HFE (gen)

Razlikovati: Hemohromatoza.
HFE
Dostupne strukture
PDBPretraga ortologa: PDBe RCSB
Spisak PDB ID kodova

1DE4, 1A6Z

Identifikatori
AliasiHFE
Vanjski ID-jeviOMIM: 613609 MGI: 109191 HomoloGene: 88330 GeneCards: HFE
Lokacija gena (čovjek)
Hromosom 6 (čovjek)
Hrom.Hromosom 6 (čovjek)[1]
Hromosom 6 (čovjek)
Genomska lokacija za HFE
Genomska lokacija za HFE
Bend6p22.2Početak26,087,281 bp[1]
Kraj26,098,343 bp[1]
Lokacija gena (miš)
Hromosom 13 (miš)
Hrom.Hromosom 13 (miš)[2]
Hromosom 13 (miš)
Genomska lokacija za HFE
Genomska lokacija za HFE
Bend13 A3.1|13 9.88 cMPočetak23,886,017 bp[2]
Kraj23,894,837 bp[2]
Obrazac RNK ekspresije




Više referentnih podataka o ekspresiji
Ontologija gena
Molekularna funkcija• peptide antigen binding
• beta-2-microglobulin binding
• co-receptor binding
• GO:0001948, GO:0016582 vezivanje za proteine
• transferrin receptor binding
• signaling receptor binding
• natural killer cell lectin-like receptor binding
Ćelijska komponenta• integral component of membrane
• reciklirajući endosom
• HFE-transferrin receptor complex
• membrana
• basal part of cell
• ćelijska membrana
• apical part of cell
• integral component of plasma membrane
• terminal web
• early endosome
• MHC class I protein complex
• perinuklearno područje citoplazme
• GO:0016023 citoplazmatska vezikula
• external side of plasma membrane
• Vanćelijsko
Biološki proces• negative regulation of T cell antigen processing and presentation
• positive regulation of peptide hormone secretion
• positive regulation of receptor-mediated endocytosis
• cellular response to iron ion
• antigen processing and presentation
• negative regulation of receptor binding
• regulation of protein localization to cell surface
• antigen processing and presentation of peptide antigen via MHC class I
• female pregnancy
• positive regulation of pathway-restricted SMAD protein phosphorylation
• response to iron ion starvation
• iron ion homeostasis
• negative regulation of antigen processing and presentation of endogenous peptide antigen via MHC class I
• ion transport
• BMP signaling pathway
• cellular response to iron ion starvation
• response to iron ion
• multicellular organismal iron ion homeostasis
• positive regulation of ferrous iron binding
• positive regulation of transferrin receptor binding
• positive regulation of signaling receptor activity
• liver regeneration
• GO:1901313 positive regulation of gene expression
• negative regulation of T cell cytokine production
• acute-phase response
• negative regulation of proteasomal ubiquitin-dependent protein catabolic process
• negative regulation of ubiquitin-dependent protein catabolic process
• positive regulation of receptor binding
• negative regulation of signaling receptor activity
• positive regulation of protein binding
• hormone biosynthetic process
• negative regulation of CD8-positive, alpha-beta T cell activation
• cellular iron ion homeostasis
• iron ion import across plasma membrane
• transferrin transport
• GO:0034622 protein-containing complex assembly
• T cell mediated cytotoxicity
• GO:0046730, GO:0046737, GO:0046738, GO:0046736 Imuni odgovor
• natural killer cell activation
• natural killer cell mediated cytotoxicity
• susceptibility to natural killer cell mediated cytotoxicity
• GO:1900400 regulation of iron ion transport
Izvori:Amigo / QuickGO
Ortolozi
VrsteČovjekMiš
Entrez

3077

15216

Ensembl

ENSG00000010704

ENSMUSG00000006611

UniProt

Q30201

P70387

RefSeq (mRNK)
NM_000410
NM_001300749
NM_139002
NM_139003
NM_139004

NM_139005
NM_139006
NM_139007
NM_139008
NM_139009
NM_139010
NM_139011
NM_001384164

NM_010424
NM_001347493

RefSeq (bjelančevina)
NP_000401
NP_001287678
NP_620572
NP_620573
NP_620575

NP_620576
NP_620577
NP_620578
NP_620579
NP_620580
NP_001371093

NP_001334422
NP_034554

Lokacija (UCSC)Chr 6: 26.09 – 26.1 MbChr 13: 23.89 – 23.89 Mb
PubMed pretraga[3][4]
Wikipodaci
Pogledaj/uredi – čovjekPogledaj/uredi – miš

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

Dužina polipeptidnog lanca je 348 aminokiselina, а molekulska težina 40.108 Da.[6]

1020304050
MGPRARPALLLLMLLQTAVLQGRLLRSHSLHYLFMGASEQDLGLSLFEAL
GYVDDQLFVFYDHESRRVEPRTPWVSSRISSQMWLQLSQSLKGWDHMFTV
DFWTIMENHNHSKESHTLQVILGCEMQEDNSTEGYWKYGYDGQDHLEFCP
DTLDWRAAEPRAWPTKLEWERHKIRARQNRAYLERDCPAQLQQLLELGRG
VLDQQVPPLVKVTHHVTSSVTTLRCRALNYYPQNITMKWLKDKQPMDAKE
FEPKDVLPNGDGTYQGWITLAVPPGEEQRYTCQVEHPGLDQPLIVIWEPS
PSGTLVIGVISGIAVFVVILFIGILFIILRKRQGSRGAMGHYVLAERE

Funkcija

Protein 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

Poremećaj 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

HFE protein stupa u interakcije s receptorom transferina TFRC.[26][27] Njegov primarni način djelovanja je regulacija hormona skladištenja gvožđevog hepcidina.[28]

Nokaut-miš Hfe

Moguće 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

Crni 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]

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Reference

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  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000006611 - Ensembl, maj 2017
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Dopunska literatura

Vanjski linkovi

Šablon:Metabolizam gvožđa