Renal phenotype of the cystinosis mouse model is dependent upon genetic background.
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.
Nevo
Nathalie
N
Inserm, U574, Hôpital Necker-Enfants Malades, Paris, France.
Chol
Marie
M
Bailleux
Anne
A
Kalatzis
Vasiliki
V
Morisset
Ludivine
L
Devuyst
Olivier
O
Gubler
Marie-Claire
MC
Antignac
Corinne
C
D026921:Amino Acid Transport Systems, Neutral / Q000502:physiology*; D000818:Animals; D003553:Cystine / Q000378:metabolism*; D003554:Cystinosis / Q000209:etiology* / Q000473:pathology; D004195:Disease Models, Animal; D005260:Female; D007676:Kidney Failure, Chronic / Q000209:etiology* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics; D010641:Phenotype; D013045:Species Specificity
D026921:Amino Acid Transport Systems, Neutral; C534463:cystinosin protein, mouse; D003553:Cystine