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

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


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

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


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