Mutations in the iron-sulfur cluster biogenesis protein HSCB cause congenital sideroblastic anemia
Mutations in the iron-sulfur cluster biogenesis protein HSCB cause congenital sideroblastic anemia
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DOI：
10.1172/jci135479
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发表时间：
2020-10-01
影响因子：
15.9
通讯作者：
Ducamp, Sarah
中科院分区：
文献类型：
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作者：
Crispin, Andrew;Guo, Chaoshe;Ducamp, Sarah
先天性铁粒幼细胞贫血 (CSA) 可能是由线粒体铁硫 (Fe-S) 簇生物发生的主要缺陷引起的。 HSCB（热休克同源 B）编码线粒体辅助伴侣，也称为 HSC20（热休克同源蛋白 20），是线粒体热休克蛋白 A9 (HSPA9) 的伴侣。 HSCB 和 HSPA9 与谷氧还蛋白 5 (GLRX5) 一起促进新生 2-铁、2-硫簇向受体线粒体蛋白的转移。 HSPA9 和 GLRX5 的突变此前已被认为与 CSA 有关。因此，我们假设HSCB突变也可能导致CSA。我们筛选了遗传上未定义的 CSA 患者，并在一名非综合征性 CSA 女性患者中发现了 HSCB 中的移码突变和罕见的启动子变异。我们发现，在经过工程改造具有患者特异性启动子变体的患者来源的成纤维细胞和 K562 红白血病细胞中，HSCB 表达降低。此外，在 K562 细胞、斑马鱼和小鼠中进行的基因敲除和缺失实验表明，HSCB 的缺失会导致 Fe-S 簇生物发生受损、红细胞血红蛋白化缺陷以及铁细胞发育，并更广泛地扰乱体内造血作用。这些结果进一步证实了 Fe-S 簇生物发生参与红细胞生成和造血，并将 HSCB 定义为 CSA 基因。
The congenital sideroblastic anemias (CSAs) can be caused by primary defects in mitochondrial iron-sulfur (Fe-S) cluster biogenesis. HSCB (heat shock cognate B), which encodes a mitochondrial cochaperone, also known as HSC20 (heat shock cognate protein 20), is the partner of mitochondrial heat shock protein A9 (HSPA9). Together with glutaredoxin 5 (GLRX5), HSCB and HSPA9 facilitate the transfer of nascent 2-iron, 2-sulfur clusters to recipient mitochondrial proteins. Mutations in both HSPA9 and GLRX5 have previously been associated with CSA. Therefore, we hypothesized that mutations in HSCB could also cause CSA. We screened patients with genetically undefined CSA and identified a frameshift mutation and a rare promoter variant in HSCB in a female patient with non-syndromic CSA. We found that HSCB expression was decreased in patient-derived fibroblasts and K562 erythroleukemia cells engineered to have the patient-specific promoter variant. Furthermore, gene knockdown and deletion experiments performed in K562 cells, zebrafish, and mice demonstrate that loss of HSCB results in impaired Fe-S cluster biogenesis, a defect in RBC hemoglobinization, and the development of siderocytes and more broadly perturbs hematopoiesis in vivo. These results further affirm the involvement of Fe-S cluster biogenesis in erythropoiesis and hematopoiesis and define HSCB as a CSA gene.