Cystinosis: New insights into pathophysiology and clinical implications

Nephropathic cystinosis is an autosomal recessive lysosomal storage disease characterized by the accumulation and crystallization of the amino acid cystine in the lysosomes of all body cells and tissues. The main pathogenic factor is homozygous or compound heterozygous mutations in the CTNS gene (17p13.2), resulting in a defective function of the cystine transporter protein cystinosin. Although the genetic background of the disease is very well characterized, the pathogenesis of nephropathic cystinosis is not yet fully understood. In particular, no clear explanation has been documented linking lysosomal cystine accumulation to renal cell dysfunction and renal Fanconi syndrome. In the current project we will try to continue our line of research and further explore alternately hypothesized pathogenic mechanisms of cystinosis, especially podocyte dysfunction and inflammation. We will also try to develop and characterize a new zebrafish animal model for the study of cystinosis. We aim to evaluate its use in combination with the currently available mouse model to unravel different pathogenic mechanisms of cystinosis. Furthermore, we will try to explore and validate alternative therapeutic monitors that can be used clinically in addition to or instead of WBCs cystine levels.