RGD Reference Report - Cystinosin-deficient rats recapitulate the phenotype of nephropathic cystinosis. - Rat Genome Database

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Cystinosin-deficient rats recapitulate the phenotype of nephropathic cystinosis.

Authors: Hollywood, Jennifer A  Kallingappa, Prasanna K  Cheung, Pang Yuk  Martis, Renita M  Sreebhavan, Sree  'Atiola, Robert D  Chatterjee, Aparajita  Buckels, Emma J  Matthews, Brya G  Lewis, Paula M  Davidson, Alan J 
Citation: Hollywood JA, etal., Am J Physiol Renal Physiol. 2022 Aug 1;323(2):F156-F170. doi: 10.1152/ajprenal.00277.2021. Epub 2022 Jun 13.
RGD ID: 155630629
Pubmed: PMID:35695380   (View Abstract at PubMed)
DOI: DOI:10.1152/ajprenal.00277.2021   (Journal Full-text)

The lysosomal storage disease cystinosis is caused by mutations in CTNS, encoding the cystine transporter cystinosin, and in its severest form leads to proximal tubule dysfunction followed by kidney failure. Patients receive the drug-based therapy cysteamine from diagnosis. However, despite long-term treatment, cysteamine only slows the progression of end-stage renal disease. Preclinical testing in cystinotic rodents is required to evaluate new therapies; however, the current models are suboptimal. To solve this problem, we generated a new cystinotic rat model using CRISPR/Cas9-mediated gene editing to disrupt exon 3 of Ctns and measured various parameters over a 12-mo time course. Ctns-/- rats display hallmarks of cystinosis by 3-6 mo of age, as demonstrated by a failure to thrive, excessive thirst and urination, cystine accumulation in tissues, corneal cystine crystals, loss of LDL receptor-related protein 2 in proximal tubules, and immune cell infiltration. High levels of glucose, calcium, albumin, and protein were excreted at 6 mo of age, consistent with the onset of Fanconi syndrome, with a progressive diminution of urine urea and creatinine from 9 mo of age, indicative of chronic kidney disease. Kidney histology and immunohistochemistry showed proximal tubule atrophy and glomerular damage as well as classic "swan neck" lesions. Overall, Ctns-/- rats show a disease progression that more faithfully recapitulates nephropathic cystinosis than existing rodent models. The Ctns-/- rat provides an excellent new rodent model of nephropathic cystinosis that is ideally suited for conducting preclinical drug testing and is a powerful tool to advance cystinosis research.NEW & NOTEWORTHY Animal models of disease are essential to perform preclinical testing of new therapies before they can progress to clinical trials. The cystinosis field has been hampered by a lack of suitable animal models that fully recapitulate the disease. Here, we generated a rat model of cystinosis that closely models the human condition in a timeframe that makes them an excellent model for preclinical drug testing as well as being a powerful tool to advance research.

RGD Manual Disease Annotations    Click to see Annotation Detail View

Object SymbolSpeciesTermQualifierEvidenceWithNotesSourceOriginal Reference(s)
CTNSHumancystinosis  ISOCtns (Rattus norvegicus) RGD 
CtnsRatcystinosis  IMP  RGD 
CtnsMousecystinosis  ISOCtns (Rattus norvegicus) RGD 
CTNSHumanFanconi syndrome  ISOCtns (Rattus norvegicus) RGD 
CtnsRatFanconi syndrome  IMP  RGD 
CtnsMouseFanconi syndrome  ISOCtns (Rattus norvegicus) RGD 

Gene Ontology Annotations    Click to see Annotation Detail View

Biological Process


Objects Annotated

Genes (Rattus norvegicus)
Ctns  (cystinosin, lysosomal cystine transporter)

Genes (Mus musculus)
Ctns  (cystinosis, nephropathic)

Genes (Homo sapiens)
CTNS  (cystinosin, lysosomal cystine transporter)

Objects referenced in this article
Strain CD-Ctnsem2Vjupk null Rattus norvegicus
Strain CD-Ctnsem3Vjupk null Rattus norvegicus
Strain CD-Ctnsem4Vjupk null Rattus norvegicus
Gene Ctnsem2Vjupk cystinosin, lysosomal cystine transporter; CRISPR/Cas9 induced mutant 2, Vjupk Rattus norvegicus
Gene Ctnsem3Vjupk cystinosin, lysosomal cystine transporter; CRISPR/Cas9 induced mutant 3, Vjupk Rattus norvegicus
Gene Ctnsem4Vjupk cystinosin, lysosomal cystine transporter; CRISPR/Cas9 induced mutant 4, Vjupk Rattus norvegicus

Additional Information