美国辛辛那提儿童医院医疗中心Daniel T. Starczynowski研究团队发现，生殖系DDX41突变导致无效的造血和骨髓异常增生。2021年9月1日，《细胞—干细胞》杂志在线发表了这项成果。

研究人员表示，DDX41突变是成人骨髓增生异常综合征（MDS）中最常见的生殖系改变。大多数受影响的个体怀有生殖系单等位的DDX41突变，随后在其另一个DDX41等位基因中获得体细胞突变，通常是错义R525H。

研究人员发现，具有双等位移码和R525H突变的造血祖细胞（HPC）会发生细胞周期停止和凋亡，导致小鼠骨髓衰竭。从机制上讲，DDX41对小核糖核酸（snoRNA）的加工、核糖体的组装和蛋白质的合成至关重要。尽管单倍体DDX41突变不影响年轻小鼠的造血功能，但老年小鼠的一个亚群会出现MDS的特征。在MDS患者的骨髓（BM）中的非显性造血干细胞克隆中，DDX41的双等位突变的频率很低。嵌合单倍体DDX41突变BM细胞和少量双倍体突变BM细胞的小鼠在较年轻时出现造血缺陷，这表明双倍体DDX41突变细胞在单倍体DDX41突变BM的背景下具有疾病调节作用。

附：英文原文

Title: Germline DDX41 mutations cause ineffective hematopoiesis and myelodysplasia

Author: Timothy M. Chlon, Emily Stepanchick, Courtney E. Hershberger, Noah J. Daniels, Kathleen M. Hueneman, Ashley Kuenzi Davis, Kwangmin Choi, Yi Zheng, Carmelo Gurnari, Torsten Haferlach, Richard A. Padgett, Jaroslaw P. Maciejewski, Daniel T. Starczynowski

Issue&Volume: 2021-09-01

Abstract: DDX41 mutations are the most common germline alterations in adult myelodysplastic syndromes(MDSs). The majority of affected individuals harbor germline monoallelic frameshiftDDX41 mutations and subsequently acquire somatic mutations in their other DDX41 allele,typically missense R525H. Hematopoietic progenitor cells (HPCs) with biallelic frameshiftand R525H mutations undergo cell cycle arrest and apoptosis, causing bone marrow failurein mice. Mechanistically, DDX41 is essential for small nucleolar RNA (snoRNA) processing,ribosome assembly, and protein synthesis. Although monoallelic DDX41 mutations donot affect hematopoiesis in young mice, a subset of aged mice develops features ofMDS. Biallelic mutations in DDX41 are observed at a low frequency in non-dominanthematopoietic stem cell clones in bone marrow (BM) from individuals with MDS. Micechimeric for monoallelic DDX41 mutant BM cells and a minor population of biallelicmutant BM cells develop hematopoietic defects at a younger age, suggesting that biallelicDDX41 mutant cells are disease modifying in the context of monoallelic DDX41 mutantBM.

DOI: 10.1016/j.stem.2021.08.004

Source: https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(21)00341-6