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Human Genetic Defects in Srp19 and Srpra Cause Severe Congenital Neutropenia With Distinctive Proteome Changes Publisher Pubmed



Linder MI1 ; Mizoguchi Y1, 12 ; Hesse S1 ; Csaba G3 ; Tatematsu M1 ; Lyszkiewicz M1 ; Zietara N1 ; Jeske T1, 4 ; Hastreiter M1 ; Rohlfs M1 ; Liu Y1, 5 ; Grabowski P6 ; Ahomaa K4 ; Maierbegandt D7 Show All Authors
Authors
  1. Linder MI1
  2. Mizoguchi Y1, 12
  3. Hesse S1
  4. Csaba G3
  5. Tatematsu M1
  6. Lyszkiewicz M1
  7. Zietara N1
  8. Jeske T1, 4
  9. Hastreiter M1
  10. Rohlfs M1
  11. Liu Y1, 5
  12. Grabowski P6
  13. Ahomaa K4
  14. Maierbegandt D7
  15. Schwestka M8
  16. Pazhakh V8, 9
  17. Isiaku AI8
  18. Briones Miranda B8
  19. Blombery P9
  20. Saito MK10
  21. Rusha E2
  22. Alizadeh Z11
  23. Pourpak Z11
  24. Kobayashi M12
  25. Rezaei N13
  26. Unal E14
  27. Hauck F1
  28. Drukker M2
  29. Walzog B7
  30. Rappsilber J6
  31. Zimmer R3
  32. Lieschke GJ8
  33. Klein C1
Show Affiliations
Authors Affiliations
  1. 1. Department of Pediatrics, Dr. von Hauner Children's Hospital, University Hospital, Ludwig-Maximilians-Universitat (LMU), Munich, Germany
  2. 2. Institute of Stem Cell Research and the Induced Pluripotent Stem Cell Core Facility, Helmholtz Center Munich, Neuherberg, Germany
  3. 3. Department of Informatics, Institute of Bioinformatics, LMU, Munich, Germany
  4. 4. Institute of Bioinformatics and Systems Biology, Helmholtz Center Munich, Neuherberg, Germany
  5. 5. Laboratory of Genomic and Precision Medicine, Wuxi School of Medicine, Jiangnan University, Jiangsu, Wuxi, China
  6. 6. Bioanalytics, Institute of Biotechnology, Technical University of Berlin, Berlin, Germany
  7. 7. Department of Cardiovascular Physiology and Pathophysiology, Biomedical Center, Planegg-Martinsried, and Walter Brendel Centre of Experimental Medicine, University Hospital, LMU, Munich, Germany
  8. 8. Australian Regenerative Medicine Institute, Monash University, Clayton, VIC, Australia
  9. 9. Department of Pathology, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
  10. 10. Department of Clinical Application, Center for iPS cell Research and Application, Kyoto University, Kyoto, Japan
  11. 11. Immunology, Asthma and Allergy Research Institute, Tehran University of Medical Sciences, Teheran, Iran
  12. 12. Department of Pediatrics, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan
  13. 13. Research Center for Immunodeficiencies, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
  14. 14. Division of Pediatric Hematology & Oncology, Department of Pediatrics, Erciyes University, Kayseri, Turkey

Source: Blood Published:2023


Abstract

The mechanisms of coordinated changes in proteome composition and their relevance for the differentiation of neutrophil granulocytes are not well studied. Here, we discover 2 novel human genetic defects in signal recognition particle receptor alpha (SRPRA) and SRP19, constituents of the mammalian cotranslational targeting machinery, and characterize their roles in neutrophil granulocyte differentiation. We systematically study the proteome of neutrophil granulocytes from patients with variants in the SRP genes, HAX1, and ELANE, and identify global as well as specific proteome aberrations. Using in vitro differentiation of human induced pluripotent stem cells and in vivo zebrafish models, we study the effects of SRP deficiency on neutrophil granulocyte development. In a heterologous cell–based inducible protein expression system, we validate the effects conferred by SRP dysfunction for selected proteins that we identified in our proteome screen. Thus, SRP-dependent protein processing, intracellular trafficking, and homeostasis are critically important for the differentiation of neutrophil granulocytes. © 2023 The American Society of Hematology