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Somatic genetic rescue of a germline ribosome assembly defect

Tan, Shengjiang, Kermasson, Laëtitia, 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, Cécile, Nitschké, Patrick, Parisot, Mélanie, Pouliet, Aurore, Radford-Weiss, Isabelle, Tores, Frédéric, de Villartay, Jean-Pierre, Zarhrate, Mohammed, Koh, Ai Ling, Phua, Kong Boo, Reversade, Bruno, Bond, Peter J., Bellanné-Chantelot, Christine, Callebaut, Isabelle, Delhommeau, François, Donadieu, Jean, Warren, Alan J., Revy, Patrick·2021·Nature Communications
DOI 10.1038/s41467-021-24999-5
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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.

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Metadata

Authors
Tan, S., Kermasson, L., Hilcenko, C., Kargas, V., Traynor, D., Boukerrou, A. Z., Escudero-Urquijo, N., Faille, A., Bertrand, A., Rossmann, M., Goyenechea, B., Jin, L., Moreil, J., Alibeu, O., Beaupain, B., Bôle-Feysot, C., Fumagalli, S., Kaltenbach, S., Martignoles, J.-A., Masson, C., Nitschké, P., Parisot, M., Pouliet, A., Radford-Weiss, I., Tores, F., de Villartay, J.-P., Zarhrate, M., Koh, A. L., Phua, K. B., Reversade, B., Bond, P. J., Bellanné-Chantelot, C., Callebaut, I., Delhommeau, F., Donadieu, J., Warren, A. J., & Revy, P.
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2021-08-19
Volume
12
Issue
1
ISSN
2041-1723
DOI
10.1038/s41467-021-24999-5
Cited by
80
References
10
Language
en
Update notices
correction (2022-06-22)
Licence
Funders
  • Ligue Contre le Cancer (Equipe Labellisée La Ligue ‘LIGUE 2020’)
  • Agence Nationale de la Recherche (ANR-10-IAHU-01)

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CoChat. (2026). Citation check: Somatic genetic rescue of a germline ribosome assembly defect. https://app.cochat.ai/papers/10.1038/s41467-021-24999-5
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Tan, S., Kermasson, L., Hilcenko, C., Kargas, V., Traynor, D., Boukerrou, A. Z., Escudero-Urquijo, N., Faille, A., Bertrand, A., Rossmann, M., Goyenechea, B., Jin, L., Moreil, J., Alibeu, O., Beaupain, B., Bôle-Feysot, C., Fumagalli, S., Kaltenbach, S., Martignoles, J.-A., . . . Revy, P. (2021). Somatic genetic rescue of a germline ribosome assembly defect. Nature Communications. https://doi.org/10.1038/s41467-021-24999-5

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