Unveiling the role of RPS17 and SLC4A1 in diamond-Blackfan Anemia: A zebrafish-based study

IF 2.1 4区医学 Q3 HEMATOLOGY

Blood Cells Molecules and Diseases Pub Date : 2025-02-25 DOI:10.1016/j.bcmd.2025.102912

Kyeongmin Kim , Hyerin Lee , Soyul Ahn , Yun Hak Kim , Chang-Kyu Oh

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引用次数: 0

Abstract

Diamond-Blackfan Anemia (DBA) is a rare congenital disorder characterized by macrocytic anemia, physical abnormalities, and growth delays. Although RPS19 mutations have been more extensively studied in DBA compared to other ribosomal protein genes, the pathological mechanisms of genes such as RPS17 remain largely unexplored. This study aimed to investigate the role of RPS17 haploinsufficiency in DBA, focusing on its downstream effects on erythropoiesis and the involvement of SLC4A1, a critical erythrocyte membrane protein essential for red blood cell stability. Transcriptomic analysis of publicly available RNA sequencing data from DBA patients revealed significant downregulation of SLC4A1 in RPS17-mutated cases. To validate these findings, we generated a zebrafish model of DBA by knocking down rps17 using morpholino injections. Zebrafish embryos with rps17 knockdown exhibited reduced erythropoiesis, impaired hemoglobin synthesis, consistent with DBA. Further analysis confirmed decreased slc4a1a expression in rps17-morphants. Independent knockdown of slc4a1a in zebrafish resulted in similar erythropoietic defects, highlighting its critical role in red blood cell membrane integrity and function. This study identifies slc4a1 as a key downstream target of RPS17 haploinsufficiency and provides novel insights into the molecular mechanisms of DBA. By establishing zebrafish as an effective in vivo model, this research offers potential therapeutic targets for treating DBA and related erythropoietic disorders.

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揭示RPS17和SLC4A1在diamond-Blackfan贫血中的作用：一项基于斑马鱼的研究

Diamond-Blackfan Anemia （DBA）是一种罕见的先天性疾病，以巨细胞性贫血、身体异常和生长迟缓为特征。尽管与其他核糖体蛋白基因相比，RPS19突变在DBA中的研究更为广泛，但RPS17等基因的病理机制仍在很大程度上未被探索。本研究旨在探讨RPS17单倍不全在DBA中的作用，重点关注其对红细胞生成的下游影响以及SLC4A1的参与，SLC4A1是红细胞稳定所必需的关键红细胞膜蛋白。对DBA患者公开获得的RNA测序数据的转录组学分析显示，rps17突变病例中SLC4A1显著下调。为了验证这些发现，我们使用morpholino注射剂敲除rps17，生成了斑马鱼DBA模型。rps17基因敲低的斑马鱼胚胎表现出红细胞生成减少，血红蛋白合成受损，与DBA一致。进一步分析证实，slc4a1a在rps17-morphants中的表达降低。在斑马鱼中，slc4a1a的独立敲低导致了类似的红细胞生成缺陷，突出了其在红细胞膜完整性和功能中的关键作用。本研究确定slc4a1是RPS17单倍不足的关键下游靶点，并为DBA的分子机制提供了新的见解。通过建立斑马鱼作为有效的体内模型，本研究为治疗DBA及相关的红细胞生成疾病提供了潜在的治疗靶点。

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来源期刊

Blood Cells Molecules and Diseases 医学-血液学

CiteScore

4.90

自引率

0.00%

发文量

审稿时长

14 days

期刊介绍： Blood Cells, Molecules & Diseases emphasizes not only blood cells, but also covers the molecular basis of hematologic disease and studies of the diseases themselves. This is an invaluable resource to all those interested in the study of hematology, cell biology, immunology, and human genetics.