King Richard, Lin Zesen, Balbin-Cuesta Ginette, Myers Gregg, Friedman Ann, Zhu Guojing, McGee Beth, Saunders Thomas L, Kurita Ryo, Nakamura Yukio, Engel James Douglas, Reddy Pavan, Khoriaty Rami
Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA.
University of Michigan Rogel Cancer Center, Ann Arbor, MI, USA.
Sci Adv. 2021 Nov 26;7(48):eabj5293. doi: 10.1126/sciadv.abj5293. Epub 2021 Nov 24.
Congenital dyserythropoietic anemia type II (CDAII) results from loss-of-function mutations in . In contrast to humans, SEC23B-deficient mice deletion do not exhibit CDAII but die perinatally with pancreatic degeneration. Here, we demonstrate that expression of the full SEC23A protein (the SEC23B paralog) from the endogenous regulatory elements of completely rescues the SEC23B-deficient mouse phenotype. Consistent with these data, while mice with erythroid-specific deletion of either or do not exhibit CDAII, we now show that mice with erythroid-specific deletion of all four alleles die in mid-embryogenesis with features of CDAII and that mice with deletion of three alleles exhibit a milder erythroid defect. To test whether the functional overlap between the paralogs is conserved in human erythroid cells, we generated SEC23B-deficient HUDEP-2 cells. Upon differentiation, these cells exhibited features of CDAII, which were rescued by increased expression of SEC23A, suggesting a novel therapeutic strategy for CDAII.
II型先天性红细胞生成异常性贫血（CDAII）是由……功能丧失性突变引起的。与人类不同，SEC23B基因敲除的小鼠不会表现出CDAII，而是在围产期死于胰腺退化。在此，我们证明，从……的内源性调控元件表达完整的SEC23A蛋白（SEC23B的旁系同源物）可完全挽救SEC23B基因敲除小鼠的表型。与这些数据一致，虽然红细胞特异性敲除……或……的小鼠不会表现出CDAII，但我们现在表明，红细胞特异性敲除所有四个……等位基因的小鼠在胚胎中期死亡，具有CDAII的特征，而敲除三个……等位基因的小鼠表现出较轻的红细胞缺陷。为了测试……旁系同源物之间的功能重叠在人类红细胞中是否保守，我们构建了SEC23B缺陷的HUDEP-2细胞。分化后，这些细胞表现出CDAII的特征，通过增加SEC23A的表达得以挽救，这为CDAII提供了一种新的治疗策略。
