title: Cystinosis (ctns) zebrafish mutant shows pronephric glomerular and tubular dysfunction.
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.
authors.affiliation: Department of Paediatric Nephrology &Growth and Regeneration, University Hospitals Leuven KU Leuven - University of Leuven, Leuven, Belgium.|Department of Clinical and Chemical Pathology, Faculty of Medicine, Cairo University, Cairo, Egypt.
authors.forename: Mohamed A
authors.initials: MA
authors.lastname: Elmonem
authors.affiliation: Department of Pathology, Leiden University Medical Centre, The Netherlands.
authors.forename: Ramzi
authors.initials: R
authors.lastname: Khalil
authors.affiliation: Department of Cellular and Molecular Medicine, Switch Laboratory, VIB, University Hospitals Leuven KU Leuven - University of Leuven, Leuven, Belgium.
authors.forename: Ladan
authors.initials: L
authors.lastname: Khodaparast
authors.affiliation: Department of Cellular and Molecular Medicine, Switch Laboratory, VIB, University Hospitals Leuven KU Leuven - University of Leuven, Leuven, Belgium.
authors.forename: Laleh
authors.initials: L
authors.lastname: Khodaparast
authors.affiliation: Department of Paediatric Nephrology &Growth and Regeneration, University Hospitals Leuven KU Leuven - University of Leuven, Leuven, Belgium.
authors.forename: Fanny O
authors.initials: FO
authors.lastname: Arcolino
authors.affiliation: Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom.
authors.forename: Joseph
authors.initials: J
authors.lastname: Morgan
authors.affiliation: Laboratory of Proteomics and Metabolomics, Children's Hospital and Research Institute "Bambino Gesù" IRCCS, Rome, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Pastore
authors.affiliation: Department of Development and Regeneration, Laboratory for Developmental and Stem Cell Biology, Skeletal Biology and Engineering Research Centre, KU Leuven - University of Leuven, Leuven, Belgium.|Department of Biochemistry and Molecular Biology, Medical University, Lublin, Poland.
authors.forename: Przemko
authors.initials: P
authors.lastname: Tylzanowski
authors.affiliation: Laboratory for Molecular Bio-discovery, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven - University of Leuven, Leuven, Belgium.
authors.forename: Annelii
authors.initials: A
authors.lastname: Ny
authors.affiliation: Faculty of Biology, Medicine and Health, University of Manchester, Manchester, United Kingdom.
authors.forename: Martin
authors.initials: M
authors.lastname: Lowe
authors.affiliation: Laboratory for Molecular Bio-discovery, Department of Pharmaceutical and Pharmacological Sciences, KU Leuven - University of Leuven, Leuven, Belgium.
authors.forename: Peter A
authors.initials: PA
authors.lastname: de Witte
authors.affiliation: Department of Pathology, Leiden University Medical Centre, The Netherlands.
authors.forename: Hans J
authors.initials: HJ
authors.lastname: Baelde
authors.affiliation: Department of Paediatric Nephrology &Growth and Regeneration, University Hospitals Leuven KU Leuven - University of Leuven, Leuven, Belgium.|Department of Paediatric Nephrology, Radboud University Medical Centre, Nijmegen, The Netherlands.
authors.forename: Lambertus P
authors.initials: LP
authors.lastname: van den Heuvel
authors.affiliation: Department of Paediatric Nephrology &Growth and Regeneration, University Hospitals Leuven KU Leuven - University of Leuven, Leuven, Belgium.
authors.forename: Elena
authors.initials: E
authors.lastname: Levtchenko
mesh_terms: D000595:Amino Acid Sequence; D026921:Amino Acid Transport Systems, Neutral / Q000235:genetics* / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D003553:Cystine / Q000378:metabolism; D003554:Cystinosis / Q000235:genetics* / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D004195:Disease Models, Animal; D055786:Gene Knockout Techniques; D005919:Glomerular Filtration Rate; D006801:Humans; D007678:Kidney Glomerulus / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D007687:Kidney Tubules, Proximal / Q000378:metabolism* / Q000473:pathology / Q000648:ultrastructure; D008124:Locomotion; D008247:Lysosomes / Q000378:metabolism; D009154:Mutation; D010641:Phenotype; D050199:Podocytes / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D015027:Zebrafish
chemical_list: D026921:Amino Acid Transport Systems, Neutral; C111445:CTNS protein, human; D003553:Cystine