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Title: Somatic genetic rescue of a germline ribosome assembly defect
Authors: Tan, Shengjiang
Kermasson, Laetitia
Hilcenko, Christine
Kargas, Vasileios
Traynor, David
Boukerrou, Ahmed Z.
Escudero-Urquijo, Norberto
Faille, Alexandre
Bertrand, Alexis
Rossmann, Maxim
Goyenechea, Beatriz
Jin, Li
Moreil, Jonathan
Alibeu, Olivier
Beaupain, Blandine
Bôle-Feysot, Christine
Fumagalli, Stefano
Kaltenbach, Sophie
Martignoles, Jean-Alain
Masson, Cecile
Nitschké, Patrick
Parisot, Melanie
Pouliet, Aurore
Radford-Weiss, Isabelle
Tores, Frederic
de Villartay, Jean-Pierre
Zarhrate, Mohammed
Koh, Ai Ling 
Phua, Kong Boo 
Reversade, Bruno 
Bond, Peter J. 
Bellanné-Chantelot, Christine
Callebaut, Isabelle
Delhommeau, Francois
Donadieu, Jean
Warren, Alan J.
Revy, Patrick
Issue Date: 19-Aug-2021
Publisher: Nature Research
Citation: Tan, Shengjiang, Kermasson, Laetitia, Hilcenko, Christine, Kargas, Vasileios, Traynor, David, Boukerrou, Ahmed Z., Escudero-Urquijo, Norberto, Faille, Alexandre, Bertrand, Alexis, Rossmann, Maxim, Goyenechea, Beatriz, Jin, Li, Moreil, Jonathan, Alibeu, Olivier, Beaupain, Blandine, Bôle-Feysot, Christine, Fumagalli, Stefano, Kaltenbach, Sophie, Martignoles, Jean-Alain, Masson, Cecile, Nitschké, Patrick, Parisot, Melanie, Pouliet, Aurore, Radford-Weiss, Isabelle, Tores, Frederic, de Villartay, Jean-Pierre, Zarhrate, Mohammed, Koh, Ai Ling, Phua, Kong Boo, Reversade, Bruno, Bond, Peter J., Bellanné-Chantelot, Christine, Callebaut, Isabelle, Delhommeau, Francois, Donadieu, Jean, Warren, Alan J., Revy, Patrick (2021-08-19). Somatic genetic rescue of a germline ribosome assembly defect. Nature Communications 12 (1) : 5044. ScholarBank@NUS Repository.
Rights: Attribution 4.0 International
Abstract: Indirect somatic genetic rescue (SGR) of a germline mutation is thought to be rare in inherited Mendelian disorders. Here, we establish that acquired mutations in the EIF6 gene are a frequent mechanism of SGR in Shwachman-Diamond syndrome (SDS), a leukemia predisposition disorder caused by a germline defect in ribosome assembly. Biallelic mutations in the SBDS or EFL1 genes in SDS impair release of the anti-association factor eIF6 from the 60S ribosomal subunit, a key step in the translational activation of ribosomes. Here, we identify diverse mosaic somatic genetic events (point mutations, interstitial deletion, reciprocal chromosomal translocation) in SDS hematopoietic cells that reduce eIF6 expression or disrupt its interaction with the 60S subunit, thereby conferring a selective advantage over non-modified cells. SDS-related somatic EIF6 missense mutations that reduce eIF6 dosage or eIF6 binding to the 60S subunit suppress the defects in ribosome assembly and protein synthesis across multiple SBDS-deficient species including yeast, Dictyostelium and Drosophila. Our data suggest that SGR is a universal phenomenon that may influence the clinical evolution of diverse Mendelian disorders and support eIF6 suppressor mimics as a therapeutic strategy in SDS. © 2021, The Author(s).
Source Title: Nature Communications
ISSN: 2041-1723
DOI: 10.1038/s41467-021-24999-5
Rights: Attribution 4.0 International
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