VPS4A Mutations in Humans Cause Syndromic Congenital Dyserythropoietic Anemia due to Cytokinesis and Trafficking Defects
VPS4A Mutations in Humans Cause Syndromic Congenital Dyserythropoietic Anemia due to Cytokinesis and Trafficking Defects
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DOI：
10.1016/j.ajhg.2020.10.013
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发表时间：
2020-12-03
影响因子：
9.8
通讯作者：
Kalfa, Theodosia A.
中科院分区：
文献类型：
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作者：
Seu, Katie G.;Trump, Lisa R.;Kalfa, Theodosia A.
先天性红细胞生成不良性贫血（CDA）登记的目的是促进CDA的自然史，生物学和分子发病机制的调查。登记的三个无关个体患有以CDA和严重神经发育迟缓为特征的综合征。他们被发现在VPS 4A中有错义突变，VPS 4A是一种编码ATP酶的基因，该基因在各种细胞过程中调节ESCRT-III机制，包括细胞分裂、内体囊泡运输和病毒出芽。骨髓研究显示双核成红细胞和具有胞质桥的成红细胞，表明胞质分裂和凋亡异常。发现循环红细胞在其膜中保留转铁蛋白受体（CD 71），表明VPS 4A对于正常网织红细胞成熟是关键的。使用先证者衍生的诱导多能干细胞（iPSC 5），我们已经成功地模拟了这种综合征的血液学方面在体外，重演他们的红细胞生成障碍表型。我们的研究结果表明，VPS 4A突变导致胞质分裂和运输缺陷，导致人类疾病，对红细胞生成和神经发育产生不利影响。
The Congenital Dyserythropoietic Anemia (CDA) Registry was established with the goal to facilitate investigations of natural history, biology, and molecular pathogenetic mechanisms of CDA. Three unrelated individuals enrolled in the registry had a syndrome characterized by CDA and severe neurodevelopmental delay. They were found to have missense mutations in VPS4A, a gene coding for an ATPase that regulates the ESCRT-III machinery in a variety of cellular processes including cell division, endosomal vesicle trafficking, and viral budding. Bone marrow studies showed binucleated erythroblasts and erythroblasts with cytoplasmic bridges indicating abnormal cytokinesis and abscission. Circulating red blood cells were found to retain transferrin receptor (CD71) in their membrane, demonstrating that VPS4A is critical for normal reticulocyte maturation. Using proband-derived induced pluripotent stem cells (iPSC5), we have successfully modeled the hematologic aspects of this syndrome in vitro, recapitulating their dyserythropoietic phenotype. Our findings demonstrate that VPS4A mutations cause cytokinesis and trafficking defects leading to a human disease with detrimental effects to erythropoiesis and neurodevelopment.