Mutations in tropomyosin 4 underlie a rare form of human macrothrombocytopenia.
Mutations in tropomyosin 4 underlie a rare form of human macrothrombocytopenia.
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DOI：
10.1172/jci86154
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发表时间：
2017-03-01
期刊：
影响因子：
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通讯作者：
Kile BT
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文献类型：
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作者：
Pleines I;Woods J;Chappaz S;Kew V;Foad N;Ballester-Beltrán J;Aurbach K;Lincetto C;Lane RM;Schevzov G;Alexander WS;Hilton DJ;Astle WJ;Downes K;Nurden P;Westbury SK;Mumford AD;Obaji SG;Collins PW;Delerue F;Ittner LM;Bryce NS;Holliday M;Lucas CA;Hardeman EC;Ouwehand WH;Gunning PW;Turro E;Tijssen MR;Kile BT
血小板是对血液凝固至关重要的无核细胞。它们由称为巨核细胞的大型多倍体前体细胞产生。先前在近70，000人中进行的全基因组关联研究表明，编码肌动蛋白细胞骨架调节剂原肌球蛋白4（TPM 4）的基因中的单核苷酸变体（SNV）对血小板的计数和体积产生影响。血小板数量和体积是心脏病发作和中风的独立危险因素。在这里，我们已经确定了2个不相关的家庭在桥出血和血小板疾病（BPD）收集谁携带的TPM 4变异，导致截断的TPM 4蛋白和分离与巨血小板减少症，一种疾病的特点是低血小板计数。N-乙基-N-亚硝基脲诱导的Tpm 4错义突变或Tpm 4位点的靶向失活导致小鼠基因剂量依赖性巨血小板减少症。Tpm 4缺陷小鼠的所有其他血细胞计数均正常。人和小鼠巨核细胞中TPM 4表达不足导致血小板生成终末阶段的缺陷，并对血小板功能产生轻微影响。总之，我们的研究结果证明了TPM 4在人类和小鼠血小板生物发生中的非冗余作用，并揭示了TPM 4中的截短变体导致先前未描述的显性孟德尔血小板疾病。
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.