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Molecular and Cellular Biology, November 2002, p. 7622-7632, Vol. 22, No. 21
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.21.7622-7632.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Intralysosomal Cystine Accumulation in Mice Lacking Cystinosin, the Protein Defective in Cystinosis

Stéphanie Cherqui,1 Caroline Sevin,1,{dagger} Ghislaine Hamard,2 Vasiliki Kalatzis,1 Mireille Sich,1 Marie O. Pequignot,3 Karïn Gogat,3 Marc Abitbol,3 Michel Broyer,1 Marie-Claire Gubler,1 and Corinne Antignac1,4*

INSERM U423,1 Department of Genetics,4 Université René Descartes, Hôpital Necker-Enfants Malades, Plate-forme de Recombinaison Homologue, Institut Cochin-Port-Royal,2 CERTO, EA 2502, Université René Descartes, Faculté de Médecine Necker, Paris, France3

Received 24 June 2002/ Accepted 19 July 2002

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-ßgal-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.

* Corresponding author. Mailing address: INSERM U423, Hôpital Necker-Enfants Malades, 149, rue de Sèvres, 75015 Paris, France. Phone: (33) 1-44-49-50-98. Fax: (33) 1-44-49-02-90. E-mail: antignac{at}necker.fr.

{dagger} Present address: INSERM U561, Hôpital Saint-Vincent de Paul, 82 avenue Denfert, Rochereau, 75014 Paris, France.

Molecular and Cellular Biology, November 2002, p. 7622-7632, Vol. 22, No. 21
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.21.7622-7632.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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