CLCN5
Gen CLCN5 kod ljudi, nalazi se na hromosomu X. Kodira hloridni kanal Cl-/H+ izmjenjivač ClC-5. ClC-5 koji se uglavnom eksprimira u bubregu, posebno u proksimalnim tubulama, gdje učestvuje u preuzimanju albumina i proteina niske molekulse težine, što je jedan od glavnih fiziološka uloga ćelija proksimalnih tubula. Mutacije u genu CLCN5 uzrokuju X-vezano recesivnu nefropatiju pod nazivom Dentova bolest (Dentova bolest 1 MIM#300009) okarakterizirana prekomjernim gubitkom proteina niske molekulske težine i kalcijem u urinu (hiperkalciurija), nefrokalcinoza (prisustvo agregata kalcij-fosfata u tubulskom lumenu i/ili intersticiju) i nefrolitijaza]ma urinarnom traktom. (kamen u bubregu).
Aminokiselinska sekvenca
urediDužina polipeptidnog lanca je 746 aminokiselina, a molekulska težina 83.147 Da.
10 | 20 | 30 | 40 | 50 | ||||
---|---|---|---|---|---|---|---|---|
MDFLEEPIPG | VGTYDDFNTI | DWVREKSRDR | DRHREITNKS | KESTWALIHS | ||||
VSDAFSGWLL | MLLIGLLSGS | LAGLIDISAH | WMTDLKEGIC | TGGFWFNHEH | ||||
CCWNSEHVTF | EERDKCPEWN | SWSQLIISTD | EGAFAYIVNY | FMYVLWALLF | ||||
AFLAVSLVKV | FAPYACGSGI | PEIKTILSGF | IIRGYLGKWT | LVIKTITLVL | ||||
AVSSGLSLGK | EGPLVHVACC | CGNILCHCFN | KYRKNEAKRR | EVLSAAAAAG | ||||
VSVAFGAPIG | GVLFSLEEVS | YYFPLKTLWR | SFFAALVAAF | TLRSINPFGN | ||||
SRLVLFYVEF | HTPWHLFELV | PFILLGIFGG | LWGALFIRTN | IAWCRKRKTT | ||||
QLGKYPVIEV | LVVTAITAIL | AFPNEYTRMS | TSELISELFN | DCGLLDSSKL | ||||
CDYENRFNTS | KGGELPDRPA | GVGVYSAMWQ | LALTLILKIV | ITIFTFGMKI | ||||
PSGLFIPSMA | VGAIAGRLLG | VGMEQLAYYH | QEWTVFNSWC | SQGADCITPG | ||||
LYAMVGAAAC | LGGVTRMTVS | LVVIMFELTG | GLEYIVPLMA | AAMTSKWVAD | ||||
ALGREGIYDA | HIRLNGYPFL | EAKEEFAHKT | LAMDVMKPRR | NDPLLTVLTQ | ||||
DSMTVEDVET | IISETTYSGF | PVVVSRESQR | LVGFVLRRDL | IISIENARKK | ||||
QDGVVSTSII | YFTEHSPPLP | PYTPPTLKLR | NILDLSPFTV | TDLTPMEIVV | ||||
DIFRKLGLRQ | CLVTHNGRLL | GIITKKDVLK | HIAQMANQDP | DSILFN |
Struktura
urediLjudski CLCN5 gen (MIM#300008, referentna sekvenca NG_007159.2) je lokalizovan u pericentromernom regionu na hromosoma X, sekvenca Xp11.23. Proteže se na oko 170 Kb genomske DNK, ima kodirajuću regiju od 2,238 bp i sastoji se od 17 egzona, uključujući 11 egzona (od 2 do 12).[5][6][7][8] Gen CLCN5 ima 8 paraloga (CLCN1, CLCN2, CLCN3, CLCN4, CLCN6, CLCN7, CLCNKA, CLCNKB) i 201 ortologa među viličastim kičmenjacima (Gnathostomata).
Otkriveno je pet različitih CLCN5 genskih transkripata, od kojih dvije (varijante transkripta 3 [NM_000084.5] i 4 [NM_001282163.1]) kodiraju kanonski 746-aminokiselinski protein, dvije (varijante transkripta 1 [NM_001127899.3] i 2 [NM_001127898.3]) NH2-terminalni prošireni protein od 816 aminokiselina[9] a jedna ne kodira nijedan protein (varijanta transkripta 5, [NM_001272102.2]). Pet prim neprevedena regija (5'UTR) CLCN5-a je složena struktura i nije u potpunosti razjašnjena. Predviđeno je da će dva jaka i jedan slabi promotor biti prisutni u genu CLCN5.[10][11] Several different 5’ alternatively used exons have been recognized in the human kidney.[9][10][11][12] Tri promotora pokreću sa različitim stepenom efikasnosti 11 različitih iRNK, pri čemu transkripcija počinje sa najmanje tri različita početna mesta.[10]
Lokalizacija i funkcija
urediClC-5 pripada porodici hloridnih kanala koji su regulatori ekscitabilnosti membrane, transepitelnog transporta i volumena ćelija u različitim tkivima). Na osnovu homologija sekvenci, devet ClC proteina sisara može se grupisati u tri klase, od kojih se prva (ClC-1, ClC-2, ClC-Ka i ClC-Kb) prvenstveno eksprimira u plazmamembranama, dok su druga dva (ClC-3, ClC-4 i ClC-5 i ClC-6 i ClC-7) prvenstveno eksprimirana u organelskim membranama.[13]
ClC-5 je eksprimiran u malim do umjerenim razinama u mozgu, mišićima, crijevima, ali visoko u bubrezima, prvenstveno u ćelijama proksimalnih tubula segmenta S3, u alfa interkaliranim ćelijama korteksa sabirnih kanala i u korteksmom i medulskom debelom uzlaznom nastavku Henleove petlje.[14][15][16][17][18][19]
Ćelije proksimalnih tubula (PTC) su glavno mjesto ekspresije ClC-5. Pomoću procesa receptorom posredovane endocitoze, preuzimaju albumin i proteine niske molekulske težine koji slobodno prolaze kroz glomerulski filter. ClC-5 se nalazi u ranim endosomima PTC-a, gdje se kolokalizira s elektrogenom vakuolskom H+‐ATPazom (V‐ATPaze). ClC-5 u ovom odjeljku doprinosi održavanju intraendosomske kiselosti pH. Zakiseljavanje okoline je neophodno za disocijaciju liganda od njegovog receptora. Receptor se zatim reciklira u apikalnu membranu, dok se ligand transportuje do kasnog endosoma i lizosoma, gdje se razgrađuje. ClC-5 podržava efikasnu acidifikaciju endosoma, bilo obezbjeđivanjem Cl− provodljivosti kako bi se uravnotežila akumulacija pozitivno nabijenog H+ upumpanog V-ATPazom, ili direktnim zakiseljavanjem endosoma u paralelno sa V-ATPazom.[20]
Eksperimentalni dokazi potvrđuju da endosomna koncentracija Cl−, koju ClC-5 podiže u zamjenu za protone akumulirane od strane V-ATPaze, može igrati ulogu u endocitozama, neovisno o endosomnoj acidifikaciji, ukazujući tako na drugi mogući mehanizam kojim disfunkcija ClC-5 može poremetiti endocitozu.[21]
ClC-5 se takođe nalazi na površini ćelije PTC-a, gdje vjerovatno ima ulogu u formiranju/funkcionisanju endocitnog kompleksa koji također uključuje megalin i kubilin/amnionske receptore , natrij-vodik antiporter 3 (NHE3) i V-ATPaza.[22][23] Pokazano je da se na C-terminalu ClC-5 vezuje za aktin-depolimerizirajući protein kofilin. Kada se formira endosom u nastajanju, regrutovanje kofilina od strane ClC-5 je preduslov za lokalizovano rastvaranje aktinskog citoskeleta, čime se dozvoljava endosomu da prođe u citoplazmu. Moguće je da na površini ćelije veliki unutarćelijski C-kraj ClC-5 ima ključnu funkciju u posredovanju u sklapanju, stabilizaciji i rastavljanju endocitnog kompleksa, putem interakcija protein-protein. Stoga, ClC-5 može ostvariti dvije uloge u endocitozi posredovanoj receptorima: 1) vezikulska acidifikacija i reciklaža receptora; 2) učešće u neselektivnom unosu proteina male molekulske težine bez megalina-kubilina-amniona na apikalnoj membrani.
Klinički značaj
urediDentova bolest je uglavnom uzrokovana gubitkom funkcije, mutacijama u "CLCN5" genu (Dent disease 1; MIM#300009).[24] Dentova bolest 1 pokazuje izraženu alelnu heterogenost. Do danas je opisano 265 različitih patogenih varijanti "CLCN5". Mali broj patogenih varijanti pronađen je u više od jedne porodice.[25] Oko 48% su skraćene mutacije (nonsensne, okvirne ili složene), 37% neskraćene (misensne ili unutar okvira insercije/delecije), 10% mutacija na mjestu prerade i 5% drugih tipova (velike delecije, Alu inseercije ili 5'UTR mutacije). Funkcionalna istraživanja u oocitima Xenopus laevis (afrička kandžasta žaba) i ćelijama sisara.[21][26][27][28] enabled these CLCN5 mutations to be classified according to their functional consequences.[8][25][29][30][31] Najčešće mutacije dovode do defektnog sklapanja proteina i obrađivanja, što rezultira sa endoplazmatskkoretikulumskim zadržavanjem mutantnog proteina za dalju degradaciju putem proteasoma.
Klinička dijagnoza Dentove bolesti može se potvrditi molekulskim genetičkim testiranjem koje može otkriti mutacije u specifičnim genima za koje je poznato da uzrokuju Dentovu bolest. Međutim, oko 20-25% pacijenata sa Dentovom bolešću ostaje genetički neriješeno.
Genetičko testiranje je korisno za određivanje statusa zdravog nositelja kod majke oboljelog muškarca. U stvari, budući da je Dentova bolest X-vezano recesivno oboljenje, muškarci su češće pogođeni nego žene, a žene mogu biti heterozigotne zdrave nositeljice. Zbog X-inaktivacije, žene nositeljice mogu imati neke blage simptome Dentove bolesti, kao što su niske molekulske težine (proteinurija ili hiperkalciurija). Nositeljice će prenijeti bolest na polovinu svojih sinova, dok će polovina njihovih kćeri biti nositeljice. Oboljeli muškarci ne prenose bolest na svoje sinove jer na muškarce prenose hromosom Y, ali sve njihove kćeri će naslijediti mutirani hromosom X. Preimplantacijsko i preneonatusno genetičko testiranje se ne preporučuju za Dentovu bolest 1, jer je prognoza za većinu pacijenata dobra i nedostaje jasna je korelacija između genotipa i fenotipa.[32]
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Reference
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- Wu F, Roche P, Christie PT, Loh NY, Reed AA, Esnouf RM, Thakker RV (april 2003). "Modeling study of human renal chloride channel (hCLC-5) mutations suggests a structural-functional relationship". Kidney International. 63 (4): 1426–32. doi:10.1046/j.1523-1755.2003.00859.x. PMID 12631358.
- Carballo-Trujillo I, Garcia-Nieto V, Moya-Angeler FJ, Antón-Gamero M, Loris C, Méndez-Alvarez S, Claverie-Martin F (april 2003). "Novel truncating mutations in the ClC-5 chloride channel gene in patients with Dent's disease". Nephrology, Dialysis, Transplantation. 18 (4): 717–23. doi:10.1093/ndt/gfg016. PMID 12637640.
- Ludwig M, Waldegger S, Nuutinen M, Bökenkamp A, Reissinger A, Steckelbroeck S, Utsch B (2004). "Four additional CLCN5 exons encode a widely expressed novel long CLC-5 isoform but fail to explain Dent's phenotype in patients without mutations in the short variant". Kidney & Blood Pressure Research. 26 (3): 176–84. doi:10.1159/000071883. PMID 12886045. S2CID 41532860.
- Hryciw DH, Wang Y, Devuyst O, Pollock CA, Poronnik P, Guggino WB (oktobar 2003). "Cofilin interacts with ClC-5 and regulates albumin uptake in proximal tubule cell lines" (PDF). The Journal of Biological Chemistry. 278 (41): 40169–76. doi:10.1074/jbc.M307890200. PMID 12904289.
External links
uredi- CLCN5 protein, human na US National Library of Medicine Medical Subject Headings (MeSH)
- Lokacija ljudskog genoma CLCN5 i stranica sa detaljima o genu CLCN5 u UCSC Genome Browseru.
Ovaj članak uključuje tekst iz Nacionalne medicinske biblioteke Sjedinjenih Država, koji je u javnom vlasništvu.