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New disease loci
Mutations in EFL1, an SBDS partner, are associated with infantile pancytopenia, exocrine pancreatic insufficiency and skeletal anomalies in a Shwachman-Diamond like syndrome
  1. Polina Stepensky1,
  2. Montserrat Chacón-Flores2,
  3. Katherine H Kim3,4,
  4. Omar Abuzaitoun5,
  5. Arnulfo Bautista-Santos2,
  6. Natalia Simanovsky6,
  7. Dritan Siliqi7,
  8. Davide Altamura7,
  9. Alfonso Méndez-Godoy2,
  10. Abril Gijsbers2,
  11. Adeeb Naser Eddin1,
  12. Talia Dor8,
  13. Joel Charrow3,4,
  14. Nuria Sánchez-Puig2,
  15. Orly Elpeleg9
  1. 1Department of Pediatric Hematology, Oncology and Bone Marrow Transplantation, Hadassah, Hebrew University Medical Center, Jerusalem, Israel
  2. 2Departamento de Química de Biomacromoléculas, Instituto de Química, Universidad Nacional Autónoma de México, Ciudad de México, México
  3. 3Division of Genetics, Birth Defects and Metabolism, Ann & Robert H. Lurie Children’s Hospital of Chicago, Chicago, Illinois, USA
  4. 4Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, USA
  5. 5Nablus Speciality Hospital, Palestinian Authority, Nablus, Palestine
  6. 6Department of Medical Imaging, Hadassah, Hebrew University Medical Center, Jerusalem, Israel
  7. 7Istituto di Cristallografia, Consiglio Nazionale delle Ricerche, Bari, Italy
  8. 8Pediatric Neurology Unit, Hadassah, Hebrew University Medical Center, Jerusalem, Israel
  9. 9Monique and Jacques Roboh Department of Genetic Research, Hadassah, Hebrew University Medical Center, Jerusalem, Israel
  1. Correspondence to Nuria Sánchez-Puig; nuriasp{at}
  2. and Professor Orly Elpeleg, Monique and Jacques Roboh Department of Genetic Research, Hadassah-Hebrew University Medical Center, Jerusalem 91120, Israel; elpeleg{at}


Background For the final step of the maturation of the ribosome, the nascent 40S and 60S subunits are exported from the nucleus to the cell cytoplasm. To prevent premature association of these ribosomal subunits, eukaryotic initiation factor 6 (eIF6) binds the 60S subunit within the nucleus. Its release in the cytoplasm requires the interaction of EFL1 and SDBS proteins. In Shwachman-Diamond syndrome (SDS), a defective SDBS protein prevents eIF6 eviction, inhibiting its recycle to the nucleus and subsequent formation of the active 80S ribosome.

Objective This study aims to identify the molecular basis of an SDS-like disease, manifested by pancytopenia, exocrine pancreatic insufficiency and skeletal abnormalities in six patients from three unrelated families.

Methods Whole exome analysis was used for mutation identification. Fluorescence microscopy studies assessed the localisation of Tif6-GFP, the yeast eIF6 homologue, in yeast WT and mutant cells. Human and yeast EFL1 proteins, WT and mutants, were expressed in Saccharomyces cerevisiae BCY123 strain, and circular dichroism and small-angle X-ray scattering were used to assess the folding and flexibility of these proteins. Green malachite colorimetric assay was performed to determine the GTPase activity of WT and Efl1 mutants.

Results Four patients were homozygous for p.R1095Q variant and two patients were homozygous for p.M882K variant in EFL1. Residue R1095 and M882 are conserved across species. Neither the GTPase activity of the mutant proteins nor its activation by the SDBD protein or the 60S ribosomal subunit were affected. Complementation of efl1Δ yeast cells with the EFL1 mutants rescued the slow growth phenotype. Nonetheless, Tif6-GFP was relocalised to the cytoplasm in mutant yeast cells in contrast to its nuclear localisation in WT cells.

Conclusions Mutations in EFL1 clinically manifest as SDS-like phenotype. Similar to the molecular pathology of SDS, mutant EFL1 proteins do not promote the release of cytoplasmic Tif6 from the 60S subunit, likely preventing the formation of mature ribosomes.

  • Ribosome
  • exocrine pancreatic insufficiency
  • pancytopenia
  • Shwachman-Diamond syndrome

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  • Contributors PS, KHK and MCF contributed equally. PS, OA, NS, ANE, TD and OE led patients’ recruitment, clinical phenotyping and genetic analysis. MCF, ABS, DS, DA, AG, AMG and NSP performed and analysed all functional studies. All the authors assisted in the assembly and editing of the manuscript.

  • Patient consent Obtained.

  • Patient consent NSP acknowledges the financial support from DGAPA-PAPIIT project IN201615. PS and OA are supported by funding from the Deutsche Forschungsgemeinschaft (DECIDE, DFG WA 1597/4–1). This work was supported in part by the Trudy Mandel Louis Charitable Trust to OE.

  • Ethics approval The Ethical Committee of Hadassah Medical Center.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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