PUBLICATION
Loss of sdhb in zebrafish larvae recapitulates human paraganglioma characteristics
- Authors
- Dona, M., Waaijers, S., Richter, S., Eisenhofer, G., Korving, J., Kamel, S.M., Bakkers, J., Rapizzi, E., Rodenburg, R.J., Zethof, J., Gorissen, M., Flik, G., Deen, P.M.T., Timmers, H.J.
- ID
- ZDB-PUB-201120-54
- Date
- 2020
- Source
- Endocrine-related cancer 28(1): 65-77 (Journal)
- Registered Authors
- Bakkers, Jeroen, Dona, Margo, Flik, Gert, Gorissen, Marnix, Timmers, Henri
- Keywords
- none
- MeSH Terms
-
- Animals
- Humans
- Larva/metabolism*
- Paraganglioma/genetics*
- Succinate Dehydrogenase/metabolism*
- Zebrafish
- PubMed
- 33156815 Full text @ Endocr. Relat. Cancer
Citation
Dona, M., Waaijers, S., Richter, S., Eisenhofer, G., Korving, J., Kamel, S.M., Bakkers, J., Rapizzi, E., Rodenburg, R.J., Zethof, J., Gorissen, M., Flik, G., Deen, P.M.T., Timmers, H.J. (2020) Loss of sdhb in zebrafish larvae recapitulates human paraganglioma characteristics. Endocrine-related cancer. 28(1):65-77.
Abstract
Pheochromocytomas and paragangliomas (PPGLs) caused by mutations in the B-subunit of the succinate dehydrogenase (SDHB) have the highest metastatic rate among PPGLs, and effective systemic therapy is lacking. To unravel underlying pathogenic mechanisms, and to evaluate therapeutic strategies, suitable in vivo models are needed. The available systemic Sdhb knock-out mice cannot model the human PPGL phenotype: heterozygous Sdhb mice lack a disease phenotype, and homozygous Sdhb mice are embryonically lethal. Using CRISPR/cas9 technology, we introduced a protein-truncating germline lesion into the zebrafish sdhb gene. Heterozygous sdhb mutants were viable and displayed no obvious morphological or developmental defects. Homozygous sdhb larvae were viable, but exhibited a decreased lifespan. Morphological analysis revealed incompletely or non-inflated swim bladders in homozygous sdhb mutants at day 6. Although no differences in number and ultrastructure of the mitochondria were observed. Clear defects in energy metabolism and swimming behaviour were observed in homozygous sdhb mutantlarvae. Functional and metabolomic analyses revealed decreased mitochondrial complex 2 activity and significant succinate accumulation in the homozygous sdhb mutant larvae, mimicking the metabolic effects observed in SDHB-associated PPGLs. This is the first study to present a vertebrate animal model that mimics metabolic effects of SDHB-associated PPGLs. This model will be useful in unraveling pathomechanisms behind SDHB-associated PPGLs. We can now study the metabolic effects of sdhb disruption during different developmental stages and develop screening assays to identify novel therapeutic targets in vivo. Besides oncological syndromes, our model might also be useful for paediatric mitochondrial disease caused by loss of the SDHB gene.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping