Infantile nephropathic cystinosis is a rare, autosomal recessive disease caused 
by a defect in the transport of cystine across the lysosomal membrane and 
characterized by early onset of renal proximal tubular dysfunction. Late-onset 
cystinosis, a rarer form of the disorder, is characterized by onset of symptoms 
between 12 and 15 years of age. We previously characterized the cystinosis gene, 
CTNS, and identified pathogenic mutations in patients with infantile 
nephropathic cystinosis, including a common, approximately 65 kb deletion which 
encompasses exons 1-10. Structure predictions suggested that the gene product, 
cystinosin, is a novel integral lysosomal membrane protein. We now examine the 
predicted effect of mutations on this model of cystinosin. In this study, we 
screened patients with infantile nephropathic cystinosis, those with late-onset 
cystinosis and patients whose phenotype does not fit the classical definitions. 
We found 23 different mutations in CTNS; 14 are novel mutations. Out of 25 
patients with infantile nephropathic cystinosis, 12 have two severely truncating 
mutations, which is consistent with a loss of functional protein, and 13 have 
missense or in-frame deletions, which would result in disruption of 
transmembrane domains and loss of protein function. Mutations found in two 
late-onset patients affect functionally unimportant regions of cystinosin, which 
accounts for their milder phenotype. For three patients, the age of onset of 
cystinosis was <7 years but the course of the disease was milder than the 
infantile nephropathic form. This suggests that the missense mutations found in 
these individuals allow production of functional protein and may also indicate 
regions of cystinosin which are not functionally important.