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

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 LuzzattoOlivier Bluteau, Jean Soulier, Robert B. Darnell, Brunangelo Falini, Inderjeet Dokal, Keisuke Ito, John G. Clohessy, Pier Paolo Pandolfi*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

74 Scopus citations


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.

Original languageAmerican English
Pages (from-to)1518-1529
Number of pages12
JournalNature Genetics
Issue number10
StatePublished - 1 Oct 2019
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2019, The Author(s), under exclusive licence to Springer Nature America, Inc.


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