CTNS (gene) explained

CTNS may also refer to the Center for Theology and the Natural Sciences.

CTNS is the gene that encodes the protein cystinosin in humans. Cystinosin is a lysosomal seven-transmembrane protein that functions as an active transporter for the export of cystine molecules out of the lysosome.^[1]

Mutations in CTNS are responsible for cystinosis, an autosomal recessive lysosomal storage disease.^[2]

Gene

The CTNS gene is located on the p arm of human chromosome 17, at position 13.2. It spans base pairs 3,636,468 and 3,661,542, and comprises 12 exons.^[3]

In 1995, the gene was localized to the short arm of chromosome 17.^[4] An international collaborative effort finally succeeded in isolating CTNS by positional cloning in 1998.

The CTNS^N323K, CTNS^K280R, and CTNS^N288K mutations completely stop the movement of CySS out of the lysosome via cystinosin.^[2] interestingly, CTNS^N323K and CTNS^K280R are related to juvenile nephropathic cystinosis while CTNS^N288K mutations are found in cases with infantile nephropathic cystinosis.^[1]

Tissue distribution

The gene is expressed in the lysosomes of all organs and tissues.^[5] Cystinosin has also been found in melanosomes in melanocytes.^[6]

Structure

Cystinosin is a seven-transmembrane domain receptor embedded in the lysosomal membrane, and is a member of the lysosomal cystine transporter family of transport proteins.^[7] It comprises 367 amino acid residues, and has a molecular mass of 41738 Da. Cystinosin has seven N-glycosylation sites in the N-terminus region, spanning a range of 128 amino acid residues.^[8]

The receptor also has two sorting motifs; a GYDQL motif in the C-terminus region, and a YFPQA motif, known as the 'PQ loop,' on the fifth inter-transmembrane α-helix moiety.^[9]

Cystinosin embeds in the lysosomal membrane with the C-terminus region facing the cytosol and the N-terminus region facing the lumen.^[10]

Mechanism

The protein obeys Michaelis-Menton kinetics and has an associated K_M of 278 ± 49 μM.^[11]

The GYDQL and YFPQA motifs on the C-terminal binds cystinosin to the lysosome. Mutations in the GYDQL motif cause a repositioning of cystinosin to being partially on the plasma membrane and partially on the lysosome. Mutations in both GYDQL and YFPQA motifs cause cystinosin to position itself to the plasma membrane instead of lysosomes^[10]

An increase in acidity in the lumen of the lysosome initiates the reaction of CySS and H⁺ being transported into the cytosol.^[10]

Function

Cystinosin functions as a symporter which actively transports protons and cystine, the oxidized cysteine dimer, out of the lysosome. Cystinosin only transports L-CySS while other cystine transporters will work on various amino acids.^[10] If cystine builds up in the lysosome it will inhibit the normal functioning of the organelle making the transport function important in the regular functioning of cells.

Cystinosin has also been discovered in melanosomes and has been linked to the control and regulation of melanin.

Clinical significance

Cystinosis

Mutations in CTNS gene can result in cystinosis. Cystinosis is a type of lysosomal transport disorder, a subset of lysosomal storage disorders.^[12] Variation in the encoded cystinosin protein results in an inhibition or loss in its ability to transport cystine out of the lysosome. Cystine molecules accumulate and form crystals within the lysosome, impairing its function.

Mutations

Cystinosis is presented in patients with a range of CTNS mutations; as of 2017, over 100 have been identified.^{[13] [14]} The most common mutation is a 57,257 base pair deletion commonly referred to as the 57 kb deletion. This was formally known as the 65 kb deletion; a misnomer originating from early incorrect estimates.^{[15] [16]} Other reported mutations include other deletions, missense mutations, and in-frame deletions and insertions.^{[17] [18]}

The type and extent of mutation determines the type and severity of cystinosis in the carrier.^[19] This is a result of the degree of transport inhibition caused by the misfolding of cystinosin. For example, mild cystinosis is typically associated with mutations that do not affect the amino acids in the transmembrane domains of cystinosin. In contrast, infantile nephropathic cystinosis, the most severe form of the disease, is most commonly associated with a total loss of activity.

Gene deletion resulting in the absence of either of the sorting motifs results in the delocalization of cystinosin to the cellular plasma membrane.^[20]

Model systems

Human models for cystinosin are typically derived from cystinotic renal tubular cell lines.^{[21] [22]}

Non-human protein homologs for cystinosin include ERS1 in Saccharomyces cerevisiae (yeast cells) and the Caenorhabditis elegans protein, C41C4.7.^[23] Murine ctns has also been used.^[24]

See also

• Cystinosis
• Lysosomal storage disorders
• Lysosomal Cystine Transporter Family

Further reading

• Anikster Y, Shotelersuk V, Gahl WA . CTNS mutations in patients with cystinosis . Human Mutation . 14 . 6 . 454–458 . 2000 . 10571941 . 10.1002/(SICI)1098-1004(199912)14:6<454::AID-HUMU2>3.0.CO;2-H . 23669974 .
• Gahl WA, Thoene JG, Schneider JA . Cystinosis . The New England Journal of Medicine . 347 . 2 . 111–121 . July 2002 . 12110740 . 10.1056/NEJMra020552 .
• Kalatzis V, Antignac C . Cystinosis: from gene to disease . Nephrology, Dialysis, Transplantation . 17 . 11 . 1883–1886 . November 2002 . 12401840 . 10.1093/ndt/17.11.1883 . free .
• Thoene J, Lemons R, Anikster Y, Mullet J, Paelicke K, Lucero C, Gahl W, Schneider J, Shu SG, Campbell HT . 6 . Mutations of CTNS causing intermediate cystinosis . Molecular Genetics and Metabolism . 67 . 4 . 283–293 . August 1999 . 10444339 . 10.1006/mgme.1999.2876 .
• McGowan-Jordan J, Stoddard K, Podolsky L, Orrbine E, McLaine P, Town M, Goodyer P, MacKenzie A, Heick H . 6 . Molecular analysis of cystinosis: probable Irish origin of the most common French Canadian mutation . European Journal of Human Genetics . 7 . 6 . 671–678 . September 1999 . 10482956 . 10.1038/sj.ejhg.5200349 . free .
• Anikster Y, Lucero C, Guo J, Huizing M, Shotelersuk V, Bernardini I, McDowell G, Iwata F, Kaiser-Kupfer MI, Jaffe R, Thoene J, Schneider JA, Gahl WA . 6 . Ocular nonnephropathic cystinosis: clinical, biochemical, and molecular correlations . Pediatric Research . 47 . 1 . 17–23 . January 2000 . 10625078 . 10.1203/00006450-200001000-00007 . free .
• Cherqui S, Kalatzis V, Forestier L, Poras I, Antignac C . Identification and characterisation of the murine homologue of the gene responsible for cystinosis, Ctns . BMC Genomics . 1 . 2 . 2003 . 11121245 . 29086 . 10.1186/1471-2164-1-2 . free .
• Phornphutkul C, Anikster Y, Huizing M, Braun P, Brodie C, Chou JY, Gahl WA . 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 . American Journal of Human Genetics . 69 . 4 . 712–721 . October 2001 . 11505338 . 1226058 . 10.1086/323484 .
• Rupar CA, Matsell D, Surry S, Siu V . A G339R mutation in the CTNS gene is a common cause of nephropathic cystinosis in the south western Ontario Amish Mennonite population . Journal of Medical Genetics . 38 . 9 . 615–616 . September 2001 . 11565547 . 1734937 . 10.1136/jmg.38.9.615 .
• Kleta R, Anikster Y, Lucero C, Shotelersuk V, Huizing M, Bernardini I, Park M, Thoene J, Schneider J, Gahl WA . 6 . CTNS mutations in African American patients with cystinosis . Molecular Genetics and Metabolism . 74 . 3 . 332–337 . November 2001 . 11708862 . 10.1006/mgme.2001.3218 .
• Kiehntopf M, Schickel J, Gönne B, Koch HG, Superti-Furga A, Steinmann B, Deufel T, Harms E . 6 . Analysis of the CTNS gene in patients of German and Swiss origin with nephropathic cystinosis . Human Mutation . 20 . 3 . 237 . September 2002 . 12204010 . 10.1002/humu.9063 . 25080378 . free .

External links

• GeneReviews/NCBI/NIH/UW entry on Cystinosis
  • Genetics Home Reference page on CTNS.
• Genetic Testing Registry.

Notes and References

1. David D, Princiero Berlingerio S, Elmonem MA, Oliveira Arcolino F, Soliman N, van den Heuvel B, Gijsbers R, Levtchenko E . 6 . Molecular Basis of Cystinosis: Geographic Distribution, Functional Consequences of Mutations in the CTNS Gene, and Potential for Repair . Nephron . 141 . 2 . 133–146 . 2019 . 30554218 . 10.1159/000495270 . 58767583 . free .
2. Town M, Jean G, Cherqui S, Attard M, Forestier L, Whitmore SA, Callen DF, Gribouval O, Broyer M, Bates GP, van't Hoff W, Antignac C . 6 . A novel gene encoding an integral membrane protein is mutated in nephropathic cystinosis . Nature Genetics . 18 . 4 . 319–324 . April 1998 . 9537412 . 10.1038/ng0498-319 . 10629789 .
3. Shotelersuk V, Larson D, Anikster Y, McDowell G, Lemons R, Bernardini I, Guo J, Thoene J, Gahl WA . 6 . CTNS mutations in an American-based population of cystinosis patients . American Journal of Human Genetics . 63 . 5 . 1352–1362 . November 1998 . 9792862 . 1377545 . 10.1086/302118 .
4. Linkage of the gene for cystinosis to markers on the short arm of chromosome 17. The Cystinosis Collaborative Research Group . Nature Genetics . 10 . 2 . 246–248 . June 1995 . 7663525 . 10.1038/ng0695-246 . 22093385 . The Cystinosis Collaborative Research Group .
5. Nesterova G, Gahl WA . Cystinosis: the evolution of a treatable disease . Pediatric Nephrology . 28 . 1 . 51–59 . January 2013 . 22903658 . 3505515 . 10.1007/s00467-012-2242-5 .
6. Chiaverini C, Sillard L, Flori E, Ito S, Briganti S, Wakamatsu K, Fontas E, Berard E, Cailliez M, Cochat P, Foulard M, Guest G, Niaudet P, Picardo M, Bernard FX, Antignac C, Ortonne JP, Ballotti R . 6 . Cystinosin is a melanosomal protein that regulates melanin synthesis . FASEB Journal . 26 . 9 . 3779–3789 . September 2012 . 22649030 . 10.1096/fj.11-201376 . free . 11334825 .
7. Web site: Transporter Classification Database. 2017-10-13. www.tcdb.org. 2017-10-13. https://web.archive.org/web/20140103031444/http://tcdb.org/. 2014-01-03. dead.
8. Kalatzis V, Cherqui S, Antignac C, Gasnier B . Cystinosin, the protein defective in cystinosis, is a H(+)-driven lysosomal cystine transporter . The EMBO Journal . 20 . 21 . 5940–5949 . November 2001 . 11689434 . 125690 . 10.1093/emboj/20.21.5940 .
9. Andrzejewska Z, Névo N, Thomas L, Bailleux A, Chauvet V, Benmerah A, Antignac C . Lysosomal Targeting of Cystinosin Requires AP-3 . Traffic . 16 . 7 . 712–726 . July 2015 . 25753619 . 10.1111/tra.12277 . 25009057 . free .
10. Sumayao R, Newsholme P, McMorrow T . The Role of Cystinosin in the Intermediary Thiol Metabolism and Redox Homeostasis in Kidney Proximal Tubular Cells . Antioxidants . 7 . 12 . 179 . December 2018 . 30513914 . 6315507 . 10.3390/antiox7120179 . free .
11. Ruivo R, Bellenchi GC, Chen X, Zifarelli G, Sagné C, Debacker C, Pusch M, Supplisson S, Gasnier B . 6 . Mechanism of proton/substrate coupling in the heptahelical lysosomal transporter cystinosin . Proceedings of the National Academy of Sciences of the United States of America . 109 . 5 . E210–E217 . January 2012 . 22232659 . 3277178 . 10.1073/pnas.1115581109 . free .
12. Mancini GM, Havelaar AC, Verheijen FW . Lysosomal transport disorders . Journal of Inherited Metabolic Disease . 23 . 3 . 278–292 . May 2000 . 10863944 . 10.1023/a:1005640214408 . 19489712 .
13. Doneray H, Aldahmesh M, Yilmaz G, Cinici E, Orbak Z . Infantile Nephropathic Cystinosis: A Novel CTNS Mutation . The Eurasian Journal of Medicine . 49 . 2 . 148–151 . June 2017 . 28638260 . 5469843 . 10.5152/eurasianjmed.2017.17039 .
14. Owen EP, Nandhlal J, Leisegang F, Van der Watt G, Nourse P, Gajjar P . Common mutation causes cystinosis in the majority of black South African patients . Pediatric Nephrology . 30 . 4 . 595–601 . April 2015 . 25326109 . 10.1007/s00467-014-2980-7 . 22240586 .
15. Touchman JW, Anikster Y, Dietrich NL, Maduro VV, McDowell G, Shotelersuk V, Bouffard GG, Beckstrom-Sternberg SM, Gahl WA, Green ED . 6 . The genomic region encompassing the nephropathic cystinosis gene (CTNS): complete sequencing of a 200-kb segment and discovery of a novel gene within the common cystinosis-causing deletion . Genome Research . 10 . 2 . 165–173 . February 2000 . 10673275 . 310836 . 10.1101/gr.10.2.165 .
16. Anikster Y, Lucero C, Touchman JW, Huizing M, McDowell G, Shotelersuk V, Green ED, Gahl WA . 6 . Identification and detection of the common 65-kb deletion breakpoint in the nephropathic cystinosis gene (CTNS) . Molecular Genetics and Metabolism . 66 . 2 . 111–116 . February 1999 . 10068513 . 10.1006/mgme.1998.2790 .
17. Kalatzis V, Nevo N, Cherqui S, Gasnier B, Antignac C . Molecular pathogenesis of cystinosis: effect of CTNS mutations on the transport activity and subcellular localization of cystinosin . Human Molecular Genetics . 13 . 13 . 1361–1371 . July 2004 . 15128704 . 10.1093/hmg/ddh152 . free .
18. Tang S, Danda S, Zoleikhaeian M, Simon M, Huang T . An Indian boy with nephropathic cystinosis: a case report and molecular analysis of CTNS mutation . Genetic Testing and Molecular Biomarkers . 13 . 4 . 435–438 . August 2009 . 19580442 . 10.1089/gtmb.2008.0156 .
19. Attard M, Jean G, Forestier L, Cherqui S, van't Hoff W, Broyer M, Antignac C, Town M . 6 . Severity of phenotype in cystinosis varies with mutations in the CTNS gene: predicted effect on the model of cystinosin . Human Molecular Genetics . 8 . 13 . 2507–2514 . December 1999 . 10556299 . 10.1093/hmg/8.13.2507 . free .
20. Cherqui S, Kalatzis V, Trugnan G, Antignac C . The targeting of cystinosin to the lysosomal membrane requires a tyrosine-based signal and a novel sorting motif . The Journal of Biological Chemistry . 276 . 16 . 13314–13321 . April 2001 . 11150305 . 10.1074/jbc.m010562200 . free .
21. Racusen LC, Wilson PD, Hartz PA, Fivush BA, Burrow CR . Renal proximal tubular epithelium from patients with nephropathic cystinosis: immortalized cell lines as in vitro model systems . Kidney International . 48 . 2 . 536–543 . August 1995 . 7564123 . 10.1038/ki.1995.324 . free .
22. Taub ML, Springate JE, Cutuli F . Reduced phosphate transport in the renal proximal tubule cells in cystinosis is due to decreased expression of transporters rather than an energy defect . Biochemical and Biophysical Research Communications . 407 . 2 . 355–359 . April 2011 . 21392501 . 10.1016/j.bbrc.2011.03.022 .
23. Gao XD, Wang J, Keppler-Ross S, Dean N . ERS1 encodes a functional homologue of the human lysosomal cystine transporter . The FEBS Journal . 272 . 10 . 2497–2511 . May 2005 . 15885099 . 10.1111/j.1742-4658.2005.04670.x . 13035448 .
24. Cherqui S, Sevin C, Hamard G, Kalatzis V, Sich M, Pequignot MO, Gogat K, Abitbol M, Broyer M, Gubler MC, Antignac C . 6 . Intralysosomal cystine accumulation in mice lacking cystinosin, the protein defective in cystinosis . Molecular and Cellular Biology . 22 . 21 . 7622–7632 . November 2002 . 12370309 . 135682 . 10.1128/MCB.22.21.7622-7632.2002 .