Ocular Nonnephropathic Cystinosis: Clinical, Biochemical, and Molecular Correlations

Abstract

Ocular nonnephropathic cystinosis, a variant of the classic nephropathic type of cystinosis, is an autosomal recessive lysosomal storage disorder characterized by photophobia due to corneal cystine crystals but absence of renal disease. We determined the molecular basis for ocular cystinosis in four individuals. All had mutations in the cystinosis gene CTNS, indicating that ocular cystinosis is allelic with classic nephropathic cystinosis. The ocular 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 into the CTNS mRNA. The mild mutations appear to allow for residual CTNS mRNA production, significant amounts of lysosomal cystine transport, and lower levels of cellular cystine compared with those in nephropathic cystinosis. The lack of kidney involvement in ocular cystinosis may be explained by two different mechanisms. On the one hand (e.g. the G197R mutation), significant residual cystinosin activity may be present in every tissue. On the other hand (e.g. the IVS 10-3 C-->G mutation), substantial cystinosin activity may exist in the kidney because of that tissue's specific expression of factors that promote splicing of a normal CTNS transcript. Each of these mechanisms could result in minimally reduced lysosomal cystine transport in the kidneys.

Intralysosomal Cystine Accumulation in Mice Lacking Cystinosin, the Protein Defective in Cystinosis

“…CTNS mutations were thereafter detected in all forms of the disease, confirming their allelic status (1,2,30,31). CTNS is localized to 17p13 and is composed of 12 exons, with the predicted translation start site situated in exon 3 (31).…”

Functional significance of PMM2 mutations in mildly affected patients with congenital disorders of glycosylation Ia

“…45,46 There may be a range of affected target organs analogous to the ocular disorders seen in non-nephropathic cystinosis. 47 In these cases, a serious mutation is paired with a relatively mild one producing a mild phenotype. Another explanation is that other genes, i.e., the genetic background, together with environmental factors contribute to the clinical diversity of this disease.…”

Cystinosis

“…Cystinosis occurs in all ethnic groups, and 56 different mutations have been described to date, including promoter, missense, nonsense, deletion, insertion, and splicesite mutations (26,28,30 -36). The allelic disorders, intermediate cystinosis (with late-onset renal disease) and ocular cystinosis (limited to corneal involvement), are much more rare and result from the combination of one severe (nephropathic) mutation and one mild mutation in CTNS (30,33).…”

“…If missense mutations produce cystinosin proteins that remain antigenic, the antibody can be used to follow the intracellular location of the abnormal proteins. The mutations characterizing ocular (33) and intermediate (30) cystinosis will be of special interest. The antibody can be used to ascertain the expression level of the cystinosin protein in normal human tissues, as well as in ocular cystinosis tissues such as the kidney, if they become available.…”