Unknown

Dataset Information

0

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

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.

SUBMITTER: Linder MI 

PROVIDER: S-EPMC10651786 | biostudies-literature | 2023 Feb

REPOSITORIES: biostudies-literature

Json Xml
altmetric image

Publications

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

Linder Monika I MI   Mizoguchi Yoko Y   Hesse Sebastian S   Csaba Gergely G   Tatematsu Megumi M   Łyszkiewicz Marcin M   Ziȩtara Natalia N   Jeske Tim T   Hastreiter Maximilian M   Rohlfs Meino M   Liu Yanshan Y   Grabowski Piotr P   Ahomaa Kaarin K   Maier-Begandt Daniela D   Schwestka Marko M   Pazhakh Vahid V   Isiaku Abdulsalam I AI   Briones Miranda Brenda B   Blombery Piers P   Saito Megumu K MK   Rusha Ejona E   Alizadeh Zahra Z   Pourpak Zahra Z   Kobayashi Masao M   Rezaei Nima N   Unal Ekrem E   Hauck Fabian F   Drukker Micha M   Walzog Barbara B   Rappsilber Juri J   Zimmer Ralf R   Lieschke Graham J GJ   Klein Christoph C  

Blood 20230201 6

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 i  ...[more]

Similar Datasets

Transcriptomics Defective SEC61α1 underlies a novel cause of autosomal dominant severe congenital neutropenia
2020-04-09 | GSE137496 | GEO
Unknown Heterozygous variants of CLPB are a cause of severe congenital neutropenia.
| S-EPMC8814677 | biostudies-literature
Unknown Defective Sec61α1 underlies a novel cause of autosomal dominant severe congenital neutropenia.
| S-EPMC7649975 | biostudies-literature
Unknown Neutrophil Elastase Defects in Congenital Neutropenia.
| S-EPMC8100030 | biostudies-literature
Unknown Severe congenital neutropenia: genetics and pathogenesis.
| S-EPMC1500938 | biostudies-literature
Unknown Inherited biallelic CSF3R mutations in severe congenital neutropenia.
| S-EPMC4055927 | biostudies-literature
Unknown Mutations in the <i>SRP54</i> gene cause severe congenital neutropenia as well as Shwachman-Diamond-like syndrome.
| S-EPMC6536700 | biostudies-literature
Unknown The prevalence of genetic diagnoses in fetuses with severe congenital heart defects.
| S-EPMC7332415 | biostudies-literature
Unknown Mutations in Hnrnpa1 cause congenital heart defects.
| S-EPMC5821217 | biostudies-literature
Genomics Defective SEC61α1 underlies a novel cause of autosomal dominant severe congenital neutropenia
| PRJNA565728 | ENA