Transmembranski regulator provodljivosti cistaste fibroze
Transmembranski regulator provodljivosti cistaste fibroze (CFTR) je membranski protein i anionski kanal kod kičmenjaka, koji je kodiran genom CFTR sa hromosoma 7[5][6]
Genetičar Lap-Chee Tsui i njegov tim identifikovali su CFTR gen 1989. |godine, kao gen povezan sa CF (cistaste fibroze).[7]
Gen CFTR kodira ABC transportersku-klasu proteina ionski kanalionskog kanala koji provodi hlorid[8] i bikarbonatne zone kroz epitelne ćelijske membrane. Mutacije gena CFTR koje utiču na funkciju anionskih kanala dovode do disregulacije transporta tečnosti epitelne obloge (sluzi) u plućima, pankreasu i drugim organima, što dovodi do cistaste fibroze. Komplikacije uključuju zgušnjavanje sluzi u plućima s čestim respiratornim infekcijama i insuficijencijama gušterače što dovodi do pothranjenosti i dijabetesa. Ova stanja dovode do hronične invalidnosti i smanjenog životnog vijeka. Kod muških pacijenata, progresivna opstrukcija i destrukcija razvojnog vas deferens (spermne vrpce) i epididimisa je rezultat abnormalnih intralumenskih sekrecija,[9] uzrokujući urođeno odsustvo sjemenovoda i mušku neplodnost.
Gen
urediGen koji kodira ljudski CFTR protein nalazi se na hromosomu 7, na poziciji q31.2 dugog kraka (q).[6] od baznog para 116,907,253 do baznog para 117,095,955. CFTR ortolozi[10] javljaju se kod viličastih kičmenjaka.[11]
Svaki pojedinac nasljeđuje dvije kopije gena CFTR (regulator transmembranske provodljivosti cistaste fibroze). Međutim, neke od naslijeđenih kopija su izmijenjene. Do sada je CFTR gen povezan sa preko 700 različitih mutacija. Osoba sa CF nasljeđuje dvije defektne kopije CFTR gena. Ove mutacije mogu biti heterozigotne, što znači da uključuju dvije različite mutacije, i homozigotne, što znači da uključuju istu mutaciju. Delta F508 je najčešća mutacija, koja čini više od 70% svih mutacija. Oni koji su homozigoti za Delta F508 obično su pogođeni insuficijencijom pankreasa.[12]
„CFTR“ gen je korišten kod životinja kao filogenetski marker jedarne DNK.[10] Velike genomske sekvence ovog gena korištene su za istraživanje filogenije glavne grupe sisara,[13] i potvrdio grupisanje placentalnih redova u četiri glavne klade: Xenarthra, Afrotheria, Laurasiatheria i Euarchonta plus Glires.
Mutacije
urediOpisano je skoro 1000 mutacija uzroka cistaste fibroze.[14] Najčešća mutacija, DeltaF508 (ΔF508) prvenstveno poznata kao procesna mutacija koja je rezultat delecija (Δ) tri nukleotida, što rezultira gubitkom aminokiseline fenilalanina (F) na 508. poziciji na proteinu.[15] Kao rezultat toga, protein se ne savija normalno i brže se razgrađuje. Velika većina mutacija je rijetka. Distribucija i učestalost mutacija varira među različitim populacijama što ima implikacije na genetički skrining i savjetovanje.
Otkrivanje lijekova za terapiju CF kod svih pacijenata je komplikovano zbog velikog broja mutacija koje uzrokuju bolest. U idealnom slučaju, potrebna je biblioteka ćelijskih linija i testova. baziranih na ćelijama koji odgovaraju svim mutantima za skrining široko aktivnih kandidata za lijekove. Metodi ćelijskog inženjerstva uključujući fluorogene oligonukleotidne signalne sonde mogu se koristiti za otkrivanje i izolaciju klonskih ćelijskih linija za svaki mutant.[16]
Mutacije se sastoje od zamjene, dupliciranja, delecija ili skraćivanja gena CFTR. Ovo može dovesti do toga da proteini možda ne funkcionišu, rade manje efikasno, brže se razgrađuju ili su prisutni u nedovoljnom broju.[17]
Pretpostavlja se da mutacije u CFTR genu mogu dati selektivnu prednost heterozigotnim osobama. Ćelije koje eksprimiraju mutantni oblik CFTR proteina otporne su na invaziju bakterije Salmonella typhi, uzročnika tifusne groznice, a miševi koji nose jednu kopiju mutantnog CFTR-a otporni su na dijareju uzrokovanu toksinom kolere.[18]
Najčešće mutacije koje uzrokuju cistastu fibrozu i insuficijenciju pankreasa kod ljudi su:[19]
Varijanta cDNK imena (naređeno od 5' do 3') | Naziv varijante proteina | Naslijeđeni naziv varijante | rsID | No alela u CFTR2 | Alelna frekvencija u CFTR2 | % Pankreasne nedovoljnosti | Konačno određivanje varijante (juli 2020.) | |||||||
Naziv varijante proteina | Naslijeđeni naziv varijante | rsID | No alela u CFTR2 | Alelna frekvencija u CFTR2 | % Pankreasne nedovoljnosti | Konačno određivanje varijante (juli 2020.) | Varijanta naziva cDNK (naređeno od 5' do 3') | Naziv varijante proteina | Naslijeđeni naziv varijante | rsID | No alela u CFTR2 | Alelna frekvencija u CFTR2 | % Dovoljnosti pankreasa | Konačno određivanje varijante (juli 2020.) |
c.1521_1523delCTT | p.Phe508del | F508del | rs113993960 | 99061 | 0,69744 | 98% | Uzrokuje CF | |||||||
c.1624G>T | p.Gly542X | G542X | rs113993959 | 3610 | 0,02542 | 98% | Uzrokuje CF | |||||||
c.1652G>A | p.Gly551Asp | G551D | rs75527207 | 2986 | 0,02102 | 96% | Uzrokuje CF | |||||||
c.3909C>G | p.Asn1303Lys | N1303K | rs80034486 | 2246 | 0,01581 | 98% | Uzrokuje CF | |||||||
c.350G>A | p.Arg117His | R117H | rs78655421 | 1854 | 0.01305 | 23% | Različite kliničke posljedice | |||||||
c.3846G>A | p.Trp1282X | W1282X | rs77010898 | 1726 | 0,01215 | 99% | Uzrokuje CF | |||||||
c.489+1G>T | Bez naziva proteina | 621+1G->T | rs78756941 | 1323 | 0,00931 | 99% | uzrokuje CF | |||||||
c.1657C>T | p.Arg553X | R553X | rs74597325 | 1323 | 0,00931 | 97% | Uzrokuje CF | |||||||
c.1585-1G>A | Bez naziva proteina | 1717-1G->A | rs76713772 | 1216 | 0,00856 | 97% | Uzrokuje CF | |||||||
c.3718-2477C>T | Bez naziva proteina | 3849+10kbC->T | rs75039782 | 1158 | 0,00815 | 33% | uzrokuje CF | |||||||
c.2657+5G>A | Bez naziva proteina | 2789+5G->A | rs80224560 | 1027 | 0,00723 | 43% | Izaziva CF | |||||||
c.1519_1521delATC | p. Ile507del | I507del | rs121908745 | 651 | 0,00458 | 98% | Uzrokuje CF | |||||||
c.3484C>T | p.Arg1162X | R1162X | rs74767530 | 651 | 0,00458 | 97% | Uzrokuje CF | |||||||
c.254G>A | p.Gly85Glu | G85E | rs75961395 | 616 | 0.00434 | 85% | Uzrokuje CF | |||||||
c.3454G>C | p.Asp1152His | D1152H | rs75541969 | 571 | 0,00402 | 24% | Varijabilne kliničke posljedice | |||||||
c.2051_2052delAAinsG | p. Lys684SerfsX38 | 2183AA->G | rs121908799 | 542 | 0,00382 | 96% | Uzrokuje CF | |||||||
c.3528delC | p. Lys1177SerfsX15 | 3659delC | rs121908747 | 539 | 0,00379 | 99% | Uzrokuje CF | |||||||
c.1040G>C | p.Arg347Pro | R347P | rs77932196 | 533 | 0,00375 | 68% | Uzrokuje CF | |||||||
c.1210−12T[5] | Bez naziva proteina | 5T | rs1805177 | 516 | 0,00363 | 28% | Varijabilne kliničke posljedice | |||||||
c.2988+1G>A | Bez naziva proteina | 3120+1G->A | rs75096551 | 501 | 0,00353 | 98% | Uzrokuje CF | |||||||
c.1364C>A | p.Ala455Glu | A455E | rs74551128 | 500 | 0,00352 | 34% | Uzrokuje CF | |||||||
c.3140-26A>G | Bez naziva proteina | 3272-26A->G | rs76151804 | 470 | 0,00331 | 29% | Uzrokuje CF | |||||||
c.1000C>T | p.Arg334Trp | R334W | rs121909011 | 429 | 0,00302 | 40% | Uzrokuje CF | |||||||
c.1766+1G>A | Bez naziva proteina | 1898+1G->A | rs121908748 | 421 | 0,00296 | 99% | Izaziva CF | |||||||
c.54-5940_273+10250del21kb | p.Ser18ArgfsX16 | CFTRdele2,3 | Nije pronađeno | 417 | 0,00294 | 100% | Uzrokuje CF | |||||||
c.1679G>C | p.Arg560Thr | R560T | rs80055610 | 343 | 0,00241 | 98% | Uzrokuje CF | |||||||
c.617T>G | p. Leu206Trp | L206W | rs121908752 | 333 | 0,00234 | 20% | Uzrokuje CF | |||||||
c.2052dupA | p.Gln685ThrfsX4 | 2184insA | rs121908786 | 329 | 0,00232 | 85% | Uzrokuje CF | |||||||
c.262_263delTT | p. Leu88IlefsX22 | 394delTT | rs121908769 | 307 | 0,00216 | 97% | Uzrokuje CF | |||||||
c.178G>T | p.Glu60X | E60X | rs77284892 | 296 | 0.00208 | 99% | Uzrokuje CF | |||||||
c.1477C>T | p.Gln493X | Q493X | rs77101217 | 292 | 0,00206 | 98% | Uzrokuje CF | |||||||
c.579+1G>T | Bez naziva proteina | 711+1G->T | rs77188391 | 274 | 0,00193 | 98% | uzrokuje CF | |||||||
c.2052delA | p. Lys684AsnfsX38 | 2184delA | rs121908746 | 255 | 0,00180 | 98% | Uzrokuje CF | |||||||
c.200C>T | p.Pro67Leu | P67L | rs368505753 | 239 | 0,00168 | 34% | Uzrokuje CF | |||||||
c.3302T>A | p.Met1101Lys | M1101K | rs36210737 | 238 | 0,00168 | 69% | Uzrokuje CF | |||||||
c.1408A>G | p.Met470Val | M470V | rs213950 | 235 | 0,00165 | 46% | Ne izaziva CF | |||||||
c.3276C>A ili c.3276C>G | p.Tyr1092X | Y1092X | rs121908761 | 225 | 0,00158 | 98% | Uzrokuje CF | |||||||
c.3196C>T | p.Arg1066Cys | R1066C | rs78194216 | 220 | 0,00155 | 98% | Uzrokuje CF | |||||||
c.1021_1022dupTC | p.Phe342HisfsX28 | 1154insTC | rs387906360 | 214 | 0,00151 | 99% | Uzrokuje CF | |||||||
c.3773dupT | p. Leu1258PhefsX7 | 3905insT | rs121908789 | 210 | 0,00148 | 97% | Uzrokuje CF | |||||||
c.1646G>A | p.Ser549Asn | S549N | rs121908755 | 203 | 0,00143 | 84% | Uzrokuje CF | |||||||
c.1040G>A | p.Arg347His | R347H | rs77932196 | 199 | 0,00140 | 24% | Uzrokuje CF | |||||||
c.948delT | p.Phe316LeufsX12 | 1078delT | rs121908744 | 184 | 0,00130 | 99% | Uzrokuje CF | |||||||
c.1210-33_1210-6GT[12]T[4] | Bez naziva proteina | 5T;TG12 | Nije pronađeno | 182 | 0,00128 | 14% | Varijabilne kliničke posljedice | |||||||
c.3472C>T | p.Arg1158X | R1158X | rs79850223 | 179 | 0,00126 | 99% | Uzrokuje CF | |||||||
c.2834C>T | p.Ser945Leu | S945L | rs397508442 | 167 | 0,00118 | 40% | Uzrokuje CF | |||||||
c.1558G>T | p. Val520Phe | V520F | rs77646904 | 156 | 0,00110 | 98% | Uzrokuje CF | |||||||
c.443T>C | p. Ile148Thr | I148T | rs35516286 | 148 | 0,00104 | 88% | Ne izaziva CF | |||||||
c.349C>T | p.Arg117Cys | R117C | rs77834169 | 146 | 0,00103 | 24% | Uzrokuje CF |
Aminokiselinska sekvenca
uredi10 | 20 | 30 | 40 | 50 | ||||
---|---|---|---|---|---|---|---|---|
MQRSPLEKAS | VVSKLFFSWT | RPILRKGYRQ | RLELSDIYQI | PSVDSADNLS | ||||
EKLEREWDRE | LASKKNPKLI | NALRRCFFWR | FMFYGIFLYL | GEVTKAVQPL | ||||
LLGRIIASYD | PDNKEERSIA | IYLGIGLCLL | FIVRTLLLHP | AIFGLHHIGM | ||||
QMRIAMFSLI | YKKTLKLSSR | VLDKISIGQL | VSLLSNNLNK | FDEGLALAHF | ||||
VWIAPLQVAL | LMGLIWELLQ | ASAFCGLGFL | IVLALFQAGL | GRMMMKYRDQ | ||||
RAGKISERLV | ITSEMIENIQ | SVKAYCWEEA | MEKMIENLRQ | TELKLTRKAA | ||||
YVRYFNSSAF | FFSGFFVVFL | SVLPYALIKG | IILRKIFTTI | SFCIVLRMAV | ||||
TRQFPWAVQT | WYDSLGAINK | IQDFLQKQEY | KTLEYNLTTT | EVVMENVTAF | ||||
WEEGFGELFE | KAKQNNNNRK | TSNGDDSLFF | SNFSLLGTPV | LKDINFKIER | ||||
GQLLAVAGST | GAGKTSLLMV | IMGELEPSEG | KIKHSGRISF | CSQFSWIMPG | ||||
TIKENIIFGV | SYDEYRYRSV | IKACQLEEDI | SKFAEKDNIV | LGEGGITLSG | ||||
GQRARISLAR | AVYKDADLYL | LDSPFGYLDV | LTEKEIFESC | VCKLMANKTR | ||||
ILVTSKMEHL | KKADKILILH | EGSSYFYGTF | SELQNLQPDF | SSKLMGCDSF | ||||
DQFSAERRNS | ILTETLHRFS | LEGDAPVSWT | ETKKQSFKQT | GEFGEKRKNS | ||||
ILNPINSIRK | FSIVQKTPLQ | MNGIEEDSDE | PLERRLSLVP | DSEQGEAILP | ||||
RISVISTGPT | LQARRRQSVL | NLMTHSVNQG | QNIHRKTTAS | TRKVSLAPQA | ||||
NLTELDIYSR | RLSQETGLEI | SEEINEEDLK | ECFFDDMESI | PAVTTWNTYL | ||||
RYITVHKSLI | FVLIWCLVIF | LAEVAASLVV | LWLLGNTPLQ | DKGNSTHSRN | ||||
NSYAVIITST | SSYYVFYIYV | GVADTLLAMG | FFRGLPLVHT | LITVSKILHH | ||||
KMLHSVLQAP | MSTLNTLKAG | GILNRFSKDI | AILDDLLPLT | IFDFIQLLLI | ||||
VIGAIAVVAV | LQPYIFVATV | PVIVAFIMLR | AYFLQTSQQL | KQLESEGRSP | ||||
IFTHLVTSLK | GLWTLRAFGR | QPYFETLFHK | ALNLHTANWF | LYLSTLRWFQ | ||||
MRIEMIFVIF | FIAVTFISIL | TTGEGEGRVG | IILTLAMNIM | STLQWAVNSS | ||||
IDVDSLMRSV | SRVFKFIDMP | TEGKPTKSTK | PYKNGQLSKV | MIIENSHVKK | ||||
DDIWPSGGQM | TVKDLTAKYT | EGGNAILENI | SFSISPGQRV | GLLGRTGSGK | ||||
STLLSAFLRL | LNTEGEIQID | GVSWDSITLQ | QWRKAFGVIP | QKVFIFSGTF | ||||
RKNLDPYEQW | SDQEIWKVAD | EVGLRSVIEQ | FPGKLDFVLV | DGGCVLSHGH | ||||
KQLMCLARSV | LSKAKILLLD | EPSAHLDPVT | YQIIRRTLKQ | AFADCTVILC | ||||
EHRIEAMLEC | QQFLVIEENK | VRQYDSIQKL | LNERSLFRQA | ISPSDRVKLF | ||||
PHRNSSKCKS | KPQIAALKEE | TEEEVQDTRL |
Interakcije
urediPokazalo se da regulator transmembranske provodljivosti cistaste fibroze reaguje sa:
Reference
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Dopunska literatura
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Vanjski linkovi
uredi- GeneReviews/NCBI/NIH/UW entry on CFTR-Related Disorders - Cystic Fibrosis (CF, Mucoviscidosis) and Congenital Absence of the Vas Deferens (CAVD)
- The Cystic Fibrosis Transmembrane Conductance Regulator Protein
- The Human Gene Mutation Database - CFTR Records
- Cystic Fibrosis Mutation Database
- Oak Ridge National Laboratory CFTR Information
- CFTR at OMIM (National Center for Biotechnology Information)
- P13569
- P26361