title: Intralysosomal cystine accumulation in mice lacking cystinosin, the protein defective in cystinosis.
abstract: Cystinosis is an autosomal recessive disorder characterized by an accumulation of intralysosomal cystine. The causative gene, CTNS, encodes cystinosin, a seven-transmembrane-domain protein, which we recently showed to be a lysosomal cystine transporter. The most severe and frequent form of cystinosis, the infantile form, appears around 6 to 12 months, with a proximal tubulopathy (de Toni-Debré-Fanconi syndrome) and ocular damage. End-stage renal failure is reached by 10 years of age. Accumulation of cystine in all tissues eventually leads to multisystemic disease. Treatment with cysteamine, which reduces the concentration of intracellular cystine, delays disease progression but has undesirable side effects. We report the first Ctns knockout mouse model generated using a promoter trap approach. We replaced the last four Ctns exons by an internal ribosome entry site-betagal-neo cassette and showed that the truncated protein was mislocalized and nonfunctional. Ctns(-/-) mice accumulated cystine in all organs tested, and cystine crystals, pathognomonic of cystinosis, were observed. Ctns(-/-) mice developed ocular changes similar to those observed in affected individuals, bone defects and behavioral anomalies. Interestingly, Ctns(-/-) mice did not develop signs of a proximal tubulopathy, or renal failure. A preliminary therapeutic trial using an oral administration of cysteamine was carried out and demonstrated the efficiency of this treatment for cystine clearance in Ctns(-/-) mice. This animal model will prove an invaluable and unique tool for testing emerging therapeutics for cystinosis.
authors.affiliation: INSERM U423, Hôpital Necker-Enfants Malades, Paris, France.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Cherqui
authors.forename: Caroline
authors.initials: C
authors.lastname: Sevin
authors.forename: Ghislaine
authors.initials: G
authors.lastname: Hamard
authors.forename: Vasiliki
authors.initials: V
authors.lastname: Kalatzis
authors.forename: Mireille
authors.initials: M
authors.lastname: Sich
authors.forename: Marie O
authors.initials: MO
authors.lastname: Pequignot
authors.forename: Karïn
authors.initials: K
authors.lastname: Gogat
authors.forename: Marc
authors.initials: M
authors.lastname: Abitbol
authors.forename: Michel
authors.initials: M
authors.lastname: Broyer
authors.forename: Marie-Claire
authors.initials: MC
authors.lastname: Gubler
authors.forename: Corinne
authors.initials: C
authors.lastname: Antignac
mesh_terms: D000483:Alleles; D026921:Amino Acid Transport Systems, Neutral; D000818:Animals; D001842:Bone and Bones / Q000000981:diagnostic imaging / Q000473:pathology; D003553:Cystine / Q000378:metabolism*; D003554:Cystinosis / Q000000981:diagnostic imaging / Q000235:genetics* / Q000378:metabolism; D003596:Cytosine / Q000378:metabolism; D004285:Dogs; D004596:Electroretinography; D006023:Glycoproteins; D008247:Lysosomes / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics* / Q000502:physiology*; D026901:Membrane Transport Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008957:Models, Genetic; D011401:Promoter Regions, Genetic; D011859:Radiography; D011994:Recombinant Proteins / Q000378:metabolism; D012160:Retina / Q000002:abnormalities / Q000473:pathology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D014018:Tissue Distribution
chemical_list: D026921:Amino Acid Transport Systems, Neutral; C111445:CTNS protein, human; D006023:Glycoproteins; D008565:Membrane Proteins; D026901:Membrane Transport Proteins; D011994:Recombinant Proteins; D003553:Cystine; D003596:Cytosine