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

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.

• Authors: 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
• Journal: Nature genetics (Nat Genet) Vol. 51 Issue 10 Pg. 1518-1529 (10 2019) ISSN: 1546-1718 [Electronic] United States
• PMID: 31570891 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• NPM1 protein, human
• Npm1 protein, mouse
• Nuclear Proteins
• RNA, Messenger
• RNA, Ribosomal
• RNA, Small Nucleolar
• Nucleophosmin

Topics

• Animals
• Dyskeratosis Congenita (genetics, pathology)
• Epigenomics (methods)
• Gene Expression Profiling
• Germ-Line Mutation
• Hematopoietic Stem Cells
• Male
• Methylation
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Nuclear Proteins (chemistry, genetics)
• Nucleophosmin
• RNA Processing, Post-Transcriptional
• RNA, Messenger (genetics)
• RNA, Ribosomal (genetics)
• RNA, Small Nucleolar
• Transcriptome