{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T23:01:59Z","timestamp":1783724519060,"version":"3.55.0"},"reference-count":52,"publisher":"Oxford University Press (OUP)","issue":"13","license":[{"start":{"date-parts":[[2022,2,8]],"date-time":"2022-02-08T00:00:00Z","timestamp":1644278400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001711","name":"Swiss National Science Foundation","doi-asserted-by":"publisher","award":["31003A-169850"],"award-info":[{"award-number":["31003A-169850"]}],"id":[{"id":"10.13039\/501100001711","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2022,7,7]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>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 knockout 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 knockout rat model using CRISPR\/Cas9 technology. The Ctns\u2212\/\u2212 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\u2212\/\u2212 rats also present crystals in the cornea, and bone and liver defects, as observed 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\u2212\/\u2212 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\u2212\/\u2212 rat model and derived proximal tubule cell system provide invaluable tools to investigate the pathogenesis of cystinosis and to accelerate drug discovery.<\/jats:p>","DOI":"10.1093\/hmg\/ddac033","type":"journal-article","created":{"date-parts":[[2022,2,3]],"date-time":"2022-02-03T20:11:27Z","timestamp":1643919087000},"page":"2262-2278","source":"Crossref","is-referenced-by-count":13,"title":["Multisystem involvement, defective lysosomes and impaired autophagy in a novel rat model of nephropathic cystinosis"],"prefix":"10.1093","volume":"31","author":[{"given":"Patrick","family":"Krohn","sequence":"first","affiliation":[{"name":"Institute of Physiology , University of Zurich, Zurich 8057 , Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura Rita","family":"Rega","sequence":"additional","affiliation":[{"name":"Renal Diseases Research Unit , Genetics and Rare Diseases Research Area, Bambino Ges\u00f9 Children\u2019s Hospital, IRCCS, Rome 00165 , Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marianne","family":"Harvent","sequence":"additional","affiliation":[{"name":"Institute of Physiology , University of Zurich, Zurich 8057 , Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beatrice Paola","family":"Festa","sequence":"additional","affiliation":[{"name":"Institute of Physiology , University of Zurich, Zurich 8057 , Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Taranta","sequence":"additional","affiliation":[{"name":"Renal Diseases Research Unit , Genetics and Rare Diseases Research Area, Bambino Ges\u00f9 Children\u2019s Hospital, IRCCS, Rome 00165 , Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessandro","family":"Luciani","sequence":"additional","affiliation":[{"name":"Institute of Physiology , University of Zurich, Zurich 8057 , Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph","family":"Dewulf","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine , Cliniques universitaires Saint Luc, UCLouvain, Brussels 1200 , Belgium"},{"name":"Department of Biochemistry , de Duve Institute, UCLouvain, Brussels 1200 , Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessio","family":"Cremonesi","sequence":"additional","affiliation":[{"name":"Division of Clinical Chemistry and Biochemistry , University Children\u2019s Hospital Zurich, Zurich 8032 , Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca Diomedi","family":"Camassei","sequence":"additional","affiliation":[{"name":"Department of Laboratories\u2013Pathology Unit , Bambino Ges\u00f9 Children\u2019s Hospital, Rome 00165 , Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James V M","family":"Hanson","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology , University Hospital Zurich and University of Zurich, Zurich 8091 , Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina","family":"Gerth-Kahlert","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology , University Hospital Zurich and University of Zurich, Zurich 8091 , Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesco","family":"Emma","sequence":"additional","affiliation":[{"name":"Renal Diseases Research Unit , Genetics and Rare Diseases Research Area, Bambino Ges\u00f9 Children\u2019s Hospital, IRCCS, Rome 00165 , Italy"},{"name":"Department of Pediatric Subspecialties , Division of Nephrology, Children\u2019s Hospital Bambino Ges\u00f9, IRCCS, Rome 00165 , Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6909-2060","authenticated-orcid":false,"given":"Marine","family":"Berquez","sequence":"additional","affiliation":[{"name":"Institute of Physiology , University of Zurich, Zurich 8057 , Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olivier","family":"Devuyst","sequence":"additional","affiliation":[{"name":"Institute of Physiology , University of Zurich, Zurich 8057 , Switzerland"},{"name":"Institut de Recherche Exp\u00e9rimentale et Clinique , UCLouvain, Brussels , Belgium"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2022,2,8]]},"reference":[{"key":"2022070719564993900_ref1","doi-asserted-by":"crossref","first-page":"1575","DOI":"10.1152\/physrev.00008.2018","article-title":"Learning physiology from inherited kidney disorders","volume":"99","author":"Wijst","year":"2019","journal-title":"Physiol. 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