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SRP54 mutations induce congenital neutropenia via dominant-negative effects on XBP1 splicing.
- Source :
-
Blood [Blood] 2021 Mar 11; Vol. 137 (10), pp. 1340-1352. - Publication Year :
- 2021
-
Abstract
- Heterozygous de novo missense variants of SRP54 were recently identified in patients with congenital neutropenia (CN) who display symptoms that overlap with Shwachman-Diamond syndrome (SDS). Here, we investigate srp54 knockout zebrafish as the first in vivo model of SRP54 deficiency. srp54-/- zebrafish experience embryonic lethality and display multisystemic developmental defects along with severe neutropenia. In contrast, srp54+/- zebrafish are viable, fertile, and show only mild neutropenia. Interestingly, injection of human SRP54 messenger RNAs (mRNAs) that carry mutations observed in patients (T115A, T117Δ, and G226E) aggravated neutropenia and induced pancreatic defects in srp54+/- fish, mimicking the corresponding human clinical phenotypes. These data suggest that the various phenotypes observed in patients may be a result of mutation-specific dominant-negative effects on the functionality of the residual wild-type SRP54 protein. Overexpression of mutated SRP54 also consistently induced neutropenia in wild-type fish and impaired the granulocytic maturation of human promyelocytic HL-60 cells and healthy cord blood-derived CD34+ hematopoietic stem and progenitor cells. Mechanistically, srp54-mutant fish and human cells show impaired unconventional splicing of the transcription factor X-box binding protein 1 (Xbp1). Moreover, xbp1 morphants recapitulate phenotypes observed in srp54 deficiency and, importantly, injection of spliced, but not unspliced, xbp1 mRNA rescues neutropenia in srp54+/- zebrafish. Together, these data indicate that SRP54 is critical for the development of various tissues, with neutrophils reacting most sensitively to the loss of SRP54. The heterogenic phenotypes observed in patients that range from mild CN to SDS-like disease may be the result of different dominant-negative effects of mutated SRP54 proteins on downstream XBP1 splicing, which represents a potential therapeutic target.<br /> (© 2021 by The American Society of Hematology.)
- Subjects :
- Animals
Disease Models, Animal
Gene Deletion
Gene Expression Regulation, Developmental
Gene Knockout Techniques
HL-60 Cells
Humans
Models, Molecular
Mutation
Neutropenia genetics
RNA Splicing
RNA, Messenger genetics
Congenital Bone Marrow Failure Syndromes genetics
Neutropenia congenital
Signal Recognition Particle genetics
X-Box Binding Protein 1 genetics
Zebrafish genetics
Zebrafish Proteins genetics
Subjects
Details
- Language :
- English
- ISSN :
- 1528-0020
- Volume :
- 137
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- Blood
- Publication Type :
- Academic Journal
- Accession number :
- 33227812
- Full Text :
- https://doi.org/10.1182/blood.2020008115