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NPM1基因突变导致rRNA修饰改变
作者:小柯机器人 发布时间:2019/10/2 20:26:47

生殖细胞中NPM1基因突变导致rRNA的2’-O甲基化修饰改变并产生先天性角化不良症,这一成果由美国哈佛医学院Pier Paolo Pandolfi研究组取得。相关论文2019年9月30日在线发表于《自然—遗传学》。

研究人员将核糖体RNA 2'-O甲基化(2'-O-Me)与先天性角化不良症的病因联系起来。研究人员发现NPM1(nucleophosmin)蛋白是调控rRNA上2'-O-Me的关键因子,其通过直接结合C/D box小核仁RNA来调节翻译。研究人员证明2'-O-Me调控翻译对于细胞生长、分化和造血干细胞维持的重要性,并表明在成年造血干细胞中Npm1基因失活会导致骨髓衰竭。

研究人员在患有骨髓衰竭的先天性角化不全患者中鉴定出NPM1种系突变,并证明它们在小核仁RNA结合中缺乏。携带先天性角化不全生殖细胞Npm1突变的小鼠具有先天性角化不全的血液学和非血液学特征。因此,这些发现表明2'-O-Me的受损可能是人类疾病的病因。

研究人员表示,RNA修饰逐渐成为基因表达的关键决定因素。但是,缺乏关于它们与人类疾病相关性之间令人信服的基因论证。

附:英文原文

Title: Germline NPM1 mutations lead to altered rRNA 2′-O-methylation and cause dyskeratosis congenita

Author: Daphna Nachmani, Anne H. Bothmer, Silvia Grisendi, Aldo Mele, Dietmar Bothmer, Jonathan D. Lee, Emanuele Monteleone, Ke Cheng, Yang Zhang, Assaf C. Bester, Alison Guzzetti, Caitlin A. Mitchell, Lourdes M. Mendez, Olga Pozdnyakova, Paolo Sportoletti, Maria-Paola Martelli, Tom J. Vulliamy, Modi Safra, Schraga Schwartz, Lucio Luzzatto, Olivier Bluteau, Jean Soulier, Robert B. Darnell, Brunangelo Falini, Inderjeet Dokal, Keisuke Ito, John G. Clohessy, Pier Paolo Pandolfi

Issue&Volume: 2019-09-30

Abstract: 

RNA modifications are emerging as key determinants of gene expression. However, compelling genetic demonstrations of their relevance to human disease are lacking. Here, we link ribosomal RNA 2′-O-methylation (2′-O-Me) to the etiology of dyskeratosis congenita. We identify nucleophosmin (NPM1) as an essential regulator of 2′-O-Me on rRNA by directly binding C/D box small nucleolar RNAs, thereby modulating translation. We demonstrate the importance of 2′-O-Me-regulated translation for cellular growth, differentiation and hematopoietic stem cell maintenance, and show that Npm1 inactivation in adult hematopoietic stem cells results in bone marrow failure. We identify NPM1 germline mutations in patients with dyskeratosis congenita presenting with bone marrow failure and demonstrate that they are deficient in small nucleolar RNA binding. Mice harboring a dyskeratosis congenita germline Npm1 mutation recapitulate both hematological and nonhematological features of dyskeratosis congenita. Thus, our findings indicate that impaired 2′-O-Me can be etiological to human disease.

DOI: 10.1038/s41588-019-0502-z

Source:https://www.nature.com/articles/s41588-019-0502-z

期刊信息

Nature Genetics:《自然—遗传学》,创刊于1992年。隶属于施普林格·自然出版集团,最新IF:25.455
官方网址:https://www.nature.com/ng/
投稿链接:https://mts-ng.nature.com/cgi-bin/main.plex