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A new severe congenital neutropenia syndrome associated with autosomal recessive COPZ1 mutations
Blood ( IF 21.0 ) Pub Date : 2024-12-08 , DOI: 10.1182/blood.2023022576
Natalia Borbaran Bravo, Ekaterina Deordieva, Larissa Doll, Mohammad ElGamacy, Benjamin Dannenmann, Joana Azevedo, Alberto Iannuzzo, Selket Delafontaine, Moritz Lehners, Marius Kolodziej, Birte Hernandez Alvarez, Anna-Sophia Hellmuth, Malte Ritter, Betül Findik, Viktoria Zakharova, Sandro Bräuning, Sergey Kandabarau, Claudia Lengerke, Robert Feil, Isabelle Meyts, Jérôme Delon, Markus Templin, Marc Sturm, Olaf Rieß, Cornelia Zeidler, Karl Welte, Anna Shcherbina, Maksim Klimiankou, Julia Skokowa

We have identified a new inherited bone marrow failure syndrome with severe congenital neutropenia (CN) caused by autosomal recessive mutations in the coatomer protein complex I (COPI) subunit zeta 1 (COPZ1) gene. A stop-codon COPZ1 mutation and a missense mutation were found in 3 patients from 2 unrelated families. Although 2 affected siblings with a stop-codon COPZ1 mutation suffered from CN that involves other hematologic lineages and nonhematologic tissues, the patient with a missense COPZ1 mutation had isolated neutropenia. Both COPZ1 mutations were localized to a highly evolutionarily conserved region. The resulting truncated COPZ1 protein was predicted to display diminished interaction with its COPI complex partner, COPG1. These findings were consistent with the observed block in retrograde protein transport from the Golgi to the endoplasmic reticulum (ER) in human fibroblasts carrying truncated COPZ1. Human CD34+ cells with truncated or missense COPZ1 had significantly impaired granulocytic differentiation, and in zebrafish embryos, truncated Copz1 also resulted in defective myelopoiesis. Intracellularly, truncated COPZ1 downregulated JAK/STAT/CEBPE/G-CSFR signaling and hypoxia-responsive pathways, while inducing STING, interferon-stimulated genes, stimulating oxidative phosphorylation activity, and increasing reactive oxygen species levels in CD34+ cells. Missense COPZ1 deregulated interferon and JAK/STAT signaling but less than the truncated protein. Finally, treatment with the small molecule HIF1α activator IOX2 or transduction of cells with COPZ2 complementary DNA restored defective granulopoiesis in COPZ1-mutated CD34+ cells, offering potential therapeutic options.

中文翻译:


一种与常染色体隐性遗传 COPZ1 突变相关的新型严重先天性中性粒细胞减少综合征



我们确定了一种新的遗传性骨髓衰竭综合征,伴有严重的先天性中性粒细胞减少症 (CN),由辅聚体蛋白复合物 I (COPI) 亚基 zeta 1 (COPZ1) 基因的常染色体隐性突变引起。在 2 个无关家系的 3 例患者中发现终止密码子 COPZ1 突变和错义突变。尽管 2 名具有终止密码子 COPZ1 突变的受影响兄弟姐妹患有涉及其他血液学谱系和非血液学组织的 CN,但具有错义 COPZ1 突变的患者患有孤立的中性粒细胞减少症。两种 COPZ1 突变都定位于高度进化保守的区域。预计所得的截短 COPZ1 蛋白与其 COPI 复合物伴侣 COPG1 的相互作用减少。这些发现与在携带截短 COPZ1 的人成纤维细胞中观察到的蛋白质从高尔基体逆行转运到内质网 (ER) 的阻滞一致。COPZ1 截短或错义的人 CD34 + 细胞粒细胞分化显著受损,在斑马鱼胚胎中,截短的 Copz1 也会导致骨髓生成缺陷。在细胞内,截短的 COPZ1 下调 JAK/STAT/CEBPE/G-CSFR 信号传导和缺氧反应通路,同时诱导 STING、干扰素刺激基因,刺激氧化磷酸化活性,并增加 CD34+ 细胞中的活性氧水平。错义 COPZ1 使干扰素和 JAK/STAT 信号转导失调,但低于截短蛋白。最后,用小分子 HIF1α 激活剂 IOX2 处理或用 COPZ2 互补 DNA 转导细胞可恢复 COPZ1 突变的 CD34+ 细胞中的缺陷粒细胞生成,提供潜在的治疗选择。
更新日期:2024-12-08
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