CTNS
CTNS je gen koji kod ljudi kodira protein cistinozin. Cistinozin je lizosomski sedmotransmembranski protein koji funkcionira kao aktivni transporter za iznošenje molekula cistina iz lizosoma.
Mutacije u CTNS odgovorne su za cistinozu, autosomno recesivnu bolest lizosomskog skladištenja.
Otkriće
urediGodine 1995. gen je lokaliziran na kratkom kraku hromosoma 17.[5] Međunarodni zajednički napor konačno je uspio izolirati CTNS pozicijskim kloniranjem 1998.[6]
Gen
urediCTNS se nalazi na p-kraku ljudskog hromozoma 17, na poziciji 13.2.[6] Obuhvata parove baza između 3,636.468 i 3,661.542, i sadrži 12 egzona.[6][7]
Tkivna distribucija
urediGen se eksprimira u lizosomima svih organa i tkiva.[8] Cistinozin je također pronađen u melanosomima melanocita.[9]
Struktura
urediDužina polipeptidnog lanca je 367 aminokiselina, a molekulska težina 41.738 Da.[10]
Aminokiselinska sekvenca
| 10 | 20 | 30 | 40 | 50 | ||||
|---|---|---|---|---|---|---|---|---|
| MIRNWLTIFI | LFPLKLVEKC | ESSVSLTVPP | VVKLENGSST | NVSLTLRPPL | ||||
| NATLVITFEI | TFRSKNITIL | ELPDEVVVPP | GVTNSSFQVT | SQNVGQLTVY | ||||
| LHGNHSNQTG | PRIRFLVIRS | SAISIINQVI | GWIYFVAWSI | SFYPQVIMNW | ||||
| RRKSVIGLSF | DFVALNLTGF | VAYSVFNIGL | LWVPYIKEQF | LLKYPNGVNP | ||||
| VNSNDVFFSL | HAVVLTLIII | VQCCLYERGG | QRVSWPAIGF | LVLAWLFAFV | ||||
| TMIVAAVGVT | TWLQFLFCFS | YIKLAVTLVK | YFPQAYMNFY | YKSTEGWSIG | ||||
| NVLLDFTGGS | FSLLQMFLQS | YNNDQWTLIF | GDPTKFGLGV | FSIVFDVVFF | ||||
| IQHFCLYRKR | PGYDQLN |
- Simboli
C: Cistein
D: Asparaginska kiselina
E: Glutaminska kiselina
F: Fenilalanin
G: Glicin
H: Histidin
I: Izoleucin
K: Lizin
L: Leucin
M: Metionin
N: Asparagin
P: Prolin
Q: Glutamin
R: Arginin
S: Serin
T: Treonin
V: Valin
W: Triptofan
Y: Tirozin
Cistinozin je receptor sa sedam transmembranskih domena ugrađen u lizosomsku membranu i član je porodice lizosomskih cistinskih transportnih proteina.[11] Sadrži 367 aminokiselinskih ostataka i ima molekulsku masu od 41738 Da.[11] Cistinosin ima sedam mesta N-glikozilacije u N-krajnjem području, a obuhvata raspon od 128 aminokiselinskih ostataka.[12]
Receptor također ima dva motiva sortiranja; GYDQL motiv u regiji C-kraja i YFPQA motiv, poznat kao 'PQ petlja', na petom međutransmembranskom α-heliksnom dijelu.[13]
Mehanizam
urediProtein se ponaša po pravilima Michaelis-Mentenove kinetike i ima pridruženi KM of 278 ± 49 μM.[12][14]
Funkcija
urediCistinozin funkcionira kao simporter koji aktivno transportuje protone i cistin, oksidirani cisteinski dimer, iz lizosoma.[12] To je neophodno za distribuciju cistina u ostatak ćelije i omogućavanje lizosumu da nastavi s radom.
Cistinosin je također otkriven u melanosomima i povezan je sa kontrolom i regulacijom melanina.[9]
Klinički značaj
urediCistinoza
urediMutacije u CTNS mogu rezultirati cistinozom. Cistinoza je oblik poremećaja transporta lizosoma, podskup poremećaja skladištenja lizosoma.[15] Varijacije kodiranog cistinozinskog proteina rezultiraju inhibicijom ili gubitkom njegove sposobnosti da transportuje cistin iz lizosoma. Molekule cistina se akumuliraju i stvaraju kristale unutar lizosoma, narušavajući njegovu funkciju.[8]
Mutacije
urediCistinoza je prisutna kod pacijenata s nizom mutacija CTNS; od 2017. identificirano ih je preko 100.[16][17] Najčešća je mutacija delecije 57.257 baznis parova, koja se obično naziva dlecijom 57 kb. To je formalno bilo poznato kao delecija od 65 kb; pogrešan naziv koji potiče iz ranih netačnih procjena.[18][19] Ostale prijavljene mutacije uključuju drugwe delecije, misens mutacije, okvirne delecije i insercije.[20][21]
Tip i opseg mutacije određuju oblik i težinu cistinoze kod nositelja.[22] Ovo je rezultat stupnja inhibicije transporta, uzrokovanog pogrešnim savijanjem cistinozina.[20] Naprimjer, blaga cistinoza tipski je povezana s mutacijama koje ne utiču na aminokiseline u transmembranskim domenima cistinozina.[7] Suprotno tome, dječja nefropatska cistinoza, najteži oblik bolesti, najčešće je povezana s ukupnim gubitkom aktivnosti.[20]
Delecija gena koja rezultira odsustvom bilo kojeg motiva sortiranja rezultira delokalizacijom cistinozina u ćelijskoj plazmamembrani.[12][23]
Modelni sistemi
urediLjudski modeli za cistinozin obično su izvedeni iz ćelijskih linija cistinotskih bubrežnih tubula.[24][25] Ne-ljudski proteinski homolozi za cistinozin uključuju ERS1 u Saccharomyces cerevisiae (ćelije kvasaca) i protein Caenorhabditis elegans, C41C4.7.[26] Korišteni su i mišji ctns.[27]
Također pogledajte
urediReference
uredi- ^ a b c GRCh38: Ensembl release 89: ENSG00000040531 - Ensembl, maj 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000005949 - Ensembl, maj 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ McDowell GA, Gahl WA, Stephenson LA, Schneider JA, Weissenbach J, Polymeropoulos MH, Town MM, William, Hoff T, Farrall M, Mathew CG (juni 1995). "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. doi:10.1038/ng0695-246. PMID 7663525. S2CID 22093385.
- ^ a b c 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. S2CID 10629789.
- ^ a b Shotelersuk V, Larson D, Anikster Y, McDowell G, Lemons R, Bernardini I, Guo J, Thoene J, Gahl WA (novembar 1998). "CTNS mutations in an American-based population of cystinosis patients". American Journal of Human Genetics. 63 (5): 1352–62. doi:10.1086/302118. PMC 1377545. PMID 9792862.
- ^ a b Nesterova G, Gahl WA (januar 2013). "Cystinosis: the evolution of a treatable disease". Pediatric Nephrology. 28 (1): 51–9. doi:10.1007/s00467-012-2242-5. PMC 3505515. PMID 22903658.
- ^ a b 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 (septembar 2012). "Cystinosin is a melanosomal protein that regulates melanin synthesis". FASEB Journal. 26 (9): 3779–89. doi:10.1096/fj.11-201376. PMID 22649030. S2CID 11334825.
- ^ "UniProt, O60931". Pristupljeno 16. 6. 2021.
- ^ a b "Transporter Classification Database". www.tcdb.org. 13. 10. 2017. Arhivirano s originala, 3. 1. 2014. Pristupljeno 13. 10. 2017.
- ^ a b c d Kalatzis V, Cherqui S, Antignac C, Gasnier B (novembar 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. PMC 125690. PMID 11689434.
- ^ Andrzejewska Z, Névo N, Thomas L, Bailleux A, Chauvet V, Benmerah A, Antignac C (juli 2015). "Lysosomal Targeting of Cystinosin Requires AP-3". Traffic. 16 (7): 712–26. doi:10.1111/tra.12277. PMID 25753619.
- ^ Ruivo R, Bellenchi GC, Chen X, Zifarelli G, Sagné C, Debacker C, Pusch M, Supplisson S, Gasnier B (januar 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. PMC 3277178. PMID 22232659.
- ^ Mancini GM, Havelaar AC, Verheijen FW (maj 2000). "Lysosomal transport disorders". Journal of Inherited Metabolic Disease. 23 (3): 278–92. doi:10.1023/a:1005640214408. PMID 10863944. S2CID 19489712.
- ^ Doneray H, Aldahmesh M, Yilmaz G, Cinici E, Orbak Z (juni 2017). "Infantile Nephropathic Cystinosis: A Novel CTNS Mutation". The Eurasian Journal of Medicine. 49 (2): 148–151. doi:10.5152/eurasianjmed.2017.17039. PMC 5469843. PMID 28638260.
- ^ 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. S2CID 22240586.
- ^ Touchman JW, Anikster Y, Dietrich NL, Maduro VV, McDowell G, Shotelersuk V, Bouffard GG, Beckstrom-Sternberg SM, Gahl WA, Green ED (februar 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. PMC 310836. PMID 10673275.
- ^ Anikster Y, Lucero C, Touchman JW, Huizing M, McDowell G, Shotelersuk V, Green ED, Gahl WA (februar 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.
- ^ a b c Kalatzis V, Nevo N, Cherqui S, Gasnier B, Antignac C (juli 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.
- ^ 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.
- ^ Attard M, Jean G, Forestier L, Cherqui S, van't Hoff W, Broyer M, Antignac C, Town M (decembar 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.
- ^ 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.
- ^ 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. doi:10.1038/ki.1995.324. PMID 7564123.
- ^ 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.
- ^ Gao XD, Wang J, Keppler-Ross S, Dean N (maj 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. S2CID 13035448.
- ^ Cherqui S, Sevin C, Hamard G, Kalatzis V, Sich M, Pequignot MO, Gogat K, Abitbol M, Broyer M, Gubler MC, Antignac C (novembar 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. PMC 135682. PMID 12370309.
Dopunska literatura
uredi- Anikster Y, Shotelersuk V, Gahl WA (2000). "CTNS mutations in patients with cystinosis". Human Mutation. 14 (6): 454–8. doi:10.1002/(SICI)1098-1004(199912)14:6<454::AID-HUMU2>3.0.CO;2-H. PMID 10571941.
- Gahl WA, Thoene JG, Schneider JA (juli 2002). "Cystinosis". The New England Journal of Medicine. 347 (2): 111–21. doi:10.1056/NEJMra020552. PMID 12110740.
- Kalatzis V, Antignac C (novembar 2002). "Cystinosis: from gene to disease". Nephrology, Dialysis, Transplantation. 17 (11): 1883–6. doi:10.1093/ndt/17.11.1883. PMID 12401840.
- Thoene J, Lemons R, Anikster Y, Mullet J, Paelicke K, Lucero C, Gahl W, Schneider J, Shu SG, Campbell HT (august 1999). "Mutations of CTNS causing intermediate cystinosis". Molecular Genetics and Metabolism. 67 (4): 283–93. doi:10.1006/mgme.1999.2876. PMID 10444339.
- McGowan-Jordan J, Stoddard K, Podolsky L, Orrbine E, McLaine P, Town M, Goodyer P, MacKenzie A, Heick H (septembar 1999). "Molecular analysis of cystinosis: probable Irish origin of the most common French Canadian mutation". European Journal of Human Genetics. 7 (6): 671–8. doi:10.1038/sj.ejhg.5200349. PMID 10482956.
- 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 (januar 2000). "Ocular nonnephropathic cystinosis: clinical, biochemical, and molecular correlations". Pediatric Research. 47 (1): 17–23. doi:10.1203/00006450-200001000-00007. PMID 10625078.
- Cherqui S, Kalatzis V, Forestier L, Poras I, Antignac C (2003). "Identification and characterisation of the murine homologue of the gene responsible for cystinosis, Ctns". BMC Genomics. 1: 2. doi:10.1186/1471-2164-1-2. PMC 29086. PMID 11121245.
- Phornphutkul C, Anikster Y, Huizing M, Braun P, Brodie C, Chou JY, Gahl WA (oktobar 2001). "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): 712–21. doi:10.1086/323484. PMC 1226058. PMID 11505338.
- Rupar CA, Matsell D, Surry S, Siu V (septembar 2001). "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): 615–6. doi:10.1136/jmg.38.9.615. PMC 1734937. PMID 11565547.
- Kleta R, Anikster Y, Lucero C, Shotelersuk V, Huizing M, Bernardini I, Park M, Thoene J, Schneider J, Gahl WA (novembar 2001). "CTNS mutations in African American patients with cystinosis". Molecular Genetics and Metabolism. 74 (3): 332–7. doi:10.1006/mgme.2001.3218. PMID 11708862.
- Kiehntopf M, Schickel J, Gönne B, Koch HG, Superti-Furga A, Steinmann B, Deufel T, Harms E (septembar 2002). "Analysis of the CTNS gene in patients of German and Swiss origin with nephropathic cystinosis". Human Mutation. 20 (3): 237. doi:10.1002/humu.9063. PMID 12204010. S2CID 25080378.
Vanjski linkovi
uredi- GeneReviews/NCBI/NIH/UW entry on Cystinosis
- Lokacija ljudskog genoma CTNS i stranica sa detaljima o genu CTNS u UCSC Genome Browseru.
- Genetics Home Reference page on CTNS.
- Genetic Testing Registry.