EFL1 mutations impair eIF6 release to cause Shwachman-Diamond syndrome

S Tan, L Kermasson, A Hoslin, P Jaako… - Blood, The Journal …, 2019 - ashpublications.org
S Tan, L Kermasson, A Hoslin, P Jaako, A Faille, A Acevedo-Arozena, E Lengline, D Ranta…
Blood, The Journal of the American Society of Hematology, 2019ashpublications.org
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 …
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.
ashpublications.org