Diamond-Blackfan anemia, the archetype of ribosomopathy: How distinct is it from the other constitutional ribosomopathies?

IF 2.1 4区 医学 Q3 HEMATOLOGY Blood Cells Molecules and Diseases Pub Date : 2024-02-17 DOI:10.1016/j.bcmd.2024.102838
L. Da Costa , Narla Mohandas , Ludivine David-NGuyen , Jessica Platon , Isabelle Marie , Marie Françoise O'Donohue , Thierry Leblanc , Pierre-Emmanuel Gleizes
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Abstract

Diamond-Blackfan anemia (DBA) was the first ribosomopathy described in humans. DBA is a congenital hypoplastic anemia, characterized by macrocytic aregenerative anemia, manifesting by differentiation blockage between the BFU-e/CFU-e developmental erythroid progenitor stages. In 50 % of the DBA cases, various malformations are noted. Strikingly, for a hematological disease with a relative erythroid tropism, DBA is due to ribosomal haploinsufficiency in 24 different ribosomal protein (RP) genes. A few other genes have been described in DBA-like disorders, but they do not fit into the classical DBA phenotype (Sankaran et al., 2012; van Dooijeweert et al., 2022; Toki et al., 2018; Kim et al., 2017 [[1], [2], [3], [4]]).

Haploinsufficiency in a RP gene leads to defective ribosomal RNA (rRNA) maturation, which is a hallmark of DBA. However, the mechanistic understandings of the erythroid tropism defect in DBA are still to be fully defined. Erythroid defect in DBA has been recently been linked in a non-exclusive manner to a number of mechanisms that include: 1) a defect in translation, in particular for the GATA1 erythroid gene; 2) a deficit of HSP70, the GATA1 chaperone, and 3) free heme toxicity. In addition, p53 activation in response to ribosomal stress is involved in DBA pathophysiology. The DBA phenotype may thus result from the combined contributions of various actors, which may explain the heterogenous phenotypes observed in DBA patients, even within the same family.

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核糖体病的原型--钻石-巴拉克凡贫血症:它与其他体质性核糖体病的区别有多大?
菱形-贝克范贫血症(DBA)是人类首次描述的核糖体病。DBA 是一种先天性发育不全性贫血,以巨幼红细胞性贫血为特征,表现为 BFU-e/CFU-e 红细胞祖细胞发育阶段之间的分化障碍。在 50% 的 DBA 病例中,会出现各种畸形。令人震惊的是,对于一种具有相对红细胞倾向性的血液病来说,DBA 是由于 24 个不同的核糖体蛋白(RP)基因的核糖体单倍体缺乏所致。在 DBA 类疾病中还描述了其他一些基因,但它们并不符合经典的 DBA 表型(Sankaran 等人,2012 年;van Dooijeweert 等人,2022 年;Toki 等人,2018 年;Kim 等人,2017 年[[1], [2], [3], [4]])。RP 基因的单倍体缺陷导致核糖体 RNA(rRNA)成熟缺陷,这是 DBA 的特征。然而,DBA 中红细胞滋养缺陷的机理尚未完全明确。最近,DBA 中的红细胞缺陷以一种非排他性的方式与多种机制联系在一起,这些机制包括1)翻译缺陷,尤其是 GATA1 红细胞基因的翻译缺陷;2)GATA1 合子 HSP70 的缺失;3)游离血红素毒性。此外,p53 对核糖体应激反应的激活也参与了 DBA 的病理生理学。因此,DBA 的表型可能是多种因素共同作用的结果,这也许可以解释在 DBA 患者身上观察到的不同表型,即使在同一家族中也是如此。
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来源期刊
CiteScore
4.90
自引率
0.00%
发文量
42
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.
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