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NPM1基因突變導致rRNA修飾改變



本期文章:《自然—遺傳學》:Online/在線發表

生殖細胞中NPM1基因突變導致rRNA的2’-O甲基化修飾改變并產生先天性角化不良癥,這一成果由美國哈佛醫學院Pier Paolo Pandolfi研究組取得。相關論文2019年9月30日在線發表于《自然—遺傳學》。

研究人員將核糖體RNA 2'-O甲基化(2'-O-Me)與先天性角化不良癥的病因聯系起來。研究人員發現NPM1(nucleophosmin)蛋白是調控rRNA上2'-O-Me的關鍵因子,其通過直接結合C/D box小核仁RNA來調節翻譯。研究人員證明2'-O-Me調控翻譯對于細胞生長、分化和造血干細胞維持的重要性,并表明在成年造血干細胞中Npm1基因失活會導致骨髓衰竭。

研究人員在患有骨髓衰竭的先天性角化不全患者中鑒定出NPM1種系突變,并證明它們在小核仁RNA結合中缺乏。攜帶先天性角化不全生殖細胞Npm1突變的小鼠具有先天性角化不全的血液學和非血液學特征。因此,這些發現表明2'-O-Me的受損可能是人類疾病的病因。

研究人員表示,RNA修飾逐漸成為基因表達的關鍵決定因素。但是,缺乏關于它們與人類疾病相關性之間令人信服的基因論證。

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—遺傳學》,創刊于1992年。隸屬于施普林格·自然出版集團,最新IF:25.455
官方網址:https://www.nature.com/ng/
投稿鏈接:https://mts-ng.nature.com/cgi-bin/main.plex




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