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- Title
Mutations in tropomyosin 4 underlie a rare form of human macrothrombocytopenia.
- Authors
Pleines, Irina; Woods, Joanne; Chappaz, Stephane; Kew, Verity; Foad, Nicola; Ballester-Beltrán, José; Aurbach, Katja; Lincetto, Chiara; Lane, Rachael M.; Schevzov, Galina; Alexander, Warren S.; Hilton, Douglas J.; Astle, William J.; Downes, Kate; Nurden, Paquita; Westbury, Sarah K.; Mumford, Andrew D.; Obaji, Samya G.; Collins, Peter W.; BioResource, NIHR
- 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.
- Subjects
THROMBOCYTOPENIA; TROPOMYOSINS; GENETIC mutation; BLOOD platelets; MEGAKARYOCYTES; MUSCLE protein metabolism; ANIMAL experimentation; ANIMALS; GENES; GENETIC disorders; MICE; MUSCLE proteins; RESEARCH funding; SEQUENCE analysis
- Publication
Journal of Clinical Investigation, 2017, Vol 127, Issue 3, p814
- ISSN
0021-9738
- Publication type
journal article
- DOI
10.1172/JCI86154