PUBLICATION
Cystinosis (ctns) zebrafish mutant shows pronephric glomerular and tubular dysfunction
- Authors
- Elmonem, M.A., Khalil, R., Khodaparast, L., Khodaparast, L., Arcolino, F.O., Morgan, J., Pastore, A., Tylzanowski, P., Ny, A., Lowe, M., de Witte, P.A., Baelde, H.J., van den Heuvel, L.P., Levtchenko, E.
- ID
- ZDB-PUB-170216-2
- Date
- 2017
- Source
- Scientific Reports 7: 42583 (Journal)
- Registered Authors
- Lowe, Martin
- Keywords
- none
- MeSH Terms
-
- Amino Acid Sequence
- Kidney Tubules, Proximal/metabolism*
- Kidney Tubules, Proximal/pathology
- Kidney Tubules, Proximal/ultrastructure
- Cystinosis/genetics*
- Cystinosis/metabolism*
- Cystinosis/mortality
- Cystinosis/pathology
- Gene Knockout Techniques
- Animals
- Glomerular Filtration Rate
- Mutation*
- Humans
- Cystine/metabolism
- Kidney Glomerulus/metabolism*
- Kidney Glomerulus/pathology
- Kidney Glomerulus/ultrastructure
- Apoptosis/genetics
- Zebrafish
- Phenotype
- Disease Models, Animal
- Amino Acid Transport Systems, Neutral/genetics*
- Amino Acid Transport Systems, Neutral/metabolism*
- Locomotion
- Podocytes/metabolism
- Podocytes/pathology
- Podocytes/ultrastructure
- Lysosomes/metabolism
- PubMed
- 28198397 Full text @ Sci. Rep.
Citation
Elmonem, M.A., Khalil, R., Khodaparast, L., Khodaparast, L., Arcolino, F.O., Morgan, J., Pastore, A., Tylzanowski, P., Ny, A., Lowe, M., de Witte, P.A., Baelde, H.J., van den Heuvel, L.P., Levtchenko, E. (2017) Cystinosis (ctns) zebrafish mutant shows pronephric glomerular and tubular dysfunction. Scientific Reports. 7:42583.
Abstract
The human ubiquitous protein cystinosin is responsible for transporting the disulphide amino acid cystine from the lysosomal compartment into the cytosol. In humans, Pathogenic mutations of CTNS lead to defective cystinosin function, intralysosomal cystine accumulation and the development of cystinosis. Kidneys are initially affected with generalized proximal tubular dysfunction (renal Fanconi syndrome), then the disease rapidly affects glomeruli and progresses towards end stage renal failure and multiple organ dysfunction. Animal models of cystinosis are limited, with only a Ctns knockout mouse reported, showing cystine accumulation and late signs of tubular dysfunction but lacking the glomerular phenotype. We established and characterized a mutant zebrafish model with a homozygous nonsense mutation (c.706 C > T; p.Q236X) in exon 8 of ctns. Cystinotic mutant larvae showed cystine accumulation, delayed development, and signs of pronephric glomerular and tubular dysfunction mimicking the early phenotype of human cystinotic patients. Furthermore, cystinotic larvae showed a significantly increased rate of apoptosis that could be ameliorated with cysteamine, the human cystine depleting therapy. Our data demonstrate that, ctns gene is essential for zebrafish pronephric podocyte and proximal tubular function and that the ctns-mutant can be used for studying the disease pathogenic mechanisms and for testing novel therapies for cystinosis.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping