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Somatic genetic rescue of a germline ribosome assembly defect

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Tan, Shengjiang 
Kermasson, Laëtitia 
Hilcenko, Christine 
Kargas, Vasileios 
Traynor, David 


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.



Article, /631/208/737, /631/208/514/2254, /631/337/574/1789, /692/699/1541, /45/23, /64/24, /13/1, /38/22, /82/80, /96/44, article

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Nature Communications

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Nature Publishing Group UK
Ligue Contre le Cancer (Equipe Labellisée La Ligue ‘LIGUE 2020’)
Agence Nationale de la Recherche (French National Research Agency) (ANR-10-IAHU-01)