Human Genetic Defects in SRP19 and SRPRA Cause Severe Congenital Neutropenia with Distinctive Proteome Changes

Overview

Journal Blood

Publisher Elsevier

Specialty Hematology

Date 2022 Oct 12

PMID 36223592

Authors

Monika I Linder

Yoko Mizoguchi

Sebastian Hesse

Gergely Csaba

Megumi Tatematsu

Marcin Lyszkiewicz

Natalia Zitara

Tim Jeske

Maximilian Hastreiter

Meino Rohlfs

Yanshan Liu

Piotr Grabowski

Kaarin Ahomaa

Daniela Maier-Begandt

Marko Schwestka

Vahid Pazhakh

Abdulsalam I Isiaku

Brenda Briones Miranda

Piers Blombery

Megumu K Saito

Ejona Rusha

Zahra Alizadeh

Zahra Pourpak

Masao Kobayashi

Nima Rezaei

Ekrem Unal

Fabian Hauck

Micha Drukker

Barbara Walzog

Juri Rappsilber

Ralf Zimmer

Graham J Lieschke

Christoph Klein

Affiliations

Soon will be listed here.

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.

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