CTNS – Ocular Cystinosis

Ocular cystinosis is a rare autosomal recessive lysosomal storage disorder caused by biallelic mutations in the CTNS gene, encoding the cystine transporter cystinosin. Clinically, it presents with photophobia and intralysosomal cystine crystals in the cornea and conjunctiva, without the renal Fanconi syndrome seen in nephropathic cystinosis. The distinction from classic cystinosis lies in the presence of one severe and one mild CTNS allele, permitting residual cystinosin function.

Genetic studies have identified compound heterozygous CTNS mutations in 13 unrelated ocular cystinosis probands (1 case) (PMID:30957593), 4 cases (PMID:10625078), and 8 Tunisian patients (PMID:35524314). Segregation analysis in the index family confirmed parental transmission of each variant without additional affected relatives. The most recurrent missense variants affect transmembrane domains, including c.635C>T (p.Ala212Val), and splice-site or small deletion alleles such as c.206_210del (p.Ile69_Pro73del).

Variant spectrum in ocular cystinosis spans missense (e.g., p.Gly197Arg, p.Ala212Val), in-frame deletions, splice-site changes (e.g., c.853-3C>G) and small intronic deletions. The mild alleles (e.g., c.853-3C>G) allow residual CTNS mRNA production and lysosomal cystine transport, explaining ocular-only involvement.

Functional assays demonstrate that promoter mutations (c.-303G>T; c.-295G>C) disrupt an Sp1 binding site and severely reduce CTNS transcriptional activity (PMID:11505338). In vitro transport studies of cystinosin mutants show that most missense variants associated with ocular cystinosis retain partial cystine efflux capacity, consistent with their milder phenotype compared to infantile forms (PMID:15128704).

Mechanistically, CTNS pathogenicity arises from impaired lysosomal cystine export due to deficient transporter function or aberrant splicing. Recent work on an ER-retained deletion variant highlights ER-associated degradation of misfolded cystinosin and suggests chemical chaperone rescue as a potential precision therapy (PMID:37561577).

Integration of genetic and functional data supports a Strong gene–disease relationship: 13 probands with compound heterozygous CTNS variants across multiple cohorts, segregation in a familial case, and concordant functional evidence. Genetic testing for CTNS variants and functional annotation are essential for accurate diagnosis, prognosis, and guiding emerging therapies.

Key Take-home: CTNS genetic and functional assessment enables precise diagnosis of ocular cystinosis and informs tailored therapeutic strategies.

References

• Ophthalmic Genetics • 2019 • A case of ocular cystinosis associated with two potentially severe CTNS mutations. PMID:30957593
• Pediatric Research • 2000 • Ocular nonnephropathic cystinosis: clinical, biochemical, and molecular correlations. PMID:10625078
• Diagnostic Pathology • 2022 • Molecular characterization of CTNS mutations in Tunisian patients with ocular cystinosis PMID:35524314
• American Journal of Human Genetics • 2001 • The promoter of a lysosomal membrane transporter gene, CTNS, binds Sp-1, shares sequences with the promoter of an adjacent gene, CARKL, and causes cystinosis if mutated in a critical region. PMID:11505338
• Human Molecular Genetics • 2004 • Molecular pathogenesis of cystinosis: effect of CTNS mutations on the transport activity and subcellular localization of cystinosin. PMID:15128704
• The Journal of Clinical Investigation • 2023 • ER-associated degradation in cystinosis pathogenesis and the prospects of precision medicine. PMID:37561577

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