TY - JOUR
T1 - Ribosomal protein gene RPL9 variants can differentially impair ribosome function and cellular metabolism
AU - Lezzerini, Marco
AU - Penzo, Marianna
AU - O'Donohue, Marie-Françoise
AU - Marques Dos Santos Vieira, Carolina
AU - Saby, Manon
AU - Elfrink, Hyung L.
AU - Diets, Illja J.
AU - Hesse, Anne-Marie
AU - Couté, Yohann
AU - Gastou, Marc
AU - Nin-Velez, Alexandra
AU - Nikkels, Peter G. J.
AU - Olson, Alexandra N.
AU - Zonneveld-Huijssoon, Evelien
AU - Jongmans, Marjolijn C. J.
AU - Zhang, GuangJun
AU - van Weeghel, Michel
AU - Houtkooper, Riekelt H.
AU - Wlodarski, Marcin W.
AU - Kuiper, Roland P.
AU - Bierings, Marc B.
AU - van der Werff ten Bosch, Jutte
AU - Leblanc, Thierry
AU - Montanaro, Lorenzo
AU - Dinman, Jonathan D.
AU - da Costa, Lydie
AU - Gleizes, Pierre-Emmanuel
AU - MacInnes, Alyson W.
PY - 2020/1/24
Y1 - 2020/1/24
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85077766068&partnerID=8YFLogxK
U2 - https://doi.org/10.1093/nar/gkz1042
DO - https://doi.org/10.1093/nar/gkz1042
M3 - Article
C2 - 31799629
SN - 0305-1048
VL - 48
SP - 770
EP - 787
JO - Nucleic Acids Research
JF - Nucleic Acids Research
IS - 2
ER -