Abstract
The development over the past 50 years of a variety of cell lines and animal models has provided valuable tools to understand the pathophysiology of nephropathic cystinosis. Primary cultures from patient biopsies have been instrumental in determining the primary cause of cystine accumulation in the lysosomes. Immortalised cell lines have been established using different gene constructs and have revealed a wealth of knowledge concerning the molecular mechanisms that underlie cystinosis. More recently, the generation of induced pluripotent stem cells, kidney organoids and tubuloids have helped bridge the gap between in vitro and in vivo model systems. The development of genetically modified mice and rats have made it possible to explore the cystinotic phenotype in an in vivo setting. All of these models have helped shape our understanding of cystinosis and have led to the conclusion that cystine accumulation is not the only pathology that needs targeting in this multisystemic disease. This review provides an overview of the in vitro and in vivo models available to study cystinosis, how well they recapitulate the disease phenotype, and their limitations.
Highlights
Vitro and In Vivo Models to StudyInfantile nephropathic cystinosis is a rare, hereditary, autosomal recessive, lysosomal storage disease affecting 1 in 100,000–200,000 live births [1]
The development of Induced pluripotent stem cells (iPSCs), primary and immortalised cell cultures, as well as a wide spectrum of animal models, have all contributed to our current understanding of the molecular basis of cystinosis
Additional data suggests that cystine accumulation may not be responsible for all of the phenotypes observed in cystinosis
Summary
Infantile nephropathic cystinosis is a rare, hereditary, autosomal recessive, lysosomal storage disease affecting 1 in 100,000–200,000 live births [1] It is caused by mutations in the gene CTNS which encodes for cystinosin, a cystine-proton cotransporter found on the lysosomal membrane [2,3]. Cystinotic patients are usually asymptomatic at birth and develop normally until the first 6 months of life, when they present with failure to thrive, excessive thirst and urination, dehydration, and sometimes rickets These symptoms result from Fanconi syndrome, which is the excessive urinary loss of electrolytes such as glucose, phosphate, amino acids, bicarbonate, and low molecular weight proteins, as a consequence of renal proximal tubule dysfunction [5,6]. At an older age and develop photophobia, mild proximal tubule dysfunction, and ESKD at a slower rate compared to infantile nephropathic cystinosis [6] In the latter, patients display ocular symptoms with no renal phenotype and are generally diagnosed in adulthood [13]. We explore how these models are helping researchers gain a better understanding of the disease and develop improved therapies
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