The CTNS gene (Cystinosin, Lysosomal Cystine Transporter) encodes a lysosomal membrane protein responsible for transporting cystine out of lysosomes. Mutations cause cystinosis, a lysosomal storage disorder with significant neurological manifestations.
The CTNS gene is located on chromosome 17p13.2 and encodes cystinosin, a 367-amino acid integral lysosomal membrane protein that functions as a proton-driven cystine transporter[1]. Loss-of-function mutations in CTNS cause cystinosis, an autosomal recessive lysosomal storage disorder characterized by intralysosomal accumulation of the amino acid cystine throughout the body[2]. While cystinosis primarily affects the kidneys, the neurological complications — including progressive cerebral atrophy, cerebellar dysfunction, and neurocognitive impairment — place this gene at the intersection of lysosomal biology and neurodegeneration[3]. [1]
| | | [2]
|---|---| [3]
| Gene Symbol | CTNS | [4]
| Full Name | Cystinosin, Lysosomal Cystine Transporter | [5]
| Chromosomal Location | 17p13.2 | [6]
| NCBI Gene ID | 1497 |
| OMIM | 606272 |
| Ensembl | ENSG00000040531 |
| UniProt | O60931 |
| Associated Diseases | Cystinosis (infantile nephropathic, juvenile, ocular) |
Cystinosin is a seven-transmembrane-domain protein localized to the lysosomal membrane. It functions as an H⁺-driven cystine symporter, coupling the efflux of cystine from the lysosomal lumen to proton import[1]:
The CTNS protein contains several functionally important features[4]:
Beyond cystine transport, CTNS has been implicated in[5]:
Cystinosis is classified into three clinical forms based on age of onset and severity[2]:
| Form | Onset | Features | Frequency |
|---|---|---|---|
| Infantile nephropathic | 6-12 months | Renal Fanconi syndrome, growth failure, photophobia, progressive renal failure | ~95% of cases |
| Juvenile/adolescent | Late childhood | Milder renal disease, photophobia | ~5% of cases |
| Ocular (non-nephropathic) | Adulthood | Corneal cystine crystals, photophobia only | Rare |
With improved renal management and cysteamine therapy extending survival, neurological complications have become increasingly recognized[3]:
CTNS mutations illuminate fundamental principles of lysosomal dysfunction in neurodegeneration[6]:
| Variant | Effect | Phenotype |
|---|---|---|
| 57-kb deletion | Loss of exons 1-10 + upstream CARKL gene | Severe infantile nephropathic cystinosis; most common European allele (~50%) |
| c.18_21delGACT | Frameshift, premature stop | Infantile nephropathic cystinosis |
| c.681G>A (W227X) | Nonsense mutation | Infantile nephropathic cystinosis |
| c.1015G>A (G339R) | Missense in TM7 | Late-onset/juvenile cystinosis |
| c.329T>C (L110P) | Missense, partial function | Juvenile/intermediate cystinosis |
Cysteamine (Cystagon, Procysbi) is the only approved treatment for cystinosis[7]:
CTNS is ubiquitously expressed, with notable expression in[1]:
In the brain, expression is particularly high in regions vulnerable to cystine accumulation, including the hippocampus and cerebellum[3].
Gahl WA et al. Cystinosis (2002). 2002. ↩︎
Kalatzis V et al. Cystinosin, the protein defective in cystinosis, is a H+-driven lysosomal cystine transporter (2001). 2001. ↩︎
Ivanova EA et al. Endo-lysosomal dysfunction in human proximal tubular epithelial cells deficient for lysosomal cystine transporter cystinosin (2015). 2015. ↩︎
Festa BP et al. Impaired autophagy bridges lysosomal storage disease and epithelial dysfunction in the kidney (2018). 2018. ↩︎
Ariceta G et al. Cystinosis in adult and adolescent patients (2015). 2015. ↩︎
Syres K et al. Successful treatment of the murine model of cystinosis using bone marrow cell transplantation (2009). 2009. ↩︎