ACTN1 Mutations Cause Congenital Macrothrombocytopenia
ACTN1 Mutations Cause Congenital Macrothrombocytopenia
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DOI：
10.1016/j.ajhg.2013.01.015
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发表时间：
2013-03-07
影响因子：
9.8
通讯作者：
Ogawa, Seishi
中科院分区：
文献类型：
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作者：
Kunishima, Shinji;Okuno, Yusuke;Ogawa, Seishi
先天性巨血小板减少症（CMTP）是一组异质性罕见血小板疾病，其特征是先天性血小板计数减少和异常大的血小板，仅在大约一半的病例中发现了引起CMTP的突变。我们在此进行了全外显子组测序和靶向桑格测序，以鉴定引起CMTP的突变，其中怀疑是显性传播模式，但没有已知的负责突变。在13个日本CMTP受影响的家系中，我们确定了6个（46%）受ACTN 1变异与CMTP共分离的影响。在整个队列中，ACNT 1变异占CMTP病例的5.5%，是日本个体中第四大常见原因。携带ACTN 1变体的个体表现出中度巨血小板减少症伴红细胞大小不均，但要么无症状，要么只有中度出血倾向。ACTN 1编码α-辅肌动蛋白-1，辅肌动蛋白交联蛋白超家族的成员，参与细胞骨架的组织。在中国仓鼠卵巢细胞中的体外转染实验表明，改变的α-辅肌动蛋白-1破坏了正常的肌动蛋白为基础的细胞骨架结构。此外，小鼠胎肝衍生的巨核细胞与疾病相关的ACTN 1变异体的转导引起了一个混乱的肌动蛋白为基础的细胞骨架巨核细胞，导致异常大的前血小板尖端的生产，这是在数量上减少。我们的研究结果提供了一个深入了解CMTP的发病机制。
Congenital macrothrombocytopenia (CMTP) is a heterogeneous group of rare platelet disorders characterized by a congenital reduction of platelet counts and abnormally large platelets, for which CMTP-causing mutations are only found in approximately half the cases. We herein performed whole-exome sequencing and targeted Sanger sequencing to identify mutations that cause CMTP, in which a dominant mode of transmission had been suspected but for which no known responsible mutations have been documented. In 13 Japanese CMTP-affected pedigrees, we identified six (46%) affected by ACTN1 variants cosegregating with CMTP. In the entire cohort, ACNT1 variants accounted for 5.5% of the dominant forms of CMTP cases and represented the fourth most common cause in Japanese individuals. Individuals with ACTN1 variants presented with moderate macrothrombocytopenia with anisocytosis but were either asymptomatic or had only a modest bleeding tendency. ACTN1 encodes alpha-actinin-1, a member of the actin-crosslinking protein superfamily that participates in the organization of the cytoskeleton. In vitro transfection experiments in Chinese hamster ovary cells demonstrated that altered a-actinin-1 disrupted the normal actin-based cytoskeletal structure. Moreover, transduction of mouse fetal liver-derived megakaryocytes with disease-associated ACTN1 variants caused a disorganized actin-based cytoskeleton in megakaryocytes, resulting in the production of abnormally large proplatelet tips, which were reduced in number. Our findings provide an insight into the pathogenesis of CMTP.