Journal
BLOOD
Volume 134, Issue 3, Pages 277-290Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood.2018893404
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Funding
- Swedish Research Council [2014-06807]
- INSERM
- Ligue Nationale contre le Cancer (Equipe Labellisee La Ligue)
- GIS-Institut des maladies rares
- Agence Nationale de la Recherche under Investissements d'avenir program [ANR-10-IAHU-01]
- Bloodwise [12048]
- UK Medical Research Council [MC_ U105161083, MC_UP_A390_1106, 1330931]
- Wellcome Trust [100140]
- Medical Research Council
- Connor Wright Shwachman Diamond Project
- Cambridge National Institute for Health Research Biomedical Research Centre
- MRC [MR/L003368/1, MC_UP_A390_1106, MC_U105161083] Funding Source: UKRI
- Swedish Research Council [2014-06807] Funding Source: Swedish Research Council
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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.
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