Pathogenesis of cell dysfunction in nephropathic cystinosis

Abstract

Abstract Nephropathic cystinosis (NC) is an autosomal recessive disorder characterized by the accumulation of the amino acid cystine in lysosomes, due to defective transport of cystine across the lysosomal membrane. Patients suffer from severe renal Fanconi syndrome from the first months of life and progress to end-stage renal failure during their second decade. Treatment with cysteamine delays the progression of chronic renal failure and improves most NC-related symptoms. Two less severe forms of cystinosis, a juvenile and an ocular form, have also been described. NC is caused by mutations in the CTNS gene that encodes for the cystinosin protein, a transmembrane lysosomal transporter. Cystinosin is a proton symporter, co-transporting cystine and protons in the same direction. Over 50 mutations have been described, including a common 57 kb deletion. Various metabolic and structural alterations have been described in cystinotic cells. These include decreased ATP and glutathione synthesis, increased apoptotic activity and mitochondrial damage. Although much progress has been made in the molecular and clinical fields, the mechanisms linking the accumulation of cystine in lysosomes and proximal tubular cell dysfunction are still poorly understood.