Mutations in the SRP54 gene cause severe congenital neutropenia as well as Shwachman-Diamond-like syndrome PMID: 29914977

RQC and Longevity Regulation

2026-09-03

Mutations in the SRP54 gene cause severe congenital neutropenia as well as Shwachman-Diamond-like syndrome

Blood. 2018 Sep 20;132(12):1318-1331. doi: 10.1182/blood-2017-12-820308.

Christine Bellanné-Chantelot ¹ ² , Barbara Schmaltz-Panneau ² ³ , Caroline Marty ² ³ , Odile Fenneteau ⁴ , Isabelle Callebaut ⁵ , Séverine Clauin ¹ , Aurélie Docet ¹ , Gandhi-Laurent Damaj ⁶ , Thierry Leblanc ⁷ , Isabelle Pellier ⁸ , Cécile Stoven ⁹ , Sylvie Souquere ¹⁰ , Iléana Antony-Debré ² ³ , Blandine Beaupain ¹¹ , Nathalie Aladjidi ¹² , Vincent Barlogis ¹³ , Frédéric Bauduer ¹⁴ , Philippe Bensaid ¹⁵ , Odile Boespflug-Tanguy ¹⁶ , Claire Berger ¹⁷ , Yves Bertrand ¹⁸ , Liana Carausu ¹⁹ , Claire Fieschi ²⁰ , Claire Galambrun ¹³ , Aline Schmidt ²¹ ²² , Hubert Journel ²³ , Françoise Mazingue ²⁴ , Brigitte Nelken ²⁴ , Thuan Chong Quah ²⁵ , Eric Oksenhendler ²⁰ , Marie Ouachée ⁷ ¹⁸ , Marlène Pasquet ²⁶ , Véronique Saada ²⁷ , Felipe Suarez ²⁸ ²⁹ ³⁰ , Gérard Pierron ¹⁰ , William Vainchenker ² ³ , Isabelle Plo ² ³ , Jean Donadieu ¹¹ ³¹

Affiliations

1. Department of Genetics, Pitié-Salpêtrière Hospital, Assistance Publique-Hôpitaux de Paris (AP-HP), Sorbonne Université, Paris, France.
2. INSERM UMR1170 and.
3. University Paris-Saclay, Gustave Roussy, Villejuif, France.
4. Laboratory of Hematology, Robert Debré Hospital, AP-HP, Paris, France.
5. CNRS UMR7590, Sorbonne Universités, Université Pierre et Marie Curie-Paris 6-MNHN-IRD-IUC, Paris, France.
6. Department of Hematology, Centre Hospitalier Universitaire (CHU), Faculté de Médecine, University of Normandie Caen, Caen, France.
7. Department of Pediatric Hematology and Immunology, Robert Debré Hospital, AP-HP, Paris, France.
8. Department of Pediatric Hematology, Immunology and Oncology, CHU, Angers, France.
9. Department of Pediatrics, CHU La Réunion, Groupe Hospitalier Sud Réunion, France.
10. CNRS UMR9196, Gustave Roussy, Villejuif, France.
11. French Registry of Chronic Neutropenia, Trousseau Hospital, Paris, France.
12. Unit of Pediatric Hematology, Centre d'Investigation Clinique 1401 INSERM Centre d'Investigation Clinique Plurithématique, CHU Bordeaux, France.
13. Department of Pediatric Hematology, Timone Hospital, Assistance Publique-Hôpitaux de Marseille, Marseille, France.
14. Centre Hospitalier Côte Basque, Bayonne, France.
15. Department of Pediatrics, Centre Hospitalier Argenteuil, Argenteuil, France.
16. Child Neurology and Metabolic Disorders Department, Robert Debré Hospital, AP-HP, Paris, France.
17. Department of Pediatric Hematology and Oncology, CHU, Saint-Etienne, France.
18. Institut of Pediatric Hematology and Oncology, Lyon, France.
19. Department of Pediatric Hematology and Oncology, CHU, Brest, France.
20. Department of Clinical Immunology, Saint-Louis Hospital, AP-HP, Paris, France.
21. Department of Hematology, CHU, Angers, France.
22. INSERM U892/CNRS 6299, Angers University, Angers, France.
23. Department of Genetics, Bretagne-Atlantique Hospital, Vannes, France.
24. Department of Pediatric Hematology and Oncology, CHRU, Lille, France.
25. Department of Pediatrics, National University Hospital, Singapore.
26. Department of Pediatric Hematology and Oncology, CHU, Toulouse, France.
27. Laboratory of Hematology, Gustave Roussy, Villejuif, France.
28. Department of Hematology, Necker-Enfants Malades University Hospital, AP-HP, Paris, France.
29. INSERM UMR1163 and CNRS ERL 8254, Imagine Institut, Sorbonne Paris Cité, Paris, France.
30. Descartes University, Paris, France; and.
31. Department of Pediatric Hematology and Oncology, Trousseau Hospital, AP-HP, Paris, France.

Abstract

Congenital neutropenias (CNs) are rare heterogeneous genetic disorders, with about 25% of patients without known genetic defects. Using whole-exome Sequencing, we identified a heterozygous mutation in the SRP54 gene, encoding the signal recognition particle (SRP) 54 GTPase protein, in 3 sporadic cases and 1 autosomal dominant family. We subsequently sequenced the SRP54 gene in 66 probands from the French CN registry. In total, we identified 23 mutated cases (16 sporadic, 7 familial) with 7 distinct germ line SRP54 mutations including a recurrent in-frame deletion (Thr117del) in 14 cases. In nearly all patients, neutropenia was chronic and profound with promyelocytic maturation arrest, occurring within the first months of life, and required long-term granulocyte colony-stimulating factor therapy with a poor response. Neutropenia was sometimes associated with a severe neurodevelopmental delay (n = 5) and/or an exocrine pancreatic insufficiency requiring enzyme supplementation (n = 3). The SRP54 protein is a key component of the ribonucleoprotein complex that mediates the co-translational targeting of secretory and membrane proteins to the endoplasmic reticulum (ER). We showed that SRP54 was specifically upregulated during the in vitro granulocytic differentiation, and that SRP54 mutations or knockdown led to a drastically reduced proliferation of granulocytic cells associated with an enhanced P53-dependent Apoptosis. Bone marrow examination of SRP54-mutated patients revealed a major dysgranulopoiesis and features of cellular ER stress and Autophagy that were confirmed using SRP54-mutated primary cells and SRP54 knockdown cells. In conclusion, we characterized a pathological pathway, which represents the second most common cause of CN with maturation arrest in the French CN registry.