Cystinosis (ctns) zebrafish mutant shows pronephric glomerular and tubular dysfunction

• DOI: 10.1038/srep42583
• Publication Date: 2017-02-15T10:20:51Z
• Authors: Mohamed A. Elmonem; Ramzi Khalil; Ladan Khodaparast; Laleh Khodaparast; Fanny O. Arcolino; Joseph Morgan; Anna Pastore; Przemko Tylzanowski; Annelii Ny; Martin Lowe; Peter A. de Witte; Hans J. Baelde; Lambertus P. van ...; Elena Levtchenko
• Keywords: 0301 basic medicine; Podocytes; Cystinosis; Kidney Glomerulus; Apoptosis; Radboudumc 11: Renal disorders RIMLS: Radboud Institute for Molecular Life Sciences; Article; 3. Good health; Kidney Tubules, Proximal; Disease Models, Animal; Gene Knockout Techniques; 03 medical and health sciences; Amino Acid Transport Systems, Neutral; Phenotype; Mutation; Journal Article; Animals; Cystine; Humans; Amino Acid Sequence; Lysosomes; Locomotion; Zebrafish; Glomerular Filtration Rate

AbstractThe 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.