Ocular nonnephropathic cystinosis: Clinical, biochemical, and molecular correlations

Ocular nonnephropathic cystinosis, a variant of the classic nephropathic ty pe of cystinosis, is an autosomal recessive lysosomal storage disorder char acterized by photophobia due to corneal cystine crystals but absence of ren al disease. We determined the molecular basis for ocular cystinosis in four individuals. All had mutations in the cystinosis gene CTNS, indicating tha t ocular cystinosis is allelic with classic nephropathic cystinosis. The oc ular cystinosis patients each had one severe mutation and one mild mutation , the latter consisting of either a 928 G-->A (G197R) mutation or an IVS10- 3 C-->G splicing mutation resulting in the insertion of 182 bp of IVS10 int o the CTNS mRNA. The mild mutations appear to allow for residual CTNS mRNA production, significant amounts of lysosomal cystine transport, and lower l evels of cellular cystine compared with those in nephropathic cystinosis. T he lack of kidney involvement in ocular cystinosis may be explained by two different mechanisms. On the one hand (e.g. the G197R mutation), significan t residual cystinosin activity may be present in every tissue. On the other hand (e.g. the IVS10-3 C-->G mutation), substantial cystinosin activity ma y exist in the kidney because of that tissue's specific expression of facto rs that promote splicing of a normal CTNS transcript. Each of these mechani sms could result in minimally reduced lysosomal cystine transport in the ki dneys.