Mutations in tropomyosin 4 underlie a rare form of human macrothrombocytopenia

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 Westbury, Andrew D Mumford, Samya G Obaji, Fabien Delerue, Lars M Ittner, Nicole S BryceMira Holliday, Christine A Lucas, Edna C Hardeman, Willem H Ouwehand, Peter W Gunning, Ernest Turro, Marloes R Tijssen, Benjamin T Kile

Research output: Contribution to journalArticle (Academic Journal)peer-review

28 Citations (Scopus)
482 Downloads (Pure)

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.
Original languageEnglish
Pages (from-to)814-829
Number of pages16
JournalJournal of Clinical Investigation
Volume127
Issue number3
Early online date30 Jan 2017
DOIs
Publication statusPublished - 1 Mar 2017

Fingerprint Dive into the research topics of 'Mutations in tropomyosin 4 underlie a rare form of human macrothrombocytopenia'. Together they form a unique fingerprint.

Cite this