Author:

Keywords:

Science & Technology, Life Sciences & Biomedicine, Physical Sciences, Biochemistry & Molecular Biology, Chemistry, Multidisciplinary, Chemistry, kidney disease, cystinosis, zebrafish model, renal and extra renal manifestation, adult phenotypic features, CYSTEAMINE THERAPY, DANIO-RERIO, CTNS GENE, PROTEIN, ACCUMULATION, Amino Acid Transport Systems, Neutral, Animals, Cystine, Cystinosis, Disease Models, Animal, Humans, Kidney, Mutation, Phenotype, Zebrafish, Zebrafish Proteins, 12I3820N#55262059, 0399 Other Chemical Sciences, 0604 Genetics, 0699 Other Biological Sciences, Chemical Physics, 3101 Biochemistry and cell biology, 3107 Microbiology, 3404 Medicinal and biomolecular chemistry

Abstract:

Cystinosis is a rare, incurable, autosomal recessive disease caused by mutations in the CTNS gene. This gene encodes the lysosomal cystine transporter cystinosin, leading to lysosomal cystine accumulation in all cells of the body, with kidneys being the first affected organs. The current treatment with cysteamine decreases cystine accumulation, but does not reverse the proximal tubular dysfunction, glomerular injury or loss of renal function. In our previous study, we have developed a zebrafish model of cystinosis through a nonsense mutation in the CTNS gene and have shown that zebrafish larvae recapitulate the kidney phenotype described in humans. In the current study, we characterized the adult cystinosis zebrafish model and evaluated the long-term effects of the disease on kidney and extra renal organs through biochemical, histological, fertility and locomotor activity studies. We found that the adult cystinosis zebrafish presents cystine accumulation in various organs, altered kidney morphology, impaired skin pigmentation, decreased fertility, altered locomotor activity and ocular anomalies. Overall, our data indicate that the adult cystinosis zebrafish model reproduces several human phenotypes of cystinosis and may be useful for studying pathophysiology and long-term effects of novel therapies.