PUBLICATION
Mutations in the iron-sulfur cluster biogenesis protein HSCB cause congenital sideroblastic anemia
- Authors
- Crispin, A., Guo, C., Chen, C., Campagna, D.R., Schmidt, P.J., Lichtenstein, D.A., Cao, C., Sendamarai, A.K., Hildick-Smith, G.J., Huston, N.C., Boudreaux, J., Bottomley, S.S., Heeney, M.M., Paw, B.H., Fleming, M.D., Ducamp, S.
- ID
- ZDB-PUB-200708-28
- Date
- 2020
- Source
- The Journal of Clinical Investigation 130(10): 5245-5256 (Journal)
- Registered Authors
- Chen, Caiyong, Paw, Barry
- Keywords
- Bone marrow, Genetic diseases, Genetics, Hematology, Mitochondria
- MeSH Terms
-
- Adolescent
- Anemia, Sideroblastic/congenital
- Anemia, Sideroblastic/genetics*
- Anemia, Sideroblastic/metabolism
- Animals
- Child
- DNA Mutational Analysis
- Female
- Frameshift Mutation
- Gene Knockdown Techniques
- Humans
- Iron-Sulfur Proteins/deficiency
- Iron-Sulfur Proteins/genetics
- K562 Cells
- Male
- Mice
- Mice, Knockout
- Molecular Chaperones/genetics*
- Molecular Chaperones/metabolism
- Mutation*
- Pedigree
- Polymorphism, Single Nucleotide
- Promoter Regions, Genetic
- Young Adult
- Zebrafish
- PubMed
- 32634119 Full text @ Journal of Clin. Invest.
Citation
Crispin, A., Guo, C., Chen, C., Campagna, D.R., Schmidt, P.J., Lichtenstein, D.A., Cao, C., Sendamarai, A.K., Hildick-Smith, G.J., Huston, N.C., Boudreaux, J., Bottomley, S.S., Heeney, M.M., Paw, B.H., Fleming, M.D., Ducamp, S. (2020) Mutations in the iron-sulfur cluster biogenesis protein HSCB cause congenital sideroblastic anemia. The Journal of Clinical Investigation. 130(10):5245-5256.
Abstract
The congenital sideroblastic anemias (CSAs) can be caused by primary defects in mitochondrial iron-sulfur cluster (Fe-S) biogenesis. HSCB (heat shock cognate B), which encodes a mitochondrial co-chaperone, also known as HSC20 (heat shock cognate protein 20), is the partner of mitochondrial heat shock protein A9 (HSPA9). Together with glutaredoxin 5 (GLRX5), HSCB and HSPA9 facilitate the transfer of nascent two-iron, two-sulfur ([2Fe-2S]) clusters to recipient mitochondrial proteins. Mutations in both HSPA9 and GLRX5 have previously been associated with CSA. Therefore, we hypothesized that mutations in HSCB could also cause CSA. We screened patients with genetically undefined CSA and identified a frameshift mutation and a rare promoter variant in HSCB in a female patient with non-syndromic CSA. We found that HSCB expression was decreased in patient-derived fibroblasts and K562 erythroleukemia cells engineered to have the patient-specific promoter variant. Furthermore, gene knockdown and deletion experiments performed in K562 cells, zebrafish, and mice demonstrate that loss of HSCB results in impaired Fe-S cluster biogenesis, a defect in red blood cell hemoglobinization, the development of siderocytes, and more broadly perturbs hematopoiesis in vivo. These results further affirm the involvement of Fe-S biogenesis in erythropoiesis and hematopoiesis and define HSCB as a CSA gene.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping