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 Luzzatto; Olivier Bluteau; Jean Soulier; Robert B. Darnell; Brunangelo Falini; Inderjeet Dokal; Keisuke Ito; John G. Clohessy; Pier Paolo Pandolfi

doi:10.1038/s41588-019-0502-z

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 journal › Article › peer-review

86 Scopus citations

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.

Original language	English
Pages (from-to)	1518-1529
Number of pages	12
Journal	Nature Genetics
Volume	51
Issue number	10
DOIs	https://doi.org/10.1038/s41588-019-0502-z
State	Published - 1 Oct 2019
Externally published	Yes

Bibliographical note

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

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Nachmani, D., Bothmer, A. H., Grisendi, S., Mele, A., Bothmer, D., Lee, J. D., Monteleone, E., Cheng, K., Zhang, Y., Bester, A. C., Guzzetti, A., Mitchell, C. A., Mendez, L. M., Pozdnyakova, O., Sportoletti, P., Martelli, M. P., Vulliamy, T. J., Safra, M., Schwartz, S., ... Pandolfi, P. P. (2019). Germline NPM1 mutations lead to altered rRNA 2′-O-methylation and cause dyskeratosis congenita. Nature Genetics, 51(10), 1518-1529. https://doi.org/10.1038/s41588-019-0502-z

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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.",

author = "Daphna Nachmani and Bothmer, {Anne H.} and Silvia Grisendi and Aldo Mele and Dietmar Bothmer and Lee, {Jonathan D.} and Emanuele Monteleone and Ke Cheng and Yang Zhang and Bester, {Assaf C.} and Alison Guzzetti and Mitchell, {Caitlin A.} and Mendez, {Lourdes M.} and Olga Pozdnyakova and Paolo Sportoletti and Martelli, {Maria Paola} and Vulliamy, {Tom J.} and Modi Safra and Schraga Schwartz and Lucio Luzzatto and Olivier Bluteau and Jean Soulier and Darnell, {Robert B.} and Brunangelo Falini and Inderjeet Dokal and Keisuke Ito and Clohessy, {John G.} and Pandolfi, {Pier Paolo}",

note = "Publisher Copyright: {\textcopyright} 2019, The Author(s), under exclusive licence to Springer Nature America, Inc.",

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Nachmani, D, Bothmer, AH, Grisendi, S, Mele, A, Bothmer, D, Lee, JD, Monteleone, E, Cheng, K, Zhang, Y, Bester, AC, Guzzetti, A, Mitchell, CA, Mendez, LM, Pozdnyakova, O, Sportoletti, P, Martelli, MP, Vulliamy, TJ, Safra, M, Schwartz, S, Luzzatto, L, Bluteau, O, Soulier, J, Darnell, RB, Falini, B, Dokal, I, Ito, K, Clohessy, JG & Pandolfi, PP 2019, 'Germline NPM1 mutations lead to altered rRNA 2′-O-methylation and cause dyskeratosis congenita', Nature Genetics, vol. 51, no. 10, pp. 1518-1529. https://doi.org/10.1038/s41588-019-0502-z

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AU - Nachmani, Daphna

AU - Bothmer, Anne H.

AU - Grisendi, Silvia

AU - Mele, Aldo

AU - Bothmer, Dietmar

AU - Lee, Jonathan D.

AU - Monteleone, Emanuele

AU - Cheng, Ke

AU - Zhang, Yang

AU - Bester, Assaf C.

AU - Guzzetti, Alison

AU - Mitchell, Caitlin A.

AU - Mendez, Lourdes M.

AU - Pozdnyakova, Olga

AU - Sportoletti, Paolo

AU - Martelli, Maria Paola

AU - Vulliamy, Tom J.

AU - Safra, Modi

AU - Schwartz, Schraga

AU - Luzzatto, Lucio

AU - Bluteau, Olivier

AU - Soulier, Jean

AU - Darnell, Robert B.

AU - Falini, Brunangelo

AU - Dokal, Inderjeet

AU - Ito, Keisuke

AU - Clohessy, John G.

AU - Pandolfi, Pier Paolo

PY - 2019/10/1

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N2 - 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.

AB - 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.

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

Abstract

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