DTDST
Sulfatni transporter, član porodice rastvornih nosača, jest protein koji je kod ljudi kodiran genom SLC26A2.[5] SLC26A2 se naziva i transporter sulfata (DTDST) dijastrofijske displazije, a prvi su ga opisali Hästbacka et sl. u 1994.[5] Ovaj transporter sulfata (SO42–) kao podloge također prihvata hlorid, hidroksilne ione (OH–) i oksalat.[6][7] SLC26A2 se eksprimira u visokim nivoima u razvoju i zrelim hrskavicama, kao i u plućima, posteljici, debelom crijevu, bubrezima, gušterači i sjemenicima.[8][9]
Aminokiselinska sekvenca
[uredi | uredi izvor]Dužina polipeptidnog lanca je 739 aminokiselina, а molekulska težina 81.662 Da.[10]
10 | 20 | 30 | 40 | 50 | ||||
---|---|---|---|---|---|---|---|---|
MSSESKEQHN | VSPRDSAEGN | DSYPSGIHLE | LQRESSTDFK | QFETNDQCRP | ||||
YHRILIERQE | KSDTNFKEFV | IKKLQKNCQC | SPAKAKNMIL | GFLPVLQWLP | ||||
KYDLKKNILG | DVMSGLIVGI | LLVPQSIAYS | LLAGQEPVYG | LYTSFFASII | ||||
YFLLGTSRHI | SVGIFGVLCL | MIGETVDREL | QKAGYDNAHS | APSLGMVSNG | ||||
STLLNHTSDR | ICDKSCYAIM | VGSTVTFIAG | VYQVAMGFFQ | VGFVSVYLSD | ||||
ALLSGFVTGA | SFTILTSQAK | YLLGLNLPRT | NGVGSLITTW | IHVFRNIHKT | ||||
NLCDLITSLL | CLLVLLPTKE | LNEHFKSKLK | APIPIELVVV | VAATLASHFG | ||||
KLHENYNSSI | AGHIPTGFMP | PKVPEWNLIP | SVAVDAIAIS | IIGFAITVSL | ||||
SEMFAKKHGY | TVKANQEMYA | IGFCNIIPSF | FHCFTTSAAL | AKTLVKESTG | ||||
CHTQLSGVVT | ALVLLLVLLV | IAPLFYSLQK | SVLGVITIVN | LRGALRKFRD | ||||
LPKMWSISRM | DTVIWFVTML | SSALLSTEIG | LLVGVCFSIF | CVILRTQKPK | ||||
SSLLGLVEES | EVFESVSAYK | NLQIKPGIKI | FRFVAPLYYI | NKECFKSALY | ||||
KQTVNPILIK | VAWKKAAKRK | IKEKVVTLGG | IQDEMSVQLS | HDPLELHTIV | ||||
IDCSAIQFLD | TAGIHTLKEV | RRDYEAIGIQ | VLLAQCNPTV | RDSLTNGEYC | ||||
KKEEENLLFY | SVYEAMAFAE | VSKNQKGVCV | PNGLSLSSD |
Funkcija
[uredi | uredi izvor]Sulfatni transporter distrodfijske displazije je transmembranski glikoprotein uključen u patogenezu nekoliko ljudskih hondrodisplazija. U hondrocitima SLC26A2 funkcionira tako kao transportr većine ćelijskog sulfata, koji je kritičan za sulfatizaciju proteoglikana i normalno stvaranje hrskavice.[11] Osim toga, studije su pokazale da SLC26A2 utiče na proliferaciju, diferencijaciju i rast hondrocita, sugerirajući da u hondrocitu SLC26A2 daje sulfat i za strukturne i za regulatorne proteine.[12]
Klinički značaj
[uredi | uredi izvor]Nedostaci su povezani s mnogim oblicima osteohondrodisplazija.[9] These include:
- ahondrogeneza tip 1B
- dijastrofijska displazija
- atelosteogeneza, tip II
- recesivna multipla epifizna displazija
Korelacija između genotipa i fenotipa
[uredi | uredi izvor]Od njegovog prvog opisa, poznato je preko 30 mutacija u genu SLC26A2 u četiri gore recesivno naslijedive hondrodisplazije. Ahondrogeneza 1B (ACG-1B) je najteži oblik ovih hondrodisplazija, što rezultira nerazvijenošću skeleta i smrću prije ili neposredno nakon rođenja.[13] Atelosteogeneza tipa II (AO-II) može biti smrtonosna u neonatusnom periodu,[14] budući da se dijastrofijska displazija (DTD) i autosomno recesivna multipla epifizna displazija (EDM4/rMED) smatraju najtežim oblicima.
Kada je deset prethodno opisanih mutacija SLC26A2 eksprimirano u ćelijama sisara, pronađena je snažna korelacija između količine transportne aktivnosti sulfata mutiranog proteina i težine fenotipa kod pacijenata kod kojih su te mutacije identificirane.[15] Naprimjer, mutacija koja rezultira nefunkcionalnim proteinom na oba alela uvijek je pronađena s teškim fenotipom ACG-IB, ali nefunkcionalne mutacije na oba nikada nisu pronađene s manje teškim fenotipima, DTD i rMED. Mutacije pronađene u umjereno teškom fenotipu AO-II uvijek su bile rezultat nefunkcionalne mutacije na jednom alelu i djelomično funkcionalne mutacije na suprotnom alelu. Nasuprot tome, mutacije opisane u najblažem obliku hondrodisplazije, rMED, rezultiraju proteinima koji zadržavaju barem dio djelimične transportne funkcije sulfata na oba alela. To sugerira da čak i mala količina transporta sulfata posredovanog SLC26A2 u hondrocitima može ublažiti kliničku težinu hondrodisplazije. Međutim, pronađena je manje predvidljiva korelacija genotip/fenotip s mutacijom opisanom pretežno u finskoj populaciji. Ova finska mutacija nalazi se na mjestu prerade gena i rezultira niskim nivoom iRNK SLC26A2-a.[16] Različiti nivoi ekspresije proteina SLC26A2 vjerovatno su uzrok varijabilnih fenotipova opisanih sa ovom mutacijom.
Funkcionalni značaj SLC26A2 u debelom crijevu i bubregu
[uredi | uredi izvor]Imunohistohemijska analiza lokalizirala je SLC26A2 na apikalnoj membrani epitelnih ćelijaa debelog crijeva i ćelijama proksimalnih bubrežnih tubula.[6][17]
Debelo crijevo
[uredi | uredi izvor]Obilni nivoi iRNK SLC26A2-a identificirani su u tankom i debelom crijevu miševa, pacovaa i ljudi. U ljudskom crijevu SLC26A2 prisutan je u gornjoj trećini kripti, gdje je usmjeren prema apikalnoj membrani.[18] Fiziološku ulogu SLC26A2 u ljudskom crijevu tek treba utvrditi, ali on vjerovatno predstavlja izmjenjivač sulfata/oksalata koji je okarakteriziran u preparatima vezikula apikalne membrane debelog crijeva i vjerovatno ima važnu ulogu u transportu sulfata u ovom tkivu.[19] Zapravo, sugerirano je da se poremećajna sulfacija javlja tokom maligne transformacije epitelnih ćelija debelog crijeva, a studije su pokazale da je stopa rasta ćelija raka značajno povećana kada je transkripcija SLC26A2 potisnuta.[20]
Bubrezi
[uredi | uredi izvor]Protein SLC26A2 je lokaliziran na graničnoj membrani proksimalnih tubula pacovskih bubrega.[17] Na tom mjestu izmjenjuje oksalat/SO42– ili klorid/SO42–, pomoću SLC26A2 može doprinijeti kritičnom procesu reapsorpcije natrij-hlorida preko epitela proksimalnih tubula. Prema jednom predloženom modelu, anionski transporter razmjenjuje unutarćelijslki oksalat za lumens000ki hlorid, paralelno s kotransporterom Na–SO4, što rezultira neto resorpcijom natrij-hlorida.[21] Prema ovom modelu, potreban je treći transportni proces koji funkcionira kao nsčin recikliranja oksalata natrag u ćeliju i recikliranja sulfata iz ćelije u lumen. Ranije se smatralo da je SLC26A6, drugi član iste porodice anionskih transportera kao i DTDST, pruža mehanizam transporta hlorida posredovanog oksalatima ili formatom u ovom segmentu nefrona; međutim, nedavne studije na nokaut-miševima Slc26a6 postavile su pitanja o njegovoj ulozi u ovom transportnom procesu.[22] Nasuprot tome, položaj apikalne membrane i elektrohemijska svojstva SLC26A2 odgovarali bi zahtjevu anionskog izmjenjivača smještenog na apikalnoj membrani proksimalnih tubula, koji bi služio kao mehanizam transporta hlorida u zamjenu za oksalat i/ili recikliranje oksalata u zamena za sulfat.
Reference
[uredi | uredi izvor]- ^ a b c GRCh38: Ensembl release 89: ENSG00000155850 - Ensembl, maj 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000034320 - 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.
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- ^ a b Heneghan JF, Akhavein A, Salas MJ, Shmukler BE, Karniski LP, Vandorpe DH, Alper SL (juni 2010). "Regulated transport of sulfate and oxalate by SLC26A2/DTDST". American Journal of Physiology. Cell Physiology. 298 (6): C1363-75. doi:10.1152/ajpcell.00004.2010. PMC 2889644. PMID 20219950.
- ^ Ohana E, Shcheynikov N, Park M, Muallem S (februar 2012). "Solute carrier family 26 member a2 (Slc26a2) protein functions as an electroneutral SOFormula/OH-/Cl- exchanger regulated by extracellular Cl-". The Journal of Biological Chemistry. 287 (7): 5122–32. doi:10.1074/jbc.M111.297192. PMC 3281620. PMID 22190686.
- ^ Haila S, Hästbacka J, Böhling T, Karjalainen-Lindsberg ML, Kere J, Saarialho-Kere U (august 2001). "SLC26A2 (diastrophic dysplasia sulfate transporter) is expressed in developing and mature cartilage but also in other tissues and cell types". The Journal of Histochemistry and Cytochemistry. 49 (8): 973–82. doi:10.1177/002215540104900805. PMID 11457925.
- ^ a b Forlino A, Piazza R, Tiveron C, Della Torre S, Tatangelo L, Bonafè L, Gualeni B, Romano A, Pecora F, Superti-Furga A, Cetta G, Rossi A (mart 2005). "A diastrophic dysplasia sulfate transporter (SLC26A2) mutant mouse: morphological and biochemical characterization of the resulting chondrodysplasia phenotype". Human Molecular Genetics. 14 (6): 859–71. doi:10.1093/hmg/ddi079. PMID 15703192.
- ^ "UniProt, P50443" (jezik: engleski). Pristupljeno 14. 10. 2021.
- ^ "Entrez Gene: SLC26A2".
- ^ Park M, Ohana E, Choi SY, Lee MS, Park JH, Muallem S (januar 2014). "Multiple roles of the SO4(2-)/Cl-/OH- exchanger protein Slc26a2 in chondrocyte functions". The Journal of Biological Chemistry. 289 (4): 1993–2001. doi:10.1074/jbc.M113.503466. PMC 3900949. PMID 24302720.
- ^ Superti-Furga A, Hästbacka J, Wilcox WR, Cohn DH, van der Harten HJ, Rossi A, Blau N, Rimoin DL, Steinmann B, Lander ES, Gitzelmann R (januar 1996). "Achondrogenesis type IB is caused by mutations in the diastrophic dysplasia sulphate transporter gene". Nature Genetics. 12 (1): 100–2. doi:10.1038/ng0196-100. PMID 8528239. S2CID 31143438.
- ^ Hästbacka J, Superti-Furga A, Wilcox WR, Rimoin DL, Cohn DH, Lander ES (februar 1996). "Atelosteogenesis type II is caused by mutations in the diastrophic dysplasia sulfate-transporter gene (DTDST): evidence for a phenotypic series involving three chondrodysplasias". American Journal of Human Genetics. 58 (2): 255–62. PMC 1914552. PMID 8571951.
- ^ Karniski LP (oktobar 2004). "Functional expression and cellular distribution of diastrophic dysplasia sulfate transporter (DTDST) gene mutations in HEK cells". Human Molecular Genetics. 13 (19): 2165–71. doi:10.1093/hmg/ddh242. PMID 15294877.
- ^ Hästbacka J, Kerrebrock A, Mokkala K, Clines G, Lovett M, Kaitila I, de la Chapelle A, Lander ES (septembar 1999). "Identification of the Finnish founder mutation for diastrophic dysplasia (DTD)". European Journal of Human Genetics. 7 (6): 664–70. doi:10.1038/sj.ejhg.5200361. PMID 10482955.
- ^ a b Chapman JM, Karniski LP (maj 2010). "Protein localization of SLC26A2 (DTDST) in rat kidney". Histochemistry and Cell Biology. 133 (5): 541–7. doi:10.1007/s00418-010-0694-x. PMID 20369363. S2CID 13591652.
- ^ Haila S, Saarialho-Kere U, Karjalainen-Lindsberg ML, Lohi H, Airola K, Holmberg C, Hästbacka J, Kere J, Höglund P (april 2000). "The congenital chloride diarrhea gene is expressed in seminal vesicle, sweat gland, inflammatory colon epithelium, and in some dysplastic colon cells". Histochemistry and Cell Biology. 113 (4): 279–86. doi:10.1007/s004180000131. PMID 10857479. S2CID 10999468.
- ^ Tyagi S, Kavilaveettil RJ, Alrefai WA, Alsafwah S, Ramaswamy K, Dudeja PK (novembar 2001). "Evidence for the existence of a distinct SO(4)(--)-OH(-) exchange mechanism in the human proximal colonic apical membrane vesicles and its possible role in chloride transport". Experimental Biology and Medicine. 226 (10): 912–8. doi:10.1177/153537020122601006. PMID 11682697. S2CID 24469074.
- ^ Yusa A, Miyazaki K, Kimura N, Izawa M, Kannagi R (maj 2010). "Epigenetic silencing of the sulfate transporter gene DTDST induces sialyl Lewisx expression and accelerates proliferation of colon cancer cells". Cancer Research. 70 (10): 4064–73. doi:10.1158/0008-5472.CAN-09-2383. PMID 20460514.
- ^ Kuo SM, Aronson PS (juni 1996). "Pathways for oxalate transport in rabbit renal microvillus membrane vesicles". The Journal of Biological Chemistry. 271 (26): 15491–7. doi:10.1074/jbc.271.26.15491. PMID 8663096.
- ^ Knauf F, Velazquez H, Pfann V, Jiang Z, Aronson PS (januar 2019). "Characterization of renal NaCl and oxalate transport in Slc26a6 -/- mice". American Journal of Physiology. Renal Physiology. 316 (1): F128–F133. doi:10.1152/ajprenal.00309.2018. PMC 6383200. PMID 30427220.
Dopunska literatura
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- Jakkula E, Mäkitie O, Czarny-Ratajczak M, Czarny-Ratacjzak M, Jackson GC, Damignani R, Susic M, Briggs MD, Cole WG, Ala-Kokko L (mart 2005). "Mutations in the known genes are not the major cause of MED; distinctive phenotypic entities among patients with no identified mutations". European Journal of Human Genetics. 13 (3): 292–301. doi:10.1038/sj.ejhg.5201314. PMID 15523498.
- Bonafé L, Hästbacka J, de la Chapelle A, Campos-Xavier AB, Chiesa C, Forlino A, Superti-Furga A, Rossi A (decembar 2008). "A novel mutation in the sulfate transporter gene SLC26A2 (DTDST) specific to the Finnish population causes de la Chapelle dysplasia". Journal of Medical Genetics. 45 (12): 827–31. doi:10.1136/jmg.2007.057158. PMC 4361899. PMID 18708426.
- Lohi H, Kujala M, Makela S, Lehtonen E, Kestila M, Saarialho-Kere U, Markovich D, Kere J (april 2002). "Functional characterization of three novel tissue-specific anion exchangers SLC26A7, -A8, and -A9". The Journal of Biological Chemistry. 277 (16): 14246–54. doi:10.1074/jbc.M111802200. PMID 11834742.
- Lamb R, Thomson W, Ogilvie EM, Donn R (april 2007). "Positive association of SLC26A2 gene polymorphisms with susceptibility to systemic-onset juvenile idiopathic arthritis". Arthritis and Rheumatism. 56 (4): 1286–91. doi:10.1002/art.22444. PMID 17393463.
- Ikeda T, Mabuchi A, Fukuda A, Hiraoka H, Kawakami A, Yamamoto S, Machida H, Takatori Y, Kawaguchi H, Nakamura K, Ikegawa S (2001). "Identification of sequence polymorphisms in two sulfation-related genes, PAPSS2 and SLC26A2, and an association analysis with knee osteoarthritis". Journal of Human Genetics. 46 (9): 538–43. doi:10.1007/s100380170036. PMID 11558903.
- Mégarbané A, Haddad FA, Haddad-Zebouni S, Achram M, Eich G, Le Merrer M, Superti-Furga A (juli 1999). "Homozygosity for a novel DTDST mutation in a child with a 'broad bone-platyspondylic' variant of diastrophic dysplasia". Clinical Genetics. 56 (1): 71–6. doi:10.1034/j.1399-0004.1999.560110.x. PMID 10466420. S2CID 19411099.
- Markovich D (oktobar 2001). "Physiological roles and regulation of mammalian sulfate transporters". Physiological Reviews. 81 (4): 1499–533. doi:10.1152/physrev.2001.81.4.1499. PMID 11581495.
- Pecora F, Gualeni B, Forlino A, Superti-Furga A, Tenni R, Cetta G, Rossi A (septembar 2006). "In vivo contribution of amino acid sulfur to cartilage proteoglycan sulfation". The Biochemical Journal. 398 (3): 509–14. doi:10.1042/BJ20060566. PMC 1586348. PMID 16719839.
- Olsen JV, Blagoev B, Gnad F, Macek B, Kumar C, Mortensen P, Mann M (novembar 2006). "Global, in vivo, and site-specific phosphorylation dynamics in signaling networks". Cell. 127 (3): 635–48. doi:10.1016/j.cell.2006.09.026. PMID 17081983. S2CID 7827573.
- Satoh H, Susaki M, Shukunami C, Iyama K, Negoro T, Hiraki Y (maj 1998). "Functional analysis of diastrophic dysplasia sulfate transporter. Its involvement in growth regulation of chondrocytes mediated by sulfated proteoglycans". The Journal of Biological Chemistry. 273 (20): 12307–15. doi:10.1074/jbc.273.20.12307. PMID 9575183.
- Mäkitie O, Savarirayan R, Bonafé L, Robertson S, Susic M, Superti-Furga A, Cole WG (oktobar 2003). "Autosomal recessive multiple epiphyseal dysplasia with homozygosity for C653S in the DTDST gene: double-layer patella as a reliable sign". American Journal of Medical Genetics. Part A. 122A (3): 187–92. doi:10.1002/ajmg.a.20282. PMID 12966518. S2CID 1814933.
- Lohi H, Kujala M, Kerkelä E, Saarialho-Kere U, Kestilä M, Kere J (novembar 2000). "Mapping of five new putative anion transporter genes in human and characterization of SLC26A6, a candidate gene for pancreatic anion exchanger". Genomics. 70 (1): 102–12. doi:10.1006/geno.2000.6355. PMID 11087667.
- Galante LL, Schwarzbauer JE (decembar 2007). "Requirements for sulfate transport and the diastrophic dysplasia sulfate transporter in fibronectin matrix assembly". The Journal of Cell Biology. 179 (5): 999–1009. doi:10.1083/jcb.200707150. PMC 2099202. PMID 18056413.
- Rossi A, Cetta G, Piazza R, Bonaventure J, Steinmann B, Supereti-Furga A (2003). "In vitro proteoglycan sulfation derived from sulfhydryl compounds in sulfate transporter chondrodysplasias". Pediatric Pathology & Molecular Medicine. 22 (4): 311–21. doi:10.1080/15227950307720. PMID 14692227.
- Remes VM, Hästbacka JR, Poussa MS, Peltonen JI (august 2002). "Does genotype predict development of the spinal deformity in patients with diastrophic dysplasia?". European Spine Journal. 11 (4): 327–31. doi:10.1007/s00586-002-0413-y. PMC 3610472. PMID 12193993.
- Haila S, Hästbacka J, Böhling T, Karjalainen-Lindsberg ML, Kere J, Saarialho-Kere U (august 2001). "SLC26A2 (diastrophic dysplasia sulfate transporter) is expressed in developing and mature cartilage but also in other tissues and cell types". The Journal of Histochemistry and Cytochemistry. 49 (8): 973–82. doi:10.1177/002215540104900805. PMID 11457925.
- Huang QY, Li GH, Kung AW (august 2009). "The -9247 T/C polymorphism in the SOST upstream regulatory region that potentially affects C/EBPalpha and FOXA1 binding is associated with osteoporosis". Bone. 45 (2): 289–94. doi:10.1016/j.bone.2009.03.676. PMID 19371798.
- Bonafé L, Mittaz-Crettol L, Ballhausen D, Superti-Furga A (23. 1. 2014). Multiple Epiphyseal Dysplasia, Recessive. NBK1306. In Pagon RA; Bird TD; Dolan CR; et al., ured. (2002). GeneReviews [Internet]. Seattle WA: University of Washington, Seattle.
- Bonafé L, Mittaz-Crettol L, Ballhausen D, Superti-Furga A (23. 1. 2014). Atelosteogenesis Type 2. NBK1317. In GeneReviews
- Bonafé L, Mittaz-Crettol L, Ballhausen D, Superti-Furga A (18. 7. 2013). Diastrophic Dysplasia. NBK1350. In GeneReviews
Vanjski linkovi
[uredi | uredi izvor]- SLC26A2 protein, human na US National Library of Medicine Medical Subject Headings (MeSH)
Ovaj članak uključuje tekst iz Nacionalne medicinske biblioteke Sjedinjenih Država, koji je u javnom vlasništvu.