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Multisystem involvement, defective lysosomes, and impaired autophagy in a novel rat model of Nephropathic Cystinosis


Krohn, Patrick; Rega, Laura Rita; Harvent, Marianne; Festa, Beatrice Paola; Taranta, Anna; Luciani, Alessandro; Dewulf, Joseph; Cremonesi, Alessio; Camassei, Francesca Diomedi; Hanson, James V M; Gerth-Kahlert, Christina; Emma, Francesco; Berquez, Marine; Devuyst, Olivier (2022). Multisystem involvement, defective lysosomes, and impaired autophagy in a novel rat model of Nephropathic Cystinosis. Human Molecular Genetics, 31(13):2262-2278.

Abstract

Recessive mutations in the CTNS gene encoding the lysosomal transporter cystinosin cause cystinosis, a lysosomal storage disease leading to kidney failure and multisystem manifestations. A Ctns knock-out mouse model recapitulates features of cystinosis, but the delayed onset of kidney manifestations, phenotype variability, and strain effects limit its use for mechanistic and drug development studies. To provide a better model for cystinosis, we generated a Ctns knock-out rat model using CRISPR/Cas9 technology. The Ctns-/- rats display progressive cystine accumulation and crystal formation in multiple tissues including kidney, liver and thyroid. They show an early onset and progressive loss of urinary solutes, indicating generalized proximal tubule dysfunction, with development of typical swan-neck lesions, tubulointerstitial fibrosis and kidney failure, and decreased survival. The Ctns-/- rats also present crystals in the cornea, and bone and liver defects, like in patients. Mechanistically, the loss of cystinosin induces a phenotype switch associating abnormal proliferation and dedifferentiation, loss of apical receptors and transporters, and defective lysosomal activity and autophagy in the cells. Primary cultures of proximal tubule cells derived from the Ctns-/- rat kidneys confirmed the key changes caused by cystine overload, including reduced endocytic uptake, increased proliferation and defective lysosomal dynamics and autophagy. The novel Ctns-/- rat model and derived proximal tubule cell system provide invaluable tools to investigate the pathogenesis of cystinosis and to accelerate drug discovery.

Abstract

Recessive mutations in the CTNS gene encoding the lysosomal transporter cystinosin cause cystinosis, a lysosomal storage disease leading to kidney failure and multisystem manifestations. A Ctns knock-out mouse model recapitulates features of cystinosis, but the delayed onset of kidney manifestations, phenotype variability, and strain effects limit its use for mechanistic and drug development studies. To provide a better model for cystinosis, we generated a Ctns knock-out rat model using CRISPR/Cas9 technology. The Ctns-/- rats display progressive cystine accumulation and crystal formation in multiple tissues including kidney, liver and thyroid. They show an early onset and progressive loss of urinary solutes, indicating generalized proximal tubule dysfunction, with development of typical swan-neck lesions, tubulointerstitial fibrosis and kidney failure, and decreased survival. The Ctns-/- rats also present crystals in the cornea, and bone and liver defects, like in patients. Mechanistically, the loss of cystinosin induces a phenotype switch associating abnormal proliferation and dedifferentiation, loss of apical receptors and transporters, and defective lysosomal activity and autophagy in the cells. Primary cultures of proximal tubule cells derived from the Ctns-/- rat kidneys confirmed the key changes caused by cystine overload, including reduced endocytic uptake, increased proliferation and defective lysosomal dynamics and autophagy. The novel Ctns-/- rat model and derived proximal tubule cell system provide invaluable tools to investigate the pathogenesis of cystinosis and to accelerate drug discovery.

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Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Children's Hospital Zurich > Medical Clinic
04 Faculty of Medicine > University Hospital Zurich > Ophthalmology Clinic
04 Faculty of Medicine > Institute of Physiology
07 Faculty of Science > Institute of Physiology
Dewey Decimal Classification:610 Medicine & health
Uncontrolled Keywords:Genetics (clinical), Genetics, Molecular Biology, General Medicine
Language:English
Date:7 July 2022
Deposited On:01 Apr 2022 15:06
Last Modified:27 Jun 2024 01:37
Publisher:Oxford University Press
ISSN:0964-6906
OA Status:Hybrid
Free access at:PubMed ID. An embargo period may apply.
Publisher DOI:https://doi.org/10.1093/hmg/ddac033
PubMed ID:35137071
Project Information:
  • : FunderSNF
  • : Grant ID31003A-169850
  • : Project Title
  • Content: Published Version
  • Language: English
  • Licence: Creative Commons: Attribution 4.0 International (CC BY 4.0)