HFE (gen)
Ljudski regulacijski protein homeostaze gvožđa, poznat protein HFE, jest protein koji je kod ljudi kodiran genom HFE. Gen HFE nalazi se na kratkom (p) kraku kromosoma 6 na lokaciji 6p22.2 [5]
Aminokiselinska sekvenca
urediDužina polipeptidnog lanca je 348 aminokiselina, а molekulska težina 40.108 Da.[6]
10 | 20 | 30 | 40 | 50 | ||||
---|---|---|---|---|---|---|---|---|
MGPRARPALL | LLMLLQTAVL | QGRLLRSHSL | HYLFMGASEQ | DLGLSLFEAL | ||||
GYVDDQLFVF | YDHESRRVEP | RTPWVSSRIS | SQMWLQLSQS | LKGWDHMFTV | ||||
DFWTIMENHN | HSKESHTLQV | ILGCEMQEDN | STEGYWKYGY | DGQDHLEFCP | ||||
DTLDWRAAEP | RAWPTKLEWE | RHKIRARQNR | AYLERDCPAQ | LQQLLELGRG | ||||
VLDQQVPPLV | KVTHHVTSSV | TTLRCRALNY | YPQNITMKWL | KDKQPMDAKE | ||||
FEPKDVLPNG | DGTYQGWITL | AVPPGEEQRY | TCQVEHPGLD | QPLIVIWEPS | ||||
PSGTLVIGVI | SGIAVFVVIL | FIGILFIILR | KRQGSRGAMG | HYVLAERE |
Funkcija
urediProtein kodiran ovim genom je membranski protein sličan proteinima MHC klase I i asocira na beta-2 mikroglobulin (beta2M). Smatra se da ovaj protein funkcionira tako da regulira cirkulaciju unosa gvožđa, regulirajući interakciju receptora transferina s transferinom.[7]
Gen HFE sadrži sedam egzona u rasponu od 12 kb.[8] Puna dužina transkripta predstavlja šest egzona.[9]
Protein HFE sastoji se od 343 aminokiseline. Postoji nekoliko komponenti, u nizu: signalni peptid (početni dio proteina), vanćelijsko područje vezivanja receptora transferina (α1 i α2), dio koji podsjeća na molekule imunoglobulina (α3), transmembransko područje koje usidruje protein u ćelijsku membranu i kratki citoplazmatski rep.[8]
Ekspresija HFE-a prolazi kroz alternativnu preradu. Preovlađujući cjeloviti transkript HFE-a ima ~ 4,2 kb.[10] Alternativne varijante transkripta HFE –a, u određenim ćelijama ili tkivima, mogu poslužiti kao regulatorni mehanizmi gvožđa.[10]
HFE je istaknut u apsorpcijskim ćelijama tankog crijeva,[11][12] epitelnim ćelijama želuca, tkivnim makrofagima, te krvnim monocitima i granulocitima,[12][13] i sincitiotrofoblastima, transportnom tkivu gvožđa u posteljici.[14]
Klinički značaj
urediPoremećaj skladištenja gvožđa nasljedna hemohromatoza (HHC) je autosomno recesivni genetički poremećaj koji je obično posljedica defekata ovog gena.
Genetička varijanta koja uzrokuje bolest najčešće je povezana s hemohromatozom p. C282Y. Oko 1/200 ljudi sjevernoevropskog porijekla ima dvije kopije ove varijante; oni, posebno muškarci, imaju veliki rizik od razvoja hemohromatoze.[15] Ova varijanta može biti i jedan od faktora koji mijenjaju fenotip Wilsonove bolesti, zbog čega se simptomi bolesti pojavljuju ranije.[16]
Učestalosti alela HFE C282Y u etnički raznolikim populacijama a kavkazoida u zapadnoj Evropi su 5-14%[17][18] a u Sjevernoj Americi nehispanoidni kavkazoidi imaju 6-7%.[19] C282Y postoji kao polimorfizam samo u zapadnoevropskoj populaciji kavkazoida i njihovih derivata, iako je C282Y mogao nastati nezavisno kod nekavkazoida izvan Evrope.[20]
HFE H63D je kosmopolitski, ali se javlja najvećom učestalošću kod kavkazoida evropskog porijekla.[21][22] Učestalost alela H63D u etnički raznolikoj populaciji Zapadne Evrope iznosi 10-29%.[23] and in North American non-Hispanic whites are 14-15%.[24]
Otkrivene su najmanje 42 mutacije koje uključuju HFE-ove introne i egzone, od kojih većina u osoba s hemohromatozom ili članova njihove porodice.[25] Većina ovih mutacija je rijetka. Mnoge mutacije uzrokuju ili vjerovatno uzrokuju fenotipove hemohromatoza, često u složenoj heterozigotnosti s HFE C282Y. Druge mutacije su ili sinonimne ili njihov učinak na fenotipove sa gvožđem, ako ih ima, nije dokazan.[25]
Interakcije
urediHFE protein stupa u interakcije s receptorom transferina TFRC.[26][27] Njegov primarni način djelovanja je regulacija hormona skladištenja gvožđevog hepcidina.[28]
Nokaut-miš Hfe
urediMoguće je deletirati dio ili cijeli gen od inzteresakoji kod miševa (ili drugih pokusnih životinja) kao sredstvo za proučavanje funkcije gena i njegovih proteina. Takvi se miševi nazivaju "nokaut-miševima" s obzirom na ideletirani gen. Hfe je mišji ekvivalent gena ljudskee hemohromatoze HFE. Protein koji kodira Hfe je Hfe. Homozigotni miševi (dvije abnormalne kopije gena) za ciljano izbacivanje svih šest transkribiranih Hfe egzona označeni su kao Hfe–/–.[29] Svojstva koja su u vezi sa gvožđem kod miševa Hfe–/– , uključujući povećanu apsorpciju gvožđa i opterećenje jetre gvožđem, nasljeđuju se po autosomno recesivnom obrascu. Dakle, Hfe–/– mišji model simulira važne genetičke i fiziološke abnormalnosti HFE hemohromatoze.[29] Ostali nokaut-miševi generiranii su za deleciju drugog i trećeg Hfe egzona (što odgovara α1 i α2 domenima Hfe). Homozigotni miševi za ovu deleciju također su imali povećanu apsorpciju gvožđa u duodenumu, povišenu razinu zasićenja gvpžđemm u plazmi i transferinom i preopterećenje gvožđem, uglavnom u hepatocitima.[30] Takođe su stvoreni miševi koji su homozigotni za misens mutaciju u Hfe (C282Y). Ovi miševi odgovaraju osobama s hemohromatozom koje su homozigotne za HFE C282Y. Ovi miševi razvijaju opterećenje gvožđem koje je manje ozbiljno od opterećenja miša Hfe–/–.[31]
HFE mutacije i preopterećenje gvožđem kod ostalih životinja
urediCrni nosorog (Diceros bicornis) dobijaija preopterećenje gvožđem. Kako bi se utvrdilo je li gen HFE crnih nosoroga podvrgnut mutaciji kao adaptivni mehanizam za poboljšanje apsorpcije gvožđa iz heane siromašne gvožđem, Beutler et al. sekvencirali su cijelu HFE šifrirajuću regiju četiri vrste nosoroga (po dvije listojedne i ispaši). Iako je HFE dobro konzerviran među vrstama, pronađene su brojne nukleotidne razlike između nosoroga i čovjeka ili miša, od kojih su neke promijenile podrazumijvajuće aminokiseline. Samo jedan alel, p.S88T crnog nosoroga, bio je kandidat koji bi mogao negativno utjecati na funkciju HFE. p.S88T javlja se u visoko konzerviranoj regiji uključenoj u interakciju HFE i TfR1.[32]
Također pogledajte
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Reference
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- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000006611 - Ensembl, maj 2017
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Dopunska literatura
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- Beutler E (maj 2003). "The HFE Cys282Tyr mutation as a necessary but not sufficient cause of clinical hereditary hemochromatosis". Blood. 101 (9): 3347–50. doi:10.1182/blood-2002-06-1747. PMID 12707220.
- Ombiga J, Adams LA, Tang K, Trinder D, Olynyk JK (novembar 2005). "Screening for HFE and iron overload". Seminars in Liver Disease. 25 (4): 402–10. doi:10.1055/s-2005-923312. PMID 16315134.
- Distante S (2006). "Genetic predisposition to iron overload: prevalence and phenotypic expression of hemochromatosis-associated HFE-C282Y gene mutation". Scandinavian Journal of Clinical and Laboratory Investigation. 66 (2): 83–100. doi:10.1080/00365510500495616. PMID 16537242. S2CID 23644937.
- Zamboni P, Gemmati D (juli 2007). "Clinical implications of gene polymorphisms in venous leg ulcer: a model in tissue injury and reparative process". Thrombosis and Haemostasis. 98 (1): 131–7. doi:10.1160/th06-11-0625. PMID 17598005.
Vanjski linkovi
uredi- HFE protein, human na US National Library of Medicine Medical Subject Headings (MeSH)
- Q30201