Ribosomal protein gene RPL9 variants can differentially impair ribosome function and cellular metabolism

Variants in ribosomal protein (RP) genes drive Diamond-Blackfan anemia (DBA), a bone marrow failure syndrome that can also predispose individuals to cancer. Inherited and sporadic RP gene variants are also linked to a variety of phenotypes, including malignancy, in individuals with no anemia. Here w...

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Autores principales: Lezzerini, Marco, Penzo, Marianna, O’Donohue, Marie-Françoise, Marques dos Santos Vieira, Carolina, Saby, Manon, Elfrink, Hyung L, Diets, Illja J, Hesse, Anne-Marie, Couté, Yohann, Gastou, Marc, Nin-Velez, Alexandra, Nikkels, Peter G J, Olson, Alexandra N, Zonneveld-Huijssoon, Evelien, Jongmans, Marjolijn C J, Zhang, GuangJun, van Weeghel, Michel, Houtkooper, Riekelt H, Wlodarski, Marcin W, Kuiper, Roland P, Bierings, Marc B, van der Werff ten Bosch, Jutte, Leblanc, Thierry, Montanaro, Lorenzo, Dinman, Jonathan D, Da Costa, Lydie, Gleizes, Pierre-Emmanuel, MacInnes, Alyson W
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6954397/
https://www.ncbi.nlm.nih.gov/pubmed/31799629
http://dx.doi.org/10.1093/nar/gkz1042
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author Lezzerini, Marco
Penzo, Marianna
O’Donohue, Marie-Françoise
Marques dos Santos Vieira, Carolina
Saby, Manon
Elfrink, Hyung L
Diets, Illja J
Hesse, Anne-Marie
Couté, Yohann
Gastou, Marc
Nin-Velez, Alexandra
Nikkels, Peter G J
Olson, Alexandra N
Zonneveld-Huijssoon, Evelien
Jongmans, Marjolijn C J
Zhang, GuangJun
van Weeghel, Michel
Houtkooper, Riekelt H
Wlodarski, Marcin W
Kuiper, Roland P
Bierings, Marc B
van der Werff ten Bosch, Jutte
Leblanc, Thierry
Montanaro, Lorenzo
Dinman, Jonathan D
Da Costa, Lydie
Gleizes, Pierre-Emmanuel
MacInnes, Alyson W
author_facet Lezzerini, Marco
Penzo, Marianna
O’Donohue, Marie-Françoise
Marques dos Santos Vieira, Carolina
Saby, Manon
Elfrink, Hyung L
Diets, Illja J
Hesse, Anne-Marie
Couté, Yohann
Gastou, Marc
Nin-Velez, Alexandra
Nikkels, Peter G J
Olson, Alexandra N
Zonneveld-Huijssoon, Evelien
Jongmans, Marjolijn C J
Zhang, GuangJun
van Weeghel, Michel
Houtkooper, Riekelt H
Wlodarski, Marcin W
Kuiper, Roland P
Bierings, Marc B
van der Werff ten Bosch, Jutte
Leblanc, Thierry
Montanaro, Lorenzo
Dinman, Jonathan D
Da Costa, Lydie
Gleizes, Pierre-Emmanuel
MacInnes, Alyson W
author_sort Lezzerini, Marco
collection PubMed
description Variants in ribosomal protein (RP) genes drive Diamond-Blackfan anemia (DBA), a bone marrow failure syndrome that can also predispose individuals to cancer. Inherited and sporadic RP gene variants are also linked to a variety of phenotypes, including malignancy, in individuals with no anemia. Here we report an individual diagnosed with DBA carrying a variant in the 5′UTR of RPL9 (uL6). Additionally, we report two individuals from a family with multiple cancer incidences carrying a RPL9 missense variant. Analysis of cells from these individuals reveals that despite the variants both driving pre-rRNA processing defects and 80S monosome reduction, the downstream effects are remarkably different. Cells carrying the 5′UTR variant stabilize TP53 and impair the growth and differentiation of erythroid cells. In contrast, ribosomes incorporating the missense variant erroneously read through UAG and UGA stop codons of mRNAs. Metabolic profiles of cells carrying the 5′UTR variant reveal an increased metabolism of amino acids and a switch from glycolysis to gluconeogenesis while those of cells carrying the missense variant reveal a depletion of nucleotide pools. These findings indicate that variants in the same RP gene can drive similar ribosome biogenesis defects yet still have markedly different downstream consequences and clinical impacts.
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spelling pubmed-69543972020-01-16 Ribosomal protein gene RPL9 variants can differentially impair ribosome function and cellular metabolism Lezzerini, Marco Penzo, Marianna O’Donohue, Marie-Françoise Marques dos Santos Vieira, Carolina Saby, Manon Elfrink, Hyung L Diets, Illja J Hesse, Anne-Marie Couté, Yohann Gastou, Marc Nin-Velez, Alexandra Nikkels, Peter G J Olson, Alexandra N Zonneveld-Huijssoon, Evelien Jongmans, Marjolijn C J Zhang, GuangJun van Weeghel, Michel Houtkooper, Riekelt H Wlodarski, Marcin W Kuiper, Roland P Bierings, Marc B van der Werff ten Bosch, Jutte Leblanc, Thierry Montanaro, Lorenzo Dinman, Jonathan D Da Costa, Lydie Gleizes, Pierre-Emmanuel MacInnes, Alyson W Nucleic Acids Res Molecular Biology Variants in ribosomal protein (RP) genes drive Diamond-Blackfan anemia (DBA), a bone marrow failure syndrome that can also predispose individuals to cancer. Inherited and sporadic RP gene variants are also linked to a variety of phenotypes, including malignancy, in individuals with no anemia. Here we report an individual diagnosed with DBA carrying a variant in the 5′UTR of RPL9 (uL6). Additionally, we report two individuals from a family with multiple cancer incidences carrying a RPL9 missense variant. Analysis of cells from these individuals reveals that despite the variants both driving pre-rRNA processing defects and 80S monosome reduction, the downstream effects are remarkably different. Cells carrying the 5′UTR variant stabilize TP53 and impair the growth and differentiation of erythroid cells. In contrast, ribosomes incorporating the missense variant erroneously read through UAG and UGA stop codons of mRNAs. Metabolic profiles of cells carrying the 5′UTR variant reveal an increased metabolism of amino acids and a switch from glycolysis to gluconeogenesis while those of cells carrying the missense variant reveal a depletion of nucleotide pools. These findings indicate that variants in the same RP gene can drive similar ribosome biogenesis defects yet still have markedly different downstream consequences and clinical impacts. Oxford University Press 2020-01-24 2019-12-04 /pmc/articles/PMC6954397/ /pubmed/31799629 http://dx.doi.org/10.1093/nar/gkz1042 Text en © The Author(s) 2019. Published by Oxford University Press on behalf of Nucleic Acids Research. http://creativecommons.org/licenses/by/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Molecular Biology
Lezzerini, Marco
Penzo, Marianna
O’Donohue, Marie-Françoise
Marques dos Santos Vieira, Carolina
Saby, Manon
Elfrink, Hyung L
Diets, Illja J
Hesse, Anne-Marie
Couté, Yohann
Gastou, Marc
Nin-Velez, Alexandra
Nikkels, Peter G J
Olson, Alexandra N
Zonneveld-Huijssoon, Evelien
Jongmans, Marjolijn C J
Zhang, GuangJun
van Weeghel, Michel
Houtkooper, Riekelt H
Wlodarski, Marcin W
Kuiper, Roland P
Bierings, Marc B
van der Werff ten Bosch, Jutte
Leblanc, Thierry
Montanaro, Lorenzo
Dinman, Jonathan D
Da Costa, Lydie
Gleizes, Pierre-Emmanuel
MacInnes, Alyson W
Ribosomal protein gene RPL9 variants can differentially impair ribosome function and cellular metabolism
title Ribosomal protein gene RPL9 variants can differentially impair ribosome function and cellular metabolism
title_full Ribosomal protein gene RPL9 variants can differentially impair ribosome function and cellular metabolism
title_fullStr Ribosomal protein gene RPL9 variants can differentially impair ribosome function and cellular metabolism
title_full_unstemmed Ribosomal protein gene RPL9 variants can differentially impair ribosome function and cellular metabolism
title_short Ribosomal protein gene RPL9 variants can differentially impair ribosome function and cellular metabolism
title_sort ribosomal protein gene rpl9 variants can differentially impair ribosome function and cellular metabolism
topic Molecular Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6954397/
https://www.ncbi.nlm.nih.gov/pubmed/31799629
http://dx.doi.org/10.1093/nar/gkz1042
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