CTNS (gene): Difference between revisions

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''CTNS may also refer to the [[Center for Theology and the Natural Sciences]].''{{Infobox_gene}}
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<!-- The GNF_Protein_box is automatically maintained by Protein Box Bot.  See Template:PBB_Controls to Stop updates. -->
'''''CTNS''''' is the [[gene]] that encodes the [[protein]] '''cystinosin''' in humans. Cystinosin is a [[Lysosome|lysosomal]] seven-transmembrane protein that functions as an active transporter for the export of [[cystine]] molecules out of the lysosome.  
{{GNF_Protein_box
| image = 
| image_source = 
| PDB =
| Name = Cystinosis, nephropathic
| HGNCid = 2518
| Symbol = CTNS
| AltSymbols =; CTNS-LSB; PQLC4
| OMIM = 606272
| ECnumber = 
| Homologene = 3625
| MGIid = 1932872
| GeneAtlas_image1 = PBB_GE_CTNS_36566_at_tn.png
| GeneAtlas_image2 = PBB_GE_CTNS_204925_at_tn.png
| Function = {{GNF_GO|id=GO:0015184 |text = L-cystine transmembrane transporter activity}}
| Component = {{GNF_GO|id=GO:0005765 |text = lysosomal membrane}} {{GNF_GO|id=GO:0016020 |text = membrane}} {{GNF_GO|id=GO:0016021 |text = integral to membrane}}
| Process = {{GNF_GO|id=GO:0006520 |text = amino acid metabolic process}} {{GNF_GO|id=GO:0006810 |text = transport}} {{GNF_GO|id=GO:0015811 |text = L-cystine transport}}
| Orthologs = {{GNF_Ortholog_box
    | Hs_EntrezGene = 1497
    | Hs_Ensembl = ENSG00000040531
    | Hs_RefseqProtein = NP_001026851
    | Hs_RefseqmRNA = NM_001031681
    | Hs_GenLoc_db = 
    | Hs_GenLoc_chr = 17
    | Hs_GenLoc_start = 3486522
    | Hs_GenLoc_end = 3511585
    | Hs_Uniprot = O60931
    | Mm_EntrezGene = 83429
    | Mm_Ensembl = ENSMUSG00000005949
    | Mm_RefseqmRNA = NM_031251
    | Mm_RefseqProtein = NP_112541
    | Mm_GenLoc_db = 
    | Mm_GenLoc_chr = 11
    | Mm_GenLoc_start = 72999328
    | Mm_GenLoc_end = 73015214
    | Mm_Uniprot = Q3TC99
  }}
}}
'''Cystinosis, nephropathic''', also known as '''CTNS''', is a human [[gene]].<ref name="entrez">{{cite web | title = Entrez Gene: CTNS cystinosis, nephropathic| url = http://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=1497| accessdate = }}</ref>


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Mutations in ''CTNS'' are responsible for [[cystinosis]], an [[Autosome|autosomal]] [[Dominance (genetics)|recessive]] [[lysosomal storage disease]].<ref name="pmid9537412" />
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==References==
== Discovery ==
{{reflist|2}}
In 1995, the gene was localized to the [[Locus (genetics)|short arm]] of chromosome 17.<ref>{{cite journal | vauthors = | title = Linkage of the gene for cystinosis to markers on the short arm of chromosome 17. The Cystinosis Collaborative Research Group | journal = Nature Genetics | volume = 10 | issue = 2 | pages = 246–8 | date = June 1995 | pmid = 7663525 | doi = 10.1038/ng0695-246 }}</ref>  An international collaborative effort finally succeeded in isolating ''CTNS'' by [[Genetic screen|positional cloning]] in 1998.<ref name="pmid9537412">{{cite journal | vauthors = 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 | title = A novel gene encoding an integral membrane protein is mutated in nephropathic cystinosis | journal = Nature Genetics | volume = 18 | issue = 4 | pages = 319–24 | date = April 1998 | pmid = 9537412 | doi = 10.1038/ng0498-319 }}</ref>
==Further reading==
 
{{refbegin | 2}}
== Gene ==
{{PBB_Further_reading
''CTNS'' is located on the [[Locus (genetics)|p arm]] of human [[chromosome]] 17, at position 13.2.<ref name="pmid9537412" /> It spans base pairs 3,636,468 and 3,661,542, and comprises 12 [[Exon|exons]].<ref name="pmid9537412" /><ref name="Shotelersuk_1998">{{cite journal | vauthors = Shotelersuk V, Larson D, Anikster Y, McDowell G, Lemons R, Bernardini I, Guo J, Thoene J, Gahl WA | title = CTNS mutations in an American-based population of cystinosis patients | journal = American Journal of Human Genetics | volume = 63 | issue = 5 | pages = 1352–62 | date = November 1998 | pmid = 9792862 | doi = 10.1086/302118 }}</ref>
| citations =  
 
*{{cite journal  | author=Anikster Y, Shotelersuk V, Gahl WA |title=CTNS mutations in patients with cystinosis. |journal=Hum. Mutat. |volume=14 |issue= 6 |pages= 454-8 |year= 2000 |pmid= 10571941 |doi= 10.1002/(SICI)1098-1004(199912)14:6<454::AID-HUMU2>3.0.CO;2-H }}
== Tissue distribution ==
*{{cite journal  | author=Gahl WA, Thoene JG, Schneider JA |title=Cystinosis. |journal=N. Engl. J. Med. |volume=347 |issue= 2 |pages= 111-21 |year= 2002 |pmid= 12110740 |doi= 10.1056/NEJMra020552 }}
The gene is expressed in the lysosomes of all organs and tissues.<ref name = "Nesterova_2013">{{cite journal | vauthors = Nesterova G, Gahl WA | title = Cystinosis: the evolution of a treatable disease | journal = Pediatric Nephrology | volume = 28 | issue = 1 | pages = 51–9 | date = January 2013 | pmid = 22903658 | doi = 10.1007/s00467-012-2242-5 }}</ref> Cystinosin has also been found in [[Melanosome|melanosomes]] in [[Melanocyte|melanocytes]].<ref name="Chiaverini_2012">{{cite journal | vauthors = 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 | title = Cystinosin is a melanosomal protein that regulates melanin synthesis | journal = FASEB Journal | volume = 26 | issue = 9 | pages = 3779–89 | date = September 2012 | pmid = 22649030 | doi = 10.1096/fj.11-201376 }}</ref>
*{{cite journal | author=Kalatzis V, Antignac C |title=Cystinosis: from gene to disease. |journal=Nephrol. Dial. Transplant. |volume=17 |issue= 11 |pages= 1883-6 |year= 2003 |pmid= 12401840 |doi= }}
 
*{{cite journal | author=Town M, Jean G, Cherqui S, ''et al.'' |title=A novel gene encoding an integral membrane protein is mutated in nephropathic cystinosis. |journal=Nat. Genet. |volume=18 |issue= 4 |pages= 319-24 |year= 1998 |pmid= 9537412 |doi= 10.1038/ng0498-319 }}
== Structure ==
*{{cite journal  | author=Shotelersuk V, Larson D, Anikster Y, ''et al.'' |title=CTNS mutations in an American-based population of cystinosis patients. |journal=Am. J. Hum. Genet. |volume=63 |issue= 5 |pages= 1352-62 |year= 1998 |pmid= 9792862 |doi= }}
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.<ref name="www.tcdb.org">{{Cite web|url=http://www.tcdb.org/|title=Transporter Classification Database|last=|first=|date=2017-10-13|website=www.tcdb.org|archive-url=|archive-date=|dead-url=|access-date=2017-10-13}}</ref> It comprises 367 [[amino acid]] residues, and has a molecular mass of 41738 Da.<ref name="www.tcdb.org" /> Cystinosin has seven N-glycosylation sites in the N-terminus region, spanning a range of 128 amino acid residues.<ref name="Kalatzis_2001">{{cite journal | vauthors = Kalatzis V, Cherqui S, Antignac C, Gasnier B | title = Cystinosin, the protein defective in cystinosis, is a H(+)-driven lysosomal cystine transporter | journal = The EMBO Journal | volume = 20 | issue = 21 | pages = 5940–9 | date = November 2001 | pmid = 11689434 | doi = 10.1093/emboj/20.21.5940 }}</ref>
*{{cite journal  | author=Anikster Y, Lucero C, Touchman JW, ''et al.'' |title=Identification and detection of the common 65-kb deletion breakpoint in the nephropathic cystinosis gene (CTNS). |journal=Mol. Genet. Metab. |volume=66 |issue= 2 |pages= 111-6 |year= 1999 |pmid= 10068513 |doi= 10.1006/mgme.1998.2790 }}
 
*{{cite journal  | author=Thoene J, Lemons R, Anikster Y, ''et al.'' |title=Mutations of CTNS causing intermediate cystinosis. |journal=Mol. Genet. Metab. |volume=67 |issue= 4 |pages= 283-93 |year= 1999 |pmid= 10444339 |doi= 10.1006/mgme.1999.2876 }}
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 [[Alpha helix|α-helix]] moiety.<ref>{{cite journal | vauthors = Andrzejewska Z, Névo N, Thomas L, Bailleux A, Chauvet V, Benmerah A, Antignac C | title = Lysosomal Targeting of Cystinosin Requires AP-3 | journal = Traffic | volume = 16 | issue = 7 | pages = 712–26 | date = July 2015 | pmid = 25753619 | doi = 10.1111/tra.12277 }}</ref>
*{{cite journal  | author=McGowan-Jordan J, Stoddard K, Podolsky L, ''et al.'' |title=Molecular analysis of cystinosis: probable Irish origin of the most common French Canadian mutation. |journal=Eur. J. Hum. Genet. |volume=7 |issue= 6 |pages= 671-8 |year= 1999 |pmid= 10482956 |doi= 10.1038/sj.ejhg.5200349 }}
 
*{{cite journal  | author=Attard M, Jean G, Forestier L, ''et al.'' |title=Severity of phenotype in cystinosis varies with mutations in the CTNS gene: predicted effect on the model of cystinosin. |journal=Hum. Mol. Genet. |volume=8 |issue= 13 |pages= 2507-14 |year= 2000 |pmid= 10556299 |doi= }}
== Mechanism ==
*{{cite journal  | author=Anikster Y, Lucero C, Guo J, ''et al.'' |title=Ocular nonnephropathic cystinosis: clinical, biochemical, and molecular correlations. |journal=Pediatr. Res. |volume=47 |issue= 1 |pages= 17-23 |year= 2000 |pmid= 10625078 |doi=  }}
 
*{{cite journal  | author=Touchman JW, Anikster Y, Dietrich NL, ''et al.'' |title=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. |journal=Genome Res. |volume=10 |issue= 2 |pages= 165-73 |year= 2000 |pmid= 10673275 |doi= }}
The protein obeys [[Michaelis–Menten kinetics|Michaelis-Menton kinetics]] and has an associated K<sub>M</sub> of 278 ± 49 µM.<ref name="Kalatzis_2001" /><ref>{{cite journal | vauthors = Ruivo R, Bellenchi GC, Chen X, Zifarelli G, Sagné C, Debacker C, Pusch M, Supplisson S, Gasnier B | title = Mechanism of proton/substrate coupling in the heptahelical lysosomal transporter cystinosin | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 109 | issue = 5 | pages = E210-7 | date = January 2012 | pmid = 22232659 | doi = 10.1073/pnas.1115581109 }}</ref>
*{{cite journal | author=Cherqui S, Kalatzis V, Forestier L, ''et al.'' |title=Identification and characterisation of the murine homologue of the gene responsible for cystinosis, Ctns. |journal=BMC Genomics |volume=1 |issue= 1 |pages= 2 |year= 2003 |pmid= 11121245 |doi= }}
 
*{{cite journal | author=Cherqui S, Kalatzis V, Trugnan G, Antignac C |title=The targeting of cystinosin to the lysosomal membrane requires a tyrosine-based signal and a novel sorting motif. |journal=J. Biol. Chem. |volume=276 |issue= 16 |pages= 13314-21 |year= 2001 |pmid= 11150305 |doi= 10.1074/jbc.M010562200 }}
== Function ==
*{{cite journal | author=Phornphutkul C, Anikster Y, Huizing M, ''et al.'' |title=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. |journal=Am. J. Hum. Genet. |volume=69 |issue= 4 |pages= 712-21 |year= 2001 |pmid= 11505338 |doi= }}
Cystinosin functions as a [[symporter]] which actively transports protons and [[cystine]], the oxidized [[cysteine]] dimer, out of the [[lysosome]].<ref name="Kalatzis_2001" /> This is necessary to distribute cystine to the rest of the cell and allow the lysosome to continue to function.
*{{cite journal | author=Rupar CA, Matsell D, Surry S, Siu V |title=A G339R mutation in the CTNS gene is a common cause of nephropathic cystinosis in the south western Ontario Amish Mennonite population. |journal=J. Med. Genet. |volume=38 |issue= 9 |pages= 615-6 |year= 2002 |pmid= 11565547 |doi= }}
 
*{{cite journal | author=Kleta R, Anikster Y, Lucero C, ''et al.'' |title=CTNS mutations in African American patients with cystinosis. |journal=Mol. Genet. Metab. |volume=74 |issue= 3 |pages= 332-7 |year= 2002 |pmid= 11708862 |doi= 10.1006/mgme.2001.3218 }}
Cystinosin has also been discovered in melanosomes and has been linked to the control and regulation of [[melanin]].<ref name="Chiaverini_2012" />
*{{cite journal  | author=Kiehntopf M, Schickel J, Gönne B, ''et al.'' |title=Analysis of the CTNS gene in patients of German and Swiss origin with nephropathic cystinosis. |journal=Hum. Mutat. |volume=20 |issue= 3 |pages= 237 |year= 2002 |pmid= 12204010 |doi= 10.1002/humu.9063 }}
 
}}
== Clinical signficance ==
 
=== Cystinosis ===
Mutations in ''CTNS'' can result in cystinosis. [[Cystinosis]] is a type of lysosomal transport disorder, a subset of lysosomal storage disorders.<ref>{{cite journal | vauthors = Mancini GM, Havelaar AC, Verheijen FW | title = Lysosomal transport disorders | journal = Journal of Inherited Metabolic Disease | volume = 23 | issue = 3 | pages = 278–92 | date = May 2000 | pmid = 10863944 | doi = 10.1023/a:1005640214408 }}</ref> Variation in the encoded cystinosin protein results in an inhibition or loss in its ability to transport cysteine out of the lysosome. Cysteine molecules accumulate and form crystals within the lysosome, impairing its function.<ref name = "Nesterova_2013" />
 
=== Mutations ===
Cystinosis is presented in patients with a range of ''CTNS'' mutations; as of 2017, over 100 have been identified.<ref>{{cite journal | vauthors = Doneray H, Aldahmesh M, Yilmaz G, Cinici E, Orbak Z | title = Infantile Nephropathic Cystinosis: A Novel CTNS Mutation | journal = The Eurasian Journal of Medicine | volume = 49 | issue = 2 | pages = 148–151 | date = June 2017 | pmid = 28638260 | doi = 10.5152/eurasianjmed.2017.17039 }}</ref><ref>{{cite journal | vauthors = Owen EP, Nandhlal J, Leisegang F, Van der Watt G, Nourse P, Gajjar P | title = Common mutation causes cystinosis in the majority of black South African patients | journal = Pediatric Nephrology | volume = 30 | issue = 4 | pages = 595–601 | date = April 2015 | pmid = 25326109 | doi = 10.1007/s00467-014-2980-7 }}</ref> 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.<ref>{{cite journal | vauthors = Touchman JW, Anikster Y, Dietrich NL, Maduro VV, McDowell G, Shotelersuk V, Bouffard GG, Beckstrom-Sternberg SM, Gahl WA, Green ED | title = 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 | journal = Genome Research | volume = 10 | issue = 2 | pages = 165–73 | date = February 2000 | pmid = 10673275 | doi = 10.1101/gr.10.2.165 }}</ref><ref>{{cite journal | vauthors = Anikster Y, Lucero C, Touchman JW, Huizing M, McDowell G, Shotelersuk V, Green ED, Gahl WA | title = Identification and detection of the common 65-kb deletion breakpoint in the nephropathic cystinosis gene (CTNS) | journal = Molecular Genetics and Metabolism | volume = 66 | issue = 2 | pages = 111–6 | date = February 1999 | pmid = 10068513 | doi = 10.1006/mgme.1998.2790 }}</ref> Other reported mutations include other deletions, missense mutations, and in-frame deletions and insertions.<ref name = "Kalatzis_2004">{{cite journal | vauthors = Kalatzis V, Nevo N, Cherqui S, Gasnier B, Antignac C | title = Molecular pathogenesis of cystinosis: effect of CTNS mutations on the transport activity and subcellular localization of cystinosin | journal = Human Molecular Genetics | volume = 13 | issue = 13 | pages = 1361–71 | date = July 2004 | pmid = 15128704 | doi = 10.1093/hmg/ddh152 }}</ref><ref>{{cite journal | vauthors = Tang S, Danda S, Zoleikhaeian M, Simon M, Huang T | title = An Indian boy with nephropathic cystinosis: a case report and molecular analysis of CTNS mutation | journal = Genetic Testing and Molecular Biomarkers | volume = 13 | issue = 4 | pages = 435–8 | date = August 2009 | pmid = 19580442 | doi = 10.1089/gtmb.2008.0156 }}</ref>
 
The type and extent of mutation determines the type and severity of cystinosis in the carrier.<ref>{{cite journal | vauthors = Attard M, Jean G, Forestier L, Cherqui S, van't Hoff W, Broyer M, Antignac C, Town M | title = Severity of phenotype in cystinosis varies with mutations in the CTNS gene: predicted effect on the model of cystinosin | journal = Human Molecular Genetics | volume = 8 | issue = 13 | pages = 2507–14 | date = December 1999 | pmid = 10556299 | doi = 10.1093/hmg/8.13.2507 }}</ref> This is a result of the degree of transport inhibition caused by the misfolding of cystinosin.<ref name = "Kalatzis_2004" /> For example, mild cystinosis is typically associated with mutations that do not affect the amino acids in the transmembrane domains of cystinosin.<ref name="Shotelersuk_1998" /> In contrast, infantile nephropathic cystinosis, the most severe form of the disease, is most commonly associated with a total loss of activity.<ref name = "Kalatzis_2004" />
 
Gene deletion resulting in the absence of either of the sorting motifs results in the delocalization of cystinosin to the cellular plasma membrane.<ref>{{cite journal | vauthors = Cherqui S, Kalatzis V, Trugnan G, Antignac C | title = The targeting of cystinosin to the lysosomal membrane requires a tyrosine-based signal and a novel sorting motif | journal = The Journal of Biological Chemistry | volume = 276 | issue = 16 | pages = 13314–21 | date = April 2001 | pmid = 11150305 | doi = 10.1074/jbc.m010562200 }}</ref><ref name="Kalatzis_2001" />
 
== Model systems ==
Human models for cystinosin are typically derived from cystinotic [[Nephron|renal tubular]] cell lines.<ref>{{cite journal | vauthors = Racusen LC, Wilson PD, Hartz PA, Fivush BA, Burrow CR | title = Renal proximal tubular epithelium from patients with nephropathic cystinosis: immortalized cell lines as in vitro model systems | journal = Kidney International | volume = 48 | issue = 2 | pages = 536–43 | date = August 1995 | pmid = 7564123 }}</ref><ref>{{cite journal | vauthors = Taub ML, Springate JE, Cutuli F | title = Reduced phosphate transport in the renal proximal tubule cells in cystinosis is due to decreased expression of transporters rather than an energy defect | journal = Biochemical and Biophysical Research Communications | volume = 407 | issue = 2 | pages = 355–9 | date = April 2011 | pmid = 21392501 | doi = 10.1016/j.bbrc.2011.03.022 }}</ref>
 
Non-human protein [[Homology (biology)|homologs]] for cystinosin include ERS1 in ''Saccharomyces cerevisiae'' (yeast cells) and the ''Caenorhabditis elegans'' protein, C41C4.7.<ref>{{cite journal | vauthors = Gao XD, Wang J, Keppler-Ross S, Dean N | title = ERS1 encodes a functional homologue of the human lysosomal cystine transporter | journal = The FEBS Journal | volume = 272 | issue = 10 | pages = 2497–511 | date = May 2005 | pmid = 15885099 | doi = 10.1111/j.1742-4658.2005.04670.x }}</ref> Murine ctns has also been used.<ref>{{cite journal | vauthors = Cherqui S, Sevin C, Hamard G, Kalatzis V, Sich M, Pequignot MO, Gogat K, Abitbol M, Broyer M, Gubler MC, Antignac C | title = Intralysosomal cystine accumulation in mice lacking cystinosin, the protein defective in cystinosis | journal = Molecular and Cellular Biology | volume = 22 | issue = 21 | pages = 7622–32 | date = November 2002 | pmid = 12370309 | doi = 10.1128/MCB.22.21.7622-7632.2002 }}</ref>
 
== See also ==
* [[Cystinosis]]
* [[Lysosomal storage disease|Lysosomal storage disorders]]
* [[Lysosomal cystine transporter family|Lysosomal Cystine Transporter Family]]
 
== References ==
{{Reflist|33em}}
 
== Further reading ==
{{refbegin|33em}}
* {{cite journal | vauthors = Anikster Y, Shotelersuk V, Gahl WA | title = CTNS mutations in patients with cystinosis | journal = Human Mutation | volume = 14 | issue = 6 | pages = 454–8 | year = 2000 | pmid = 10571941 | doi = 10.1002/(SICI)1098-1004(199912)14:6<454::AID-HUMU2>3.0.CO;2-H }}
* {{cite journal | vauthors = Gahl WA, Thoene JG, Schneider JA | title = Cystinosis | journal = The New England Journal of Medicine | volume = 347 | issue = 2 | pages = 111–21 | date = July 2002 | pmid = 12110740 | doi = 10.1056/NEJMra020552 }}
* {{cite journal | vauthors = Kalatzis V, Antignac C | title = Cystinosis: from gene to disease | journal = Nephrology, Dialysis, Transplantation | volume = 17 | issue = 11 | pages = 1883–6 | date = November 2002 | pmid = 12401840 | doi = 10.1093/ndt/17.11.1883 }}
* {{cite journal | vauthors = Thoene J, Lemons R, Anikster Y, Mullet J, Paelicke K, Lucero C, Gahl W, Schneider J, Shu SG, Campbell HT | title = Mutations of CTNS causing intermediate cystinosis | journal = Molecular Genetics and Metabolism | volume = 67 | issue = 4 | pages = 283–93 | date = August 1999 | pmid = 10444339 | doi = 10.1006/mgme.1999.2876 }}
* {{cite journal | vauthors = McGowan-Jordan J, Stoddard K, Podolsky L, Orrbine E, McLaine P, Town M, Goodyer P, MacKenzie A, Heick H | title = Molecular analysis of cystinosis: probable Irish origin of the most common French Canadian mutation | journal = European Journal of Human Genetics | volume = 7 | issue = 6 | pages = 671–8 | date = September 1999 | pmid = 10482956 | doi = 10.1038/sj.ejhg.5200349 }}
* {{cite journal | vauthors = 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 | title = Ocular nonnephropathic cystinosis: clinical, biochemical, and molecular correlations | journal = Pediatric Research | volume = 47 | issue = 1 | pages = 17–23 | date = January 2000 | pmid = 10625078 | doi = 10.1203/00006450-200001000-00007 }}
* {{cite journal | vauthors = Cherqui S, Kalatzis V, Forestier L, Poras I, Antignac C | title = Identification and characterisation of the murine homologue of the gene responsible for cystinosis, Ctns | journal = BMC Genomics | volume = 1 | pages = 2 | year = 2003 | pmid = 11121245 | pmc = 29086 | doi = 10.1186/1471-2164-1-2 }}
* {{cite journal | vauthors = Phornphutkul C, Anikster Y, Huizing M, Braun P, Brodie C, Chou JY, Gahl WA | title = 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 | journal = American Journal of Human Genetics | volume = 69 | issue = 4 | pages = 712–21 | date = October 2001 | pmid = 11505338 | pmc = 1226058 | doi = 10.1086/323484 }}
* {{cite journal | vauthors = Rupar CA, Matsell D, Surry S, Siu V | title = A G339R mutation in the CTNS gene is a common cause of nephropathic cystinosis in the south western Ontario Amish Mennonite population | journal = Journal of Medical Genetics | volume = 38 | issue = 9 | pages = 615–6 | date = September 2001 | pmid = 11565547 | pmc = 1734937 | doi = 10.1136/jmg.38.9.615 }}
* {{cite journal | vauthors = Kleta R, Anikster Y, Lucero C, Shotelersuk V, Huizing M, Bernardini I, Park M, Thoene J, Schneider J, Gahl WA | title = CTNS mutations in African American patients with cystinosis | journal = Molecular Genetics and Metabolism | volume = 74 | issue = 3 | pages = 332–7 | date = November 2001 | pmid = 11708862 | doi = 10.1006/mgme.2001.3218 }}
* {{cite journal | vauthors = Kiehntopf M, Schickel J, Gönne B, Koch HG, Superti-Furga A, Steinmann B, Deufel T, Harms E | title = Analysis of the CTNS gene in patients of German and Swiss origin with nephropathic cystinosis | journal = Human Mutation | volume = 20 | issue = 3 | pages = 237 | date = September 2002 | pmid = 12204010 | doi = 10.1002/humu.9063 }}
{{refend}}
{{refend}}


{{protein-stub}}
== External links ==
{{WikiDoc Sources}}
* [https://www.ncbi.nlm.nih.gov/bookshelf/br.fcgi?book=gene&part=ctns GeneReviews/NCBI/NIH/UW entry on Cystinosis]
* {{UCSC gene info|CTNS}}
* [https://ghr.nlm.nih.gov/gene/CTNS# Genetics Home Reference] page on ''CTNS''.
* [https://ghr.nlm.nih.gov/condition/cystinosis#diagnosis Genetic Testing Registry].

Revision as of 04:30, 30 October 2017

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

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View/Edit Human

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.

Mutations in CTNS are responsible for cystinosis, an autosomal recessive lysosomal storage disease.[1]

Discovery

In 1995, the gene was localized to the short arm of chromosome 17.[2] An international collaborative effort finally succeeded in isolating CTNS by positional cloning in 1998.[1]

Gene

CTNS is located on the p arm of human chromosome 17, at position 13.2.[1] It spans base pairs 3,636,468 and 3,661,542, and comprises 12 exons.[1][3]

Tissue distribution

The gene is expressed in the lysosomes of all organs and tissues.[4] Cystinosin has also been found in melanosomes in melanocytes.[5]

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.[6] It comprises 367 amino acid residues, and has a molecular mass of 41738 Da.[6] Cystinosin has seven N-glycosylation sites in the N-terminus region, spanning a range of 128 amino acid residues.[7]

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.[8]

Mechanism

The protein obeys Michaelis-Menton kinetics and has an associated KM of 278 ± 49 µM.[7][9]

Function

Cystinosin functions as a symporter which actively transports protons and cystine, the oxidized cysteine dimer, out of the lysosome.[7] This is necessary to distribute cystine to the rest of the cell and allow the lysosome to continue to function.

Cystinosin has also been discovered in melanosomes and has been linked to the control and regulation of melanin.[5]

Clinical signficance

Cystinosis

Mutations in CTNS can result in cystinosis. Cystinosis is a type of lysosomal transport disorder, a subset of lysosomal storage disorders.[10] Variation in the encoded cystinosin protein results in an inhibition or loss in its ability to transport cysteine out of the lysosome. Cysteine molecules accumulate and form crystals within the lysosome, impairing its function.[4]

Mutations

Cystinosis is presented in patients with a range of CTNS mutations; as of 2017, over 100 have been identified.[11][12] 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.[13][14] Other reported mutations include other deletions, missense mutations, and in-frame deletions and insertions.[15][16]

The type and extent of mutation determines the type and severity of cystinosis in the carrier.[17] This is a result of the degree of transport inhibition caused by the misfolding of cystinosin.[15] 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.[15]

Gene deletion resulting in the absence of either of the sorting motifs results in the delocalization of cystinosin to the cellular plasma membrane.[18][7]

Model systems

Human models for cystinosin are typically derived from cystinotic renal tubular cell lines.[19][20]

Non-human protein homologs for cystinosin include ERS1 in Saccharomyces cerevisiae (yeast cells) and the Caenorhabditis elegans protein, C41C4.7.[21] Murine ctns has also been used.[22]

See also

References

  1. ↑ 1.0 1.1 1.2 1.3 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 (April 1998). "A novel gene encoding an integral membrane protein is mutated in nephropathic cystinosis". Nature Genetics. 18 (4): 319–24. doi:10.1038/ng0498-319. PMID 9537412.
  2. ↑ "Linkage of the gene for cystinosis to markers on the short arm of chromosome 17. The Cystinosis Collaborative Research Group". Nature Genetics. 10 (2): 246–8. June 1995. doi:10.1038/ng0695-246. PMID 7663525.
  3. ↑ 3.0 3.1 Shotelersuk V, Larson D, Anikster Y, McDowell G, Lemons R, Bernardini I, Guo J, Thoene J, Gahl WA (November 1998). "CTNS mutations in an American-based population of cystinosis patients". American Journal of Human Genetics. 63 (5): 1352–62. doi:10.1086/302118. PMID 9792862.
  4. ↑ 4.0 4.1 Nesterova G, Gahl WA (January 2013). "Cystinosis: the evolution of a treatable disease". Pediatric Nephrology. 28 (1): 51–9. doi:10.1007/s00467-012-2242-5. PMID 22903658.
  5. ↑ 5.0 5.1 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 (September 2012). "Cystinosin is a melanosomal protein that regulates melanin synthesis". FASEB Journal. 26 (9): 3779–89. doi:10.1096/fj.11-201376. PMID 22649030.
  6. ↑ 6.0 6.1 "Transporter Classification Database". www.tcdb.org. 2017-10-13. Retrieved 2017-10-13.
  7. ↑ 7.0 7.1 7.2 7.3 Kalatzis V, Cherqui S, Antignac C, Gasnier B (November 2001). "Cystinosin, the protein defective in cystinosis, is a H(+)-driven lysosomal cystine transporter". The EMBO Journal. 20 (21): 5940–9. doi:10.1093/emboj/20.21.5940. PMID 11689434.
  8. ↑ Andrzejewska Z, Névo N, Thomas L, Bailleux A, Chauvet V, Benmerah A, Antignac C (July 2015). "Lysosomal Targeting of Cystinosin Requires AP-3". Traffic. 16 (7): 712–26. doi:10.1111/tra.12277. PMID 25753619.
  9. ↑ Ruivo R, Bellenchi GC, Chen X, Zifarelli G, Sagné C, Debacker C, Pusch M, Supplisson S, Gasnier B (January 2012). "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): E210–7. doi:10.1073/pnas.1115581109. PMID 22232659.
  10. ↑ Mancini GM, Havelaar AC, Verheijen FW (May 2000). "Lysosomal transport disorders". Journal of Inherited Metabolic Disease. 23 (3): 278–92. doi:10.1023/a:1005640214408. PMID 10863944.
  11. ↑ Doneray H, Aldahmesh M, Yilmaz G, Cinici E, Orbak Z (June 2017). "Infantile Nephropathic Cystinosis: A Novel CTNS Mutation". The Eurasian Journal of Medicine. 49 (2): 148–151. doi:10.5152/eurasianjmed.2017.17039. PMID 28638260.
  12. ↑ Owen EP, Nandhlal J, Leisegang F, Van der Watt G, Nourse P, Gajjar P (April 2015). "Common mutation causes cystinosis in the majority of black South African patients". Pediatric Nephrology. 30 (4): 595–601. doi:10.1007/s00467-014-2980-7. PMID 25326109.
  13. ↑ Touchman JW, Anikster Y, Dietrich NL, Maduro VV, McDowell G, Shotelersuk V, Bouffard GG, Beckstrom-Sternberg SM, Gahl WA, Green ED (February 2000). "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): 165–73. doi:10.1101/gr.10.2.165. PMID 10673275.
  14. ↑ Anikster Y, Lucero C, Touchman JW, Huizing M, McDowell G, Shotelersuk V, Green ED, Gahl WA (February 1999). "Identification and detection of the common 65-kb deletion breakpoint in the nephropathic cystinosis gene (CTNS)". Molecular Genetics and Metabolism. 66 (2): 111–6. doi:10.1006/mgme.1998.2790. PMID 10068513.
  15. ↑ 15.0 15.1 15.2 Kalatzis V, Nevo N, Cherqui S, Gasnier B, Antignac C (July 2004). "Molecular pathogenesis of cystinosis: effect of CTNS mutations on the transport activity and subcellular localization of cystinosin". Human Molecular Genetics. 13 (13): 1361–71. doi:10.1093/hmg/ddh152. PMID 15128704.
  16. ↑ Tang S, Danda S, Zoleikhaeian M, Simon M, Huang T (August 2009). "An Indian boy with nephropathic cystinosis: a case report and molecular analysis of CTNS mutation". Genetic Testing and Molecular Biomarkers. 13 (4): 435–8. doi:10.1089/gtmb.2008.0156. PMID 19580442.
  17. ↑ Attard M, Jean G, Forestier L, Cherqui S, van't Hoff W, Broyer M, Antignac C, Town M (December 1999). "Severity of phenotype in cystinosis varies with mutations in the CTNS gene: predicted effect on the model of cystinosin". Human Molecular Genetics. 8 (13): 2507–14. doi:10.1093/hmg/8.13.2507. PMID 10556299.
  18. ↑ Cherqui S, Kalatzis V, Trugnan G, Antignac C (April 2001). "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): 13314–21. doi:10.1074/jbc.m010562200. PMID 11150305.
  19. ↑ Racusen LC, Wilson PD, Hartz PA, Fivush BA, Burrow CR (August 1995). "Renal proximal tubular epithelium from patients with nephropathic cystinosis: immortalized cell lines as in vitro model systems". Kidney International. 48 (2): 536–43. PMID 7564123.
  20. ↑ Taub ML, Springate JE, Cutuli F (April 2011). "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): 355–9. doi:10.1016/j.bbrc.2011.03.022. PMID 21392501.
  21. ↑ Gao XD, Wang J, Keppler-Ross S, Dean N (May 2005). "ERS1 encodes a functional homologue of the human lysosomal cystine transporter". The FEBS Journal. 272 (10): 2497–511. doi:10.1111/j.1742-4658.2005.04670.x. PMID 15885099.
  22. ↑ Cherqui S, Sevin C, Hamard G, Kalatzis V, Sich M, Pequignot MO, Gogat K, Abitbol M, Broyer M, Gubler MC, Antignac C (November 2002). "Intralysosomal cystine accumulation in mice lacking cystinosin, the protein defective in cystinosis". Molecular and Cellular Biology. 22 (21): 7622–32. doi:10.1128/MCB.22.21.7622-7632.2002. PMID 12370309.

Further reading

External links

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