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

Abstract

RNA modifications are emerging as key determinants of development and of disease. However, compelling genetic demonstrations of their relevance to human disease are lacking. Here, we link rRNA 2’-O-methylation (2’-O-Me) to the etiology of dyskeratosis congenita (DC). We identify nucleophosmin (NPM1) as an essential regulator of 2’-O-Me on rRNA by directly binding C/D box small nucleolar RNAs (snoRNAs), thereby modulating translation. We demonstrate the importance of 2’-O-Me-regulated translation for cellular growth, differentiation and hematopoietic stem cell (HSC) maintenance, and show that Npm1 inactivation in adult HSCs results in bone marrow failure (BMF). We identify NPM1 germline mutations in DC patients presenting with BMF, and demonstrate that they are deficient in snoRNA binding. Mice harboring a DC germline NPM1 mutation recapitulate both hematological and non-hematological features of DC. Thus, our findings indicate that impaired 2’-O-Me can be pathogenic and etiological to human disease.