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Gene Review

CTNS  -  cystinosin, lysosomal cystine transporter

Homo sapiens

Synonyms: CTNS-LSB, Cystinosin, PQLC4
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Disease relevance of CTNS

  • Although >55 CTNS mutations occur in patients with the lysosomal storage disorder cystinosis, no regulatory mutations have been reported, because the promoter has not been defined [1].
  • CTNS codes for the lysosomal cystine transporter, whose absence leads to intracellular cystine accumulation, widespread cellular destruction, renal Fanconi syndrome in infancy, renal glomerular failure in later childhood, and other systemic complications [2].
  • Cystinosis is an autosomal recessive lysosomal storage disease caused by mutations in CTNS [2].
  • Benign or nonnephropathic cystinosis, with symptoms related only to corneal crystals and photophobia, has been associated with two other CTNS mutations [3].

High impact information on CTNS

  • Cystinosin, the protein defective in cystinosis, is a H(+)-driven lysosomal cystine transporter [4].
  • To investigate the molecular function of cystinosin, the protein was redirected from lysosomes to the plasma membrane by deletion of its C-terminal GYDQL sorting motif (cystinosin-DeltaGYDQL), thereby exposing the intralysosomal side of cystinosin to the extracellular medium [4].
  • However, the patients' CTNS promoter mutations have no effect on CARKL promoter activity [1].
  • The CTNS promoter region shares 41 nucleotides with the promoter region of an adjacent gene of unknown function, CARKL, whose start site is 501 bp from the CTNS start site [1].
  • Using CAT reporter constructs of sequences 5' to the CTNS coding sequence, we identified the CTNS promoter as the region encompassing nucleotides -316 to +1 with respect to the transcription start site [1].

Biological context of CTNS


Anatomical context of CTNS

  • The CTNS gene product, cystinosin, has 367 amino acids and seven transmembrane domains and is thought to transport cystine out of lysosomes [3].
  • Transfection of the splice site mutant allele into CTNS null fibroblasts produced cystine depletion [8].
  • Cystinosis is an inherited disorder due to mutations in the CTNS gene which encodes cystinosin, a lysosomal transmembrane protein involved in cystine export to the cytosol [9].
  • A complete relocalization of cystinosin to the plasma membrane was obtained after deletion of half of the third cytoplasmic loop (amino acids 280-288) coupled with the deletion of the GY-DQ-L motif, demonstrating the presence of the second signal within this loop [10].
  • Antisera were screened by Western blotting and immunocytochemical analyses of transfected COS-7 cells expressing either human wild-type cystinosin, a wild-type cystinosin-green fluorescent protein (GFP) fusion protein, or a fusion protein of GFP and mutant human cystinosin with a carboxy-terminal deletion [11].

Associations of CTNS with chemical compounds

  • The targeting of cystinosin to the lysosomal membrane requires a tyrosine-based signal and a novel sorting motif [10].
  • Several gene mutations leading to the production of the faulty membrane proteins sialin and cystinosin have been identified in recent years [12].

Other interactions of CTNS

  • About 20 systems for transporting small molecules across the lysosomal membrane have been characterized but only two proteins, cystinosin and sialin, involved in the transport of cystine and sialic acid, respectively, have been cloned [13].
  • Cystinosin was stained using anti-cystinosin antibody and co-localised to the lysosomes with LAMP-2 antibody [14].

Analytical, diagnostic and therapeutic context of CTNS

  • By northern blot analysis, CTNS was not expressed in patients homozygous for the 65-kb deletion but was expressed in all 15 other patients tested [5].
  • In Western blots, bands corresponding to cystinosin or cystinosin-GFP were observed in transfected cells but no signal was detected in cells expressing the carboxy-terminal mutant; preimmune sera yielded negative results in all three cases [11].


  1. 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. Phornphutkul, C., Anikster, Y., Huizing, M., Braun, P., Brodie, C., Chou, J.Y., Gahl, W.A. Am. J. Hum. Genet. (2001) [Pubmed]
  2. FISH diagnosis of the common 57-kb deletion in CTNS causing cystinosis. Bendavid, C., Kleta, R., Long, R., Ouspenskaia, M., Muenke, M., Haddad, B.R., Gahl, W.A. Hum. Genet. (2004) [Pubmed]
  3. CTNS mutations in patients with cystinosis. Anikster, Y., Shotelersuk, V., Gahl, W.A. Hum. Mutat. (1999) [Pubmed]
  4. Cystinosin, the protein defective in cystinosis, is a H(+)-driven lysosomal cystine transporter. Kalatzis, V., Cherqui, S., Antignac, C., Gasnier, B. EMBO J. (2001) [Pubmed]
  5. CTNS mutations in an American-based population of cystinosis patients. Shotelersuk, V., Larson, D., Anikster, Y., McDowell, G., Lemons, R., Bernardini, I., Guo, J., Thoene, J., Gahl, W.A. Am. J. Hum. Genet. (1998) [Pubmed]
  6. Molecular analysis of cystinosis: probable Irish origin of the most common French Canadian mutation. McGowan-Jordan, J., Stoddard, K., Podolsky, L., Orrbine, E., McLaine, P., Town, M., Goodyer, P., MacKenzie, A., Heick, H. Eur. J. Hum. Genet. (1999) [Pubmed]
  7. ERS1 encodes a functional homologue of the human lysosomal cystine transporter. Gao, X.D., Wang, J., Keppler-Ross, S., Dean, N. FEBS J. (2005) [Pubmed]
  8. Expression of CTNS alleles: subcellular localization and aminoglycoside correction in vitro. Helip-Wooley, A., Park, M.A., Lemons, R.M., Thoene, J.G. Mol. Genet. Metab. (2002) [Pubmed]
  9. Glutathione precursors replenish decreased glutathione pool in cystinotic cell lines. Chol, M., Nevo, N., Cherqui, S., Antignac, C., Rustin, P. Biochem. Biophys. Res. Commun. (2004) [Pubmed]
  10. The targeting of cystinosin to the lysosomal membrane requires a tyrosine-based signal and a novel sorting motif. Cherqui, S., Kalatzis, V., Trugnan, G., Antignac, C. J. Biol. Chem. (2001) [Pubmed]
  11. Immunolocalization of cystinosin, the protein defective in cystinosis. Haq, M.R., Kalatzis, V., Gubler, M.C., Town, M.M., Antignac, C., Van't Hoff, W.G., Woolf, A.S. J. Am. Soc. Nephrol. (2002) [Pubmed]
  12. Sialic acid storage disease and related disorders. Strehle, E.M. Genet. Test. (2003) [Pubmed]
  13. Lysosomal membrane proteins. Winchester, B.G. Eur. J. Paediatr. Neurol. (2001) [Pubmed]
  14. Exfoliated human proximal tubular cells: a model of cystinosis and Fanconi syndrome. Laube, G.F., Haq, M.R., van't Hoff, W.G. Pediatr. Nephrol. (2005) [Pubmed]
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