New aspects of the pathogenesis of cystinosis.

Cystinosis is a lysosomal transport disorder characterized by an intra-lysosomal accumulation of cystine, the disulfide of the amino acid cysteine. It is the most common inherited cause of the renal Fanconi syndrome. There are various clinical forms, infantile, juvenile, and ocular, based on age of onset and severity of symptoms. The first clinical description appeared in the early 1900s, but it was not until 1998 that the causative gene, CTNS, was identified. CTNS encodes cystinosin, a novel seven transmembrane domain (TM) protein. Cystinosin is a lysosomal membrane protein that requires two lysosomal targeting signals: a classic GYDQL motif in its C-terminal tail and a novel conformational motif, the core of which is YFPQA, situated in the fifth inter-TM loop. Cystinosin is the lysosomal cystine transporter and its activity is H(+)-driven. A mouse model of cystinosis was recently generated and Ctns(-/-) mice accumulate cystine in all tissues. A high level of cystine accumulates in the kidney, but these mice do not present with proximal tubulopathy or renal dysfunction. The Ctns(-/-) mouse model may provide clues to the cause of the Fanconi syndrome associated with cystinosis, the origin of which remains poorly understood.