EFL1 mutations impair eIF6 release to cause Shwachman-Diamond syndrome

Author:

Tan Shengjiang123,Kermasson Laëtitia45,Hoslin Angela6,Jaako Pekka123,Faille Alexandre123,Acevedo-Arozena Abraham6789ORCID,Lengline Etienne10,Ranta Dana11,Poirée Maryline12,Fenneteau Odile13,Ducou le Pointe Hubert1415,Fumagalli Stefano1617,Beaupain Blandine18,Nitschké Patrick19,Bôle-Feysot Christine20,de Villartay Jean-Pierre45,Bellanné-Chantelot Christine21ORCID,Donadieu Jean22,Kannengiesser Caroline2324,Warren Alan J.123ORCID,Revy Patrick45ORCID

Affiliation:

1. Cambridge Institute for Medical Research, Cambridge, United Kingdom;

2. Department of Haematology, University of Cambridge, Cambridge, United Kingdom;

3. Wellcome Trust–Medical Research Council Stem Cell Institute, University of Cambridge, Cambridge, United Kingdom;

4. INSERM Unité Mixte de Recherche 1163, Laboratory of Genome Dynamics in the Immune System, Equipe Labellisée Ligue contre le cancer, Paris, France;

5. Paris Descartes–Sorbonne Paris Cité University, Imagine Institute, Paris, France;

6. Medical Research Council Mammalian Genetics Unit, Harwell, United Kingdom;

7. Unidad de Investigación, Hospital Universitario de Canarias, La Laguna, Spain;

8. Instituto de Tecnologías Biomédicas, Universidad de La Laguna, La Laguna, Spain;

9. Centro Investigación Biomédica en Red Enfermedades Neurodegenerativas, La Laguna, Spain;

10. Department of Hematology, CRNMR Aplasie Médullaire, Saint-Louis University Hospital, Assistance Publique–Hôpitaux de Paris, Paris, France;

11. Department of Haematology, Centre Hospitalier Universitaire de Nancy, Nancy, France;

12. Department of Pediatric Hematology-Oncology, Centre Hospitalier Universitaire Lenval, Nice, France;

13. Assistance Publique–Hôpitaux de Paris, Laboratory of Hematology, Robert Debré University Hospital, Paris, France;

14. Radiology Department, Armand Trousseau Hospital, Assistance Publique–Hôpitaux de Paris, Paris, France;

15. Department of Pediatric Imaging, Armand Trousseau Hospital, Sorbonne Universités, Pierre et Marie Curie-Paris University, Paris, France;

16. Institut Necker Enfants Malades, Paris, France;

17. INSERM, U1151, Université Paris Descartes Sorbonne Cité, Paris, France;

18. French Neutropenia Registry, Assistance Publique–Hôpitaux de Paris, Trousseau Hospital, Paris, France;

19. INSERM Unité Mixte de Recherche 1163, Bioinformatics Platform, Paris Descartes–Sorbonne Paris Cité University, Imagine Institute, Paris, France;

20. INSERM Unité Mixte de Recherche 1163, Genomics Platform, Paris Descartes–Sorbonne Paris Cité University, Imagine Institute, Paris, France;

21. Department of Genetics, Hospital Pitié Salpétriére Assistance Publique–Hôpitaux de Paris, Sorbonne Université, Paris, France;

22. Service d’Hémato-Oncologie Pédiatrique, Assistance Publique–Hôpitaux de Paris Hôpital Trousseau, Registre des neutropénies–Centre de référence des neutropénies chroniques, Paris, France;

23. Assistance Publique–Hôpitaux de Paris Service de Génétique, Hôpital Bichat, Paris, France; and

24. Université Paris Diderot, Sorbonne Paris Cité, Paris, France

Abstract

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.

Publisher

American Society of Hematology

Subject

Cell Biology,Hematology,Immunology,Biochemistry

Reference52 articles.

1. Molecular basis of the human ribosomopathy Shwachman-Diamond syndrome;Warren;Adv Biol Regul,2017

2. Marrow failure: a window into ribosome biology;Ruggero;Blood,2014

3. Ribosomopathies: global process, tissue specific defects;Yelick;Rare Dis,2015

4. Mechanism of eIF6 release from the nascent 60S ribosomal subunit;Weis;Nat Struct Mol Biol,2015

5. Classification of and risk factors for hematologic complications in a French national cohort of 102 patients with Shwachman-Diamond syndrome;Donadieu;Haematologica,2012

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