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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 


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.



Adolescent, Adult, Animals, Biological Phenomena, Cells, Cultured, Child, Child, Preschool, Dictyostelium, Drosophila, Eukaryotic Initiation Factors, Germ Cells, Humans, Infant, Molecular Dynamics Simulation, Mutation, Peptide Elongation Factors, Protein Binding, Protein Biosynthesis, Proteins, Ribonucleoprotein, U5 Small Nuclear, Ribosome Subunits, Large, Eukaryotic, Ribosomes, Saccharomyces cerevisiae, Sequence Homology, Amino Acid, Shwachman-Diamond Syndrome, Young Adult

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Nat Commun

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Springer Science and Business Media LLC
Bloodwise (15035)
MRC (MR/T012412/1)
Wellcome Trust (100140/Z/12/Z)
Leukaemia & Lymphoma Research (11027)
Leukaemia & Lymphoma Research (12048)
Blood Cancer UK, UK Medical Research Council, Kay Kendall Leukaemia Fund, a Wellcome Trust strategic award to the Cambridge Institute for Medical Research, a core support grant from the Wellcome Trust and MRC to the Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, the Connor Wright Project, the Cambridge National Institute for Health Research Biomedical Research Centre and the European Cooperation in Science and Technology (COST) Action CA18233 “European Network for Innovative Diagnosis and treatment of Chronic Neutropenias, EuNet INNOCHRON”.