HEATR3 variants impair nuclear import of uL18 (RPL5) and drive Diamond-Blackfan anemia

Autor: Marie-Françoise O’Donohue, Lydie Da Costa, Marco Lezzerini, Sule Unal, Clément Joret, Marije Bartels, Eva Brilstra, Marijn Scheijde-Vermeulen, Ludivine Wacheul, Kim De Keersmaecker, Stijn Vereecke, Veerle Labarque, Manon Saby, Sophie D. Lefevre, Jessica Platon, Nathalie Montel-Lehry, Nathalie Laugero, Eric Lacazette, Koen van Gassen, Riekelt H. Houtkooper, Pelin Ozlem Simsek-Kiper, Thierry Leblanc, Nese Yarali, Arda Cetinkaya, Nurten A. Akarsu, Pierre-Emmanuel Gleizes, Denis L. J. Lafontaine, Alyson W. MacInnes
Přispěvatelé: Laboratory Medicine, ACS - Diabetes & metabolism, Laboratory Genetic Metabolic Diseases, ACS - Heart failure & arrhythmias, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, Laboratory for General Clinical Chemistry
Jazyk: angličtina
Rok vydání: 2022
Předmět:
Zdroj: Blood, 139(21), 3111-3126. American Society of Hematology
O'Donohue, M-F, da Costa, L, Lezzerini, M, Unal, S, Joret, C, Bartels, M, Brilstra, E, Scheijde-Vermeulen, M, Wacheul, L, de Keersmaecker, K, Vereecke, S, Labarque, V, Saby, M, Lefevre, S D, Platon, J, Montel-Lehry, N, Laugero, N, Lacazette, E, van Gassen, K, Houtkooper, R H, Simsek-Kiper, P O, Leblanc, T, Yarali, N, Cetinkaya, A, Akarsu, N A, Gleizes, P-E, Lafontaine, D L J & MacInnes, A W 2022, ' HEATR3 variants impair nuclear import of uL18 (RPL5) and drive Diamond-Blackfan anemia ', Blood, vol. 139, no. 21, pp. 3111-3126 . https://doi.org/10.1182/blood.2021011846
ISSN: 0006-4971
DOI: 10.1182/blood.2021011846
Popis: The congenital bone marrow failure syndrome Diamond-Blackfan anemia (DBA) is typically associated with variants in ribosomal protein (RP) genes impairing erythroid cell development. Here we report multiple individuals with biallelic HEATR3 variants exhibiting bone marrow failure, short stature, facial and acromelic dysmorphic features, and intellectual disability. These variants destabilize a protein whose yeast homolog is known to synchronize the nuclear import of RPs uL5 (RPL11) and uL18 (RPL5), which are both critical for producing ribosomal subunits and for stabilizing the p53 tumor suppressor when ribosome biogenesis is compromised. Expression of HEATR3 variants or repression of HEATR3 expression in primary cells, cell lines of various origins, and yeast models impairs growth, differentiation, pre-ribosomal RNA processing, and ribosomal subunit formation reminiscent of DBA models of large subunit RP gene variants. Consistent with a role of HEATR3 in RP import, HEATR3-depleted cells or patient-derived fibroblasts display reduced nuclear accumulation of uL18. Hematopoietic progenitor cells expressing HEATR3 variants or small-hairpin RNAs knocking down HEATR3 synthesis reveal abnormal acceleration of erythrocyte maturation coupled to severe proliferation defects that are independent of p53 activation. Our study uncovers a new pathophysiological mechanism leading to DBA driven by biallelic HEATR3 variants and the destabilization of a nuclear import protein important for ribosome biogenesis. ispartof: Blood vol:139 issue:21 pages:3111-3126 ispartof: location:United States status: Published online
Databáze: OpenAIRE
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