PUBLICATION
A Zebrafish Model of 5q-Syndrome Using CRISPR/Cas9 Targeting RPS14 Reveals a p53-Independent and p53-Dependent Mechanism of Erythroid Failure
- Authors
- Ear, J., Hsueh, J., Nguyen, M., Zhang, Q., Sung, V., Chopra, R., Sakamoto, K.M., Lin, S.
- ID
- ZDB-PUB-160525-11
- Date
- 2016
- Source
- Journal of genetics and genomics = Yi chuan xue bao 43(5): 307-18 (Journal)
- Registered Authors
- Lin, Shuo
- Keywords
- 5q-syndrome, Myelodysplastic syndrome, RPS14, Ribosomopathy
- MeSH Terms
-
- Anemia/complications
- Anemia, Macrocytic/blood
- Anemia, Macrocytic/complications
- Anemia, Macrocytic/genetics*
- Animals
- Base Sequence
- CRISPR-Cas Systems/genetics*
- Chromosome Deletion
- Chromosomes, Human, Pair 5/genetics
- Disease Models, Animal
- Erythroid Cells/metabolism*
- Gene Editing*
- Mutation
- Ribosomal Proteins/deficiency
- Ribosomal Proteins/genetics*
- Tumor Suppressor Protein p53/metabolism*
- Zebrafish*
- PubMed
- 27216296 Full text @ J. Genet. Genomics
Citation
Ear, J., Hsueh, J., Nguyen, M., Zhang, Q., Sung, V., Chopra, R., Sakamoto, K.M., Lin, S. (2016) A Zebrafish Model of 5q-Syndrome Using CRISPR/Cas9 Targeting RPS14 Reveals a p53-Independent and p53-Dependent Mechanism of Erythroid Failure. Journal of genetics and genomics = Yi chuan xue bao. 43(5):307-18.
Abstract
5q-syndrome is a distinct form of myelodysplastic syndrome (MDS) where a deletion on chromosome 5 is the underlying cause. MDS is characterized by bone marrow failures, including macrocytic anemia. Genetic mapping and studies using various models support the notion that ribosomal protein S14 (RPS14) is the candidate gene for the erythroid failure. Targeted disruption of RPS14 causes an increase in p53 activity and p53-mediated apoptosis, similar to what is observed with other ribosomal proteins. However, due to the higher risk for cancer development in patients with ribosome deficiency, targeting the p53 pathway is not a viable treatment option. To better understand the pathology of RPS14 deficiency in 5q-deletion, we generated a zebrafish model harboring a mutation in the RPS14 gene. This model mirrors the anemic phenotype seen in 5q-syndrome. Moreover, the anemia is due to a late-stage erythropoietic defect, where the erythropoietic defect is initially p53-independent and then becomes p53-dependent. Finally, we demonstrate the versatility of this model to test various pharmacological agents, such as RAP-011, l-leucine, and dexamethasone in order to identify molecules that can reverse the anemic phenotype.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping