PUBLICATION
Loss of hspa9b in zebrafish recapitulates the ineffective hematopoiesis of the myelodysplastic syndromes
- Authors
- Craven, S.E., French, D., Ye, W., de Sauvage, F., and Rosenthal, A.
- ID
- ZDB-PUB-050120-2
- Date
- 2005
- Source
- Blood 105(9): 3528-3534 (Journal)
- Registered Authors
- Keywords
- none
- MeSH Terms
-
- Animals
- Apoptosis/genetics
- Blood Cells/pathology
- Embryo, Nonmammalian
- HSP70 Heat-Shock Proteins/genetics
- HSP70 Heat-Shock Proteins/physiology*
- Heat-Shock Proteins/genetics
- Heat-Shock Proteins/physiology*
- Hematopoiesis/genetics*
- Humans
- Mitochondria/pathology
- Mitochondrial Proteins/genetics
- Mitochondrial Proteins/physiology
- Models, Animal
- Mutation, Missense
- Myelodysplastic Syndromes/blood*
- Myelodysplastic Syndromes/etiology
- Myelodysplastic Syndromes/pathology
- Oxidative Stress/genetics
- Zebrafish
- Zebrafish Proteins/genetics
- Zebrafish Proteins/physiology*
- PubMed
- 15650063 Full text @ Blood
Citation
Craven, S.E., French, D., Ye, W., de Sauvage, F., and Rosenthal, A. (2005) Loss of hspa9b in zebrafish recapitulates the ineffective hematopoiesis of the myelodysplastic syndromes. Blood. 105(9):3528-3534.
Abstract
The myelodysplastic syndromes (MDS) are a heterogeneous group of often fatal hematopoietic stem cell disorders for which neither curative nor standard treatment exists. The complex karyotypes and multi-step nature of MDS have severely restricted the identification of causative genetic mutations and thus limited insight into new and more effective therapies. Here we describe a zebrafish mutant crimsonless (crs) with a developmental blood defect that closely recapitulates the ineffective hematopoiesis of MDS including anemia, dysplasia, increased blood cell apoptosis, and multi-lineage cytopenia. By positional cloning, rescue, and morpholino knockdown experiments, we demonstrate that crs encodes a conserved mitochondrial matrix chaperone HSPA9B containing a glycine-to-glutamate substitution within the substrate binding domain. This mutation compromises mitochondrial function, producing oxidative stress and apoptosis distinctly in blood cells. Thus we identify an essential role for hspa9b in hematopoiesis and implicate both loss of HSPA9B specifically and mitochondrial dysfunction generally in the pathogenesis of MDS.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping