1. EFL1 mutations impair eIF6 release to cause Shwachman-Diamond syndrome
- Author
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Tan, Shengjiang, Kermasson, Laëtitia, Hoslin, Angela, Jaako, Pekka, Faille, Alexandre, Acevedo-Arozena, Abraham, Lengline, Etienne, Ranta, Dana, Poirée, Maryline, Fenneteau, Odile, Ducou Le Pointe, Hubert, Fumagalli, Stefano, Beaupain, Blandine, Nitschké, Patrick, Bôle-Feysot, Christine, De Villartay, Jean-Pierre, Bellanné-Chantelot, Christine, Donadieu, Jean, Kannengiesser, Caroline, Warren, Alan J, and Revy, Patrick
- Subjects
Male ,Models, Molecular ,Adolescent ,Whole Genome Sequencing ,Protein Conformation ,DNA Mutational Analysis ,Infant ,Mice, Transgenic ,Peptide Elongation Factors ,Shwachman-Diamond Syndrome ,3. Good health ,Pedigree ,Disease Models, Animal ,Mice ,Structure-Activity Relationship ,Phenotype ,Peptide Initiation Factors ,Mutation ,Animals ,Humans ,Female ,Disease Susceptibility ,Cells, Cultured ,Ribonucleoprotein, U5 Small Nuclear ,Genome-Wide Association Study - Abstract
Shwachman-Diamond syndrome (SDS) is a recessive disorder typified by bone marrow failure and predisposition to hematological malignancies. SDS is predominantly caused by deficiency of the allosteric regulator Shwachman-Bodian-Diamond syndrome that cooperates with elongation factor-like GTPase 1 (EFL1) to catalyze release of the ribosome antiassociation factor eIF6 and activate translation. Here, we report biallelic mutations in EFL1 in 3 unrelated individuals with clinical features of SDS. Cellular defects in these individuals include impaired ribosomal subunit joining and attenuated global protein translation as a consequence of defective eIF6 eviction. In mice, Efl1 deficiency recapitulates key aspects of the SDS phenotype. By identifying biallelic EFL1 mutations in SDS, we define this leukemia predisposition disorder as a ribosomopathy that is caused by corruption of a fundamental, conserved mechanism, which licenses entry of the large ribosomal subunit into translation.