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 (iPSCs), 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.

先天性红细胞生成障碍 (CDA) 登记处的建立旨在促进对 CDA 的自然史、生物学和分子发病机制的研究。注册登记的三名无关个体患有以 CDA 和严重神经发育迟缓为特征的综合征。他们被发现在VPS4A 中有错义突变，一种编码 ATP 酶的基因，该酶在多种细胞过程中调节 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细胞质桥的成红细胞，表明异常胞质分裂和脱落。发现循环红细胞在其膜中保留转铁蛋白受体 (CD71)，表明 VPS4A 对正常网织红细胞成熟至关重要。使用先证者衍生的诱导多能干细胞 (iPSC)，我们成功地在体外模拟了这种综合征的血液学方面，概括了它们的红细胞生成障碍表型。我们的研究结果表明VPS4A 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。