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.