EFL1 mutations impair eIF6 release to cause Shwachman-Diamond syndrome

Shengjiang Tan, Laëtitia Kermasson, Angela Hoslin, Pekka Jaako, Alexandre Faille, Abraham Acevedo-Arozena, Etienne Lengline, Dana Ranta, Maryline Poirée, Odile Fenneteau, Hubert Ducou le Pointe, Stefano Fumagalli, Blandine Beaupain, Patrick Nitschké, Christine Bôle-Feysot, Jean-Pierre de Villartay, Christine Bellanné-Chantelot, Jean Donadieu, Caroline Kannengiesser, Alan J. Warren and Patrick Revy

Key Points

  • Biallelic EFL1 mutations cause Shwachman-Diamond syndrome.

  • EFL1 deficiency impairs eIF6 eviction from nascent 60S ribosomal subunits, reducing ribosomal subunit joining and attenuating protein synthesis.


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 SBDS that cooperates with the GTPase EFL1 to catalyze release of the ribosome anti-association factor eIF6 and activate translation. Here, we report biallelic mutations in EFL1 in three 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.

  • Submitted December 21, 2018.
  • Revision received May 11, 2019.
  • Accepted May 10, 2019.