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

66 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

Funding Information:
D.N. was supported by an EMBO long-term fellowship (no. EMBO-LTF498-2014). K.I. was supported by National Institutes of Health grants (no. R01DK98263, R01DK115577 and R01HL148852), and is a Scholar of The Leukemia and Lymphoma Society. A.H.B. was supported by the Damon Runyon Cancer Research Foundation (no. 2142-12). This work was supported in part by the European Research Council Consolidator (grant no. 311660) and Cancéropole Ile-de-France (no. 2011-1-LABEL-1-AXE2-UP7-3) to J.S; Medical Research Council (grant no. MR/PO18440/1) and Bloodwise (grant no. 14032) to I.D.; the Fondazione AIRC per la Ricerca sul Cancro IG 2016 (grant no. 18568) and the European Research Council Advanced Grant 2016 (no. 740230) to B.F.; and by an Outstanding Investigator Award R35 (grant no. CA197529) and the SHINE grant (no. 5R01DK115536) awarded by National Institutes of Health to P.P.P.

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


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