Mutations affecting the secretory COPII coat component SEC23B cause congenital dyserythropoietic anemia type II
Mutations affecting the secretory COPII coat component SEC23B cause congenital dyserythropoietic anemia type II
复制标题
DOI：
10.1038/ng.405
复制
发表时间：
2009-08-01
期刊：
影响因子：
30.8
通讯作者：
Heimpel, Hermann
中科院分区：
文献类型：
--
作者：
Schwarz, Klaus;Iolascon, Achille;Heimpel, Hermann
先天性红细胞生成异常性贫血（CDA）是表型和基因型异质性疾病（1-4）。CDA II型（CDAII）是最常见的CDA。其特征是红细胞生成无效，骨髓中存在双核和多核成红细胞，细胞核大小和DNA含量相等，提示胞质分裂障碍（5）。外周血红细胞的其他特征是蛋白质和脂质糖基化和内质网双膜残留（4，6）。其他造血谱系的发育是正常的。CDAII患者表现出进行性脾肿大、胆结石和铁超负荷，可能伴有肝硬化或心力衰竭。在这里，我们表明，编码分泌型COPII组件SEC 23 B的基因在CDAII突变。短发夹RNA（shRNA）介导的SEC 23 B表达抑制重演了胞质分裂缺陷。斑马鱼sec 23 b的敲除也导致异常的红细胞发育。我们的研究结果提供了在体内的证据SEC 23 B选择性红细胞分化，并表明，SEC 23 A和SEC 23 B，虽然高度相关的旁系同源分泌COPII组件，是非冗余的红细胞成熟。
Congenital dyserythropoietic anemias (CDAs) are phenotypically and genotypically heterogeneous diseases(1-4). CDA type II (CDAII) is the most frequent CDA. It is characterized by ineffective erythropoiesis and by the presence of bi- and multinucleated erythroblasts in bone marrow, with nuclei of equal size and DNA content, suggesting a cytokinesis disturbance(5). Other features of the peripheral red blood cells are protein and lipid dysglycosylation and endoplasmic reticulum double-membrane remnants(4,6). Development of other hematopoietic lineages is normal. Individuals with CDAII show progressive splenomegaly, gallstones and iron overload potentially with liver cirrhosis or cardiac failure. Here we show that the gene encoding the secretory COPII component SEC23B is mutated in CDAII. Short hairpin RNA (shRNA)-mediated suppression of SEC23B expression recapitulates the cytokinesis defect. Knockdown of zebrafish sec23b also leads to aberrant erythrocyte development. Our results provide in vivo evidence for SEC23B selectivity in erythroid differentiation and show that SEC23A and SEC23B, although highly related paralogous secretory COPII components, are nonredundant in erythrocyte maturation.