Biology:CTNS (gene)

From HandWiki

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

A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

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.[2] It spans base pairs 3,636,468 and 3,661,542, and comprises 12 exons.[2][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.[2]

The CTNSN323K, CTNSK280R, and CTNSN288K mutations completely stop the movement of CySS out of the lysosome via cystinosin.[2] interestingly, CTNSN323K and CTNSK280R are related to juvenile nephropathic cystinosis while CTNSN288K 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.[7] 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 KM of 278 ± 49 μM.[8][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.[8] 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.[6]

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.[5]

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.[17] For example, mild cystinosis is typically associated with mutations that do not affect the amino acids in the transmembrane domains of cystinosin.[3] In contrast, infantile nephropathic cystinosis, the most severe form of the disease, is most commonly associated with a total loss of activity.[17]

Gene deletion resulting in the absence of either of the sorting motifs results in the delocalization of cystinosin to the cellular plasma membrane.[20][8]

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

References

  1. ↑ 1.0 1.1 "Molecular Basis of Cystinosis: Geographic Distribution, Functional Consequences of Mutations in the CTNS Gene, and Potential for Repair". Nephron 141 (2): 133–146. 2019. doi:10.1159/000495270. PMID 30554218. 
  2. ↑ 2.0 2.1 2.2 2.3 "A novel gene encoding an integral membrane protein is mutated in nephropathic cystinosis". Nature Genetics 18 (4): 319–324. April 1998. doi:10.1038/ng0498-319. PMID 9537412. 
  3. ↑ 3.0 3.1 "CTNS mutations in an American-based population of cystinosis patients". American Journal of Human Genetics 63 (5): 1352–1362. November 1998. doi:10.1086/302118. PMID 9792862. 
  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. doi:10.1038/ng0695-246. PMID 7663525. 
  5. ↑ 5.0 5.1 "Cystinosis: the evolution of a treatable disease". Pediatric Nephrology 28 (1): 51–59. January 2013. doi:10.1007/s00467-012-2242-5. PMID 22903658. 
  6. ↑ 6.0 6.1 "Cystinosin is a melanosomal protein that regulates melanin synthesis". FASEB Journal 26 (9): 3779–3789. September 2012. doi:10.1096/fj.11-201376. PMID 22649030. 
  7. ↑ 7.0 7.1 "Transporter Classification Database". 2017-10-13. http://www.tcdb.org/. 
  8. ↑ 8.0 8.1 8.2 8.3 "Cystinosin, the protein defective in cystinosis, is a H(+)-driven lysosomal cystine transporter". The EMBO Journal 20 (21): 5940–5949. November 2001. doi:10.1093/emboj/20.21.5940. PMID 11689434. 
  9. ↑ "Lysosomal Targeting of Cystinosin Requires AP-3". Traffic 16 (7): 712–726. July 2015. doi:10.1111/tra.12277. PMID 25753619. 
  10. ↑ 10.0 10.1 10.2 10.3 "The Role of Cystinosin in the Intermediary Thiol Metabolism and Redox Homeostasis in Kidney Proximal Tubular Cells". Antioxidants 7 (12): 179. December 2018. doi:10.3390/antiox7120179. PMID 30513914. 
  11. ↑ "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. doi:10.1073/pnas.1115581109. PMID 22232659. 
  12. ↑ "Lysosomal transport disorders". Journal of Inherited Metabolic Disease 23 (3): 278–292. May 2000. doi:10.1023/a:1005640214408. PMID 10863944. 
  13. ↑ "Infantile Nephropathic Cystinosis: A Novel CTNS Mutation". The Eurasian Journal of Medicine 49 (2): 148–151. June 2017. doi:10.5152/eurasianjmed.2017.17039. PMID 28638260. 
  14. ↑ "Common mutation causes cystinosis in the majority of black South African patients". Pediatric Nephrology 30 (4): 595–601. April 2015. doi:10.1007/s00467-014-2980-7. PMID 25326109. 
  15. ↑ "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. doi:10.1101/gr.10.2.165. PMID 10673275. 
  16. ↑ "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. doi:10.1006/mgme.1998.2790. PMID 10068513. 
  17. ↑ 17.0 17.1 17.2 "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. doi:10.1093/hmg/ddh152. PMID 15128704. 
  18. ↑ "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. doi:10.1089/gtmb.2008.0156. PMID 19580442. 
  19. ↑ "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. doi:10.1093/hmg/8.13.2507. PMID 10556299. 
  20. ↑ "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. doi:10.1074/jbc.m010562200. PMID 11150305. 
  21. ↑ "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. doi:10.1038/ki.1995.324. PMID 7564123. 
  22. ↑ "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. doi:10.1016/j.bbrc.2011.03.022. PMID 21392501. 
  23. ↑ "ERS1 encodes a functional homologue of the human lysosomal cystine transporter". The FEBS Journal 272 (10): 2497–2511. May 2005. doi:10.1111/j.1742-4658.2005.04670.x. PMID 15885099. 
  24. ↑ "Intralysosomal cystine accumulation in mice lacking cystinosin, the protein defective in cystinosis". Molecular and Cellular Biology 22 (21): 7622–7632. November 2002. doi:10.1128/MCB.22.21.7622-7632.2002. PMID 12370309. 

Further reading

External links




Retrieved from "https://handwiki.org/wiki/index.php?title=Biology:CTNS_(gene)&oldid=2850323"