  • Joanne Woods
  • Stephane Chappaz
  • Verity Kew
  • Nicola Foad
  • Katja Aurbach
  • Chiara Lincetto
  • Rachael M Lane
  • Galina Schevzov
  • Warren S Alexander
  • Douglas J Hilton
  • William J Astle
  • Kate Downes
  • Paquita Nurden
  • Sarah K Westburyhttp://orcid.org/0000-0002-0950-8148
  • Andrew D Mumford
  • Samya G Obaji
  • Fabien Delerue
  • Lars M Ittner
  • Nicole S Bryce
  • Mira Holliday
  • Christine A Lucas
  • Edna C Hardeman
  • Willem H Ouwehand
  • Peter W Gunning
  • Ernest Turro
  • Marloes R Tijssen
  • Benjamin T Kile
Original languageEnglish
Pages (from-to)814-829
Number of pages16
JournalJournal of Clinical Investigation
Volume127
Issue number3
Early online date30 Jan 2017
DOIs
DateAccepted/In press - 1 Dec 2016
DateE-pub ahead of print - 30 Jan 2017
DatePublished (current) - 1 Mar 2017

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.

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    Rights statement: This is the final published version of the article (version of record). It first appeared online via The Journal of Clinical Investigation at https://doi.org/10.1172/JCI86154 . Please refer to any applicable terms of use of the publisher.

    Final published version, 3 MB, PDF document

    Licence: CC BY

  • Supplementary information PDF

    Rights statement: This is the final published version of the article (version of record). It first appeared online via The Journal of Clinical Investigation at https://doi.org/10.1172/JCI86154 . Please refer to any applicable terms of use of the publisher.

    Final published version, 6 MB, PDF document

    Licence: CC BY

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