PUBLICATION
Reduced EIF6 dosage attenuates TP53 activation in models of Shwachman-Diamond syndrome
- Authors
- Oyarbide, U., Bezzerri, V., Staton, M., Boni, C., Shah, A., Cipolli, M., Calo, E., Corey, S.J.
- ID
- ZDB-PUB-250219-1
- Date
- 2025
- Source
- The Journal of Clinical Investigation : (Journal)
- Registered Authors
- Corey, Seth, Oyarbide, Usua
- Keywords
- Bone marrow, Genetics, Hematology, Leukemias, Neutrophils, Oncology
- Datasets
- GEO:GSE282310
- MeSH Terms
-
- Ribosomal Proteins/genetics
- Ribosomal Proteins/metabolism
- Peptide Initiation Factors*/genetics
- Peptide Initiation Factors*/metabolism
- Zebrafish Proteins*/genetics
- Zebrafish Proteins*/metabolism
- Disease Models, Animal
- Humans
- Proteins
- Gene Dosage*
- Animals
- Anemia, Macrocytic*/genetics
- Anemia, Macrocytic*/metabolism
- Anemia, Macrocytic*/pathology
- Bone Marrow Diseases*/genetics
- Bone Marrow Diseases*/metabolism
- Bone Marrow Diseases*/pathology
- Eukaryotic Initiation Factors
- Tumor Suppressor Protein p53*/genetics
- Tumor Suppressor Protein p53*/metabolism
- Lipomatosis*/genetics
- Lipomatosis*/metabolism
- Lipomatosis*/pathology
- Exocrine Pancreatic Insufficiency*/genetics
- Exocrine Pancreatic Insufficiency*/metabolism
- Exocrine Pancreatic Insufficiency*/pathology
- Haploinsufficiency
- Zebrafish/genetics
- Zebrafish/metabolism
- Gene Knockout Techniques
- Shwachman-Diamond Syndrome
- PubMed
- 39964763 Full text @ Journal of Clin. Invest.
Citation
Oyarbide, U., Bezzerri, V., Staton, M., Boni, C., Shah, A., Cipolli, M., Calo, E., Corey, S.J. (2025) Reduced EIF6 dosage attenuates TP53 activation in models of Shwachman-Diamond syndrome. The Journal of Clinical Investigation. :.
Abstract
Shwachman-Diamond syndrome (SDS) is characterized by neutropenia, exocrine pancreatic insufficiency, and bony abnormalities with an increased risk of myeloid neoplasia. Almost all cases of SDS result from biallelic mutations in SBDS. SBDS interacts with EFL1 to displace EIF6 from the 60S ribosomal subunit. Released EIF6 permits the assembly of ribosomal large and small subunits in the cytoplasm. Decreased EIF6 levels due to haploinsufficiency or missense mutations which lead to decreased protein expression may provide a somatic genetic rescue and anti-leukemic effects. We observed accumulation of EIF6 protein in sbds knockout (KO) zebrafish models, confirmed in patient-derived tissues, and correlated with changes in ribosome proteins and TP53 pathways. The mechanism of action for this adaptive response is unknown. To address this, we generated an eif6 zebrafish KO line which do not survive past 10 days post fertilization. We also created two mutants with low Eif6 expression, 5-25% of the wildtype levels, that can survive until adulthood. We bred them with sbds-null strains and analyzed their phenotype and biochemical properties. Low Eif6 levels reduced Tp53 pathway activation but did not rescue neutropenia in Sbds-deficient zebrafish. Further studies elucidating the interplay between SBDS, EIF6, TP53, and cellular stress responses offer promising insights into SDS pathogenesis, somatic genetic rescue, and therapeutic strategies.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping