NDT Advance Access published online on October 21, 2009
Nephrology Dialysis Transplantation, doi:10.1093/ndt/gfp553
Renal phenotype of the cystinosis mouse model is dependent upon genetic background
1 Inserm, U574, Hôpital Necker-Enfants Malades, Paris, France 2 Université Paris Descartes, Faculté de Médecine René Descartes, Paris, France 3 Institut de Génétique Moléculaire de Montpellier, CNRS, Montpellier, France 4 Universités Montpellier I et II, Montpellier, France 5 Division of Nephrology, Université Catholique de Louvain, Brussels, Belgium 6 Assistance Publique-Hôpitaux de Paris, Service de Génétique, Hôpital Necker-Enfants Malades, Paris, France
Correspondence and offprint requests to: Correspondence and offprint requests to: Corinne Antignac; E-mail: corinne.antignac{at}inserm.fr
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Abstract |
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Background. Cystinosis is caused by mutations in CTNS that encodes cystinosin, the lysosomal cystine transporter. The most severe and frequent form is characterized by a proximal tubulopathy that appears around 6 to 12 months of age. In the absence of treatment, end-stage renal disease is reached by 10 years. Ctns–/– mice of a mixed 129Sv x C57BL/6 genetic background show elevated renal cystine levels; however, proximal tubulopathy or end-stage renal disease is not observed.
Methods. As renal phenotype can be influenced by genetic background, we generated congenic C57BL/6 and FVB/N Ctns–/– mice and assayed renal lesions and function by histological and biochemical studies.
Results. C57BL/6 Ctns–/– mice showed significantly higher renal cystine levels than the FVB/N strain. Moreover, C57BL/6 mice presented with pronounced histological lesions of the proximal tubules as well as a tubulopathy and progressively developed chronic renal failure. In contrast, renal dysfunction was not observed in the FVB/N strain.
Conclusions. Thus, the C57BL/6 strain represents the first Ctns–/– mouse model to show clear renal defects. In addition to highlighting the influence of genetic background on phenotype, the C57BL/6 Ctns–/– mice represent a useful model for further understanding cystinosin function in the kidney and, specifically, in the proximal tubules.
Keywords: chronic renal failure; cystinosis; genetic background; mouse model; proximal tubule dysfunction
Nathalie Nevo and Marie Chol contributed equally to this work
Received for publication: 20. 7.09
Revision received 6. 8.09.
Accepted in revised form: 22. 9.09