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

• Published in: Blood Vol. 132; no. 12; pp. 1318 - 1331
• Main Authors: Bellanné-Chantelot, Christine, Schmaltz-Panneau, Barbara, Marty, Caroline, Fenneteau, Odile, Callebaut, Isabelle, Clauin, Séverine, Docet, Aurélie, Damaj, Gandhi-Laurent, Leblanc, Thierry, Pellier, Isabelle, Stoven, Cécile, Souquere, Sylvie, Antony-Debré, Iléana, Beaupain, Blandine, Aladjidi, Nathalie, Barlogis, Vincent, Bauduer, Frédéric, Bensaid, Philippe, Boespflug-Tanguy, Odile, Berger, Claire, Bertrand, Yves, Carausu, Liana, Fieschi, Claire, Galambrun, Claire, Schmidt, Aline, Journel, Hubert, Mazingue, Françoise, Nelken, Brigitte, Quah, Thuan Chong, Oksenhendler, Eric, Ouachée, Marie, Pasquet, Marlène, Saada, Véronique, Suarez, Felipe, Pierron, Gérard, Vainchenker, William, Plo, Isabelle, Donadieu, Jean
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 20.09.2018; American Society of Hematology
• Subjects: Adolescent; Adult; Apoptosis; Autophagy; Bone Marrow Diseases - genetics; Bone Marrow Diseases - metabolism; Bone Marrow Diseases - pathology; Child; Child, Preschool; Congenital Bone Marrow Failure Syndromes; Endoplasmic Reticulum Stress; Exocrine Pancreatic Insufficiency - genetics; Exocrine Pancreatic Insufficiency - metabolism; Exocrine Pancreatic Insufficiency - pathology; Female; Humans; Infant; Infant, Newborn; Life Sciences; Lipomatosis - genetics; Lipomatosis - metabolism; Lipomatosis - pathology; Male; Middle Aged; Mutation; Neutropenia - congenital; Neutropenia - genetics; Neutropenia - metabolism; Neutropenia - pathology; Phagocytes, Granulocytes, and Myelopoiesis; Shwachman-Diamond Syndrome; Signal Recognition Particle - genetics; Up-Regulation; Young Adult
• ISSN: 0006-4971; 1528-0020; 1528-0020
• DOI: 10.1182/blood-2017-12-820308

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. •Identification of SRP54 mutations in congenital neutropenia.•SRP54 mutations induce ER stress and autophagy associated with apoptosis. [Display omitted]