A gain-of-function variant in DIAPH1 causes dominant macrothrombocytopenia and hearing loss
A gain-of-function variant in DIAPH1 causes dominant macrothrombocytopenia and hearing loss
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DOI：
10.1182/blood-2015-10-675629
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发表时间：
2016-06-09
期刊：
影响因子：
20.3
通讯作者：
Mumford, Andrew D.
中科院分区：
文献类型：
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作者：
Stritt, Simon;Nurden, Paquita;Mumford, Andrew D.
巨血小板减少症(MTP)是一组异质性疾病，其特征是循环中的血小板数量增大和减少，有时会导致异常出血。在大多数MTP中，这种表型是由于巨核细胞(MK)对血小板形成的调节改变而产生的。我们报道了编码Rho效应器透明相关蛋白1(DIAPH1)的DIAPH1，通过外显子组测序、本体表型和相似性回归确定为MTP的候选基因。我们描述了两个与MTP和感觉神经性听力损失无关的家系，它们与DIAPH1 R1213*变体分离，预测DIAPH1透明的自身调节域的部分截断。R1213*变异与培养的巨噬细胞形成血小板原减少、细胞聚集和皮质丝状肌动蛋白异常有关。同样，在血小板中，有更多的丝状肌动蛋白和稳定的微管，表明DIAPH1的结构性激活。DIAPH1R1213*在细胞中的过表达复制了在血小板中发现的细胞骨架变化。我们对一种新的血小板形成和听力损失障碍的描述扩大了DIAPH1相关疾病的范围，并为DIAPH1活性的自动调节提供了新的见解。
Macrothrombocytopenia (MTP) is a heterogeneous group of disorders characterized by enlarged and reduced numbers of circulating platelets, sometimes resulting in abnormal bleeding. In most MTP, this phenotype arises because of altered regulation of platelet formation from megakaryocytes (MKs). We report the identification of DIAPH1, which encodes the Rho-effector diaphanous-related formin 1 (DIAPH1), as a candidate gene for MTP using exome sequencing, ontological phenotyping, and similarity regression. We describe 2 unrelated pedigrees with MTP and sensorineural hearing loss that segregate with a DIAPH1 R1213* variant predicting partial truncation of the DIAPH1 diaphanous autoregulatory domain. The R1213* variant was linked to reduced proplatelet formation from cultured MKs, cell clustering, and abnormal cortical filamentous actin. Similarly, in platelets, there was increased filamentous actin and stable microtubules, indicating constitutive activation of DIAPH1. Overexpression of DIAPH1 R1213* in cells reproduced the cytoskeletal alterations found in platelets. Our description of a novel disorder of platelet formation and hearing loss extends the repertoire of DIAPH1-related disease and provides new insight into the autoregulation of DIAPH1 activity.