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Nat Genet. 2019 Oct;51(10):1518-1529. doi: 10.1038/s41588-019-0502-z. Epub 2019 Sep 30.

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

Author information

1
Cancer Research Institute, Beth Israel Deaconess Cancer Center, Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
2
Laboratory of Molecular Neuro-Oncology and Howard Hughes Medical Institute, The Rockefeller University, New York, NY, USA.
3
New York Genome Center, New York, NY, USA.
4
Hochschule Zittau/Görlitz, Institute of Ecology and Environmental Protection, Zittau, Germany.
5
Molecular Biotechnology Center and Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy.
6
Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA.
7
Institute of Hematology-Centro di Ricerche Emato-Oncologiche, University of Perugia, Perugia, Italy.
8
Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
9
Department of Molecular Genetics, Weizmann Institute of Science, Rehovot, Israel.
10
Muhimbili University of Health and Allied Sciences, Dar es Salaam, Tanzania.
11
INSERM UMR944 and CNRS UMR7212, Hôpital Saint-Louis, Paris, France.
12
Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, New York, NY, USA.
13
Cancer Research Institute, Beth Israel Deaconess Cancer Center, Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA. ppandolf@bidmc.harvard.edu.

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.

PMID:
31570891
PMCID:
PMC6858547
[Available on 2020-03-30]
DOI:
10.1038/s41588-019-0502-z

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