Human genetic defects in SRP19 and SRPRA cause severe congenital neutropenia with distinctive proteome changes

• Published in: Blood Vol. 141; no. 6; pp. 645 - 658
• Main Authors: Linder, Monika I., Mizoguchi, Yoko, Hesse, Sebastian, Csaba, Gergely, Tatematsu, Megumi, Łyszkiewicz, Marcin, Ziȩtara, Natalia, Jeske, Tim, Hastreiter, Maximilian, Rohlfs, Meino, Liu, Yanshan, Grabowski, Piotr, Ahomaa, Kaarin, Maier-Begandt, Daniela, Schwestka, Marko, Pazhakh, Vahid, Isiaku, Abdulsalam I., Briones Miranda, Brenda, Blombery, Piers, Saito, Megumu K., Rusha, Ejona, Alizadeh, Zahra, Pourpak, Zahra, Kobayashi, Masao, Rezaei, Nima, Unal, Ekrem, Hauck, Fabian, Drukker, Micha, Walzog, Barbara, Rappsilber, Juri, Zimmer, Ralf, Lieschke, Graham J., Klein, Christoph
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 09-02-2023
• Subjects: Adaptor Proteins, Signal Transducing; Animals; Human Genetics; Humans; Induced Pluripotent Stem Cells; Mammals; Proteome; Zebrafish
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood.2022016783

•SRPRA and SRP19 are novel genes affected in congenital neutropenia and essential for granule protein processing.•Comparative proteomics in neutrophils of patients with defects in SRPRA, SRP19, SRP54, HAX1, and ELANE reveal genotype-specific alterations.
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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.