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
[uredi | uredi izvor]Dužina polipeptidnog lanca je 348 aminokiselina, а molekulska težina 40.108 Da.[6]
10 | 20 | 30 | 40 | 50 | ||||
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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
[uredi | uredi izvor]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
[uredi | uredi izvor]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
[uredi | uredi izvor]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
[uredi | uredi izvor]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
[uredi | uredi izvor]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]
Također pogledajte
[uredi | uredi izvor]- Genska mutacija HFE H63D
- Hemohromatoza
Napomena
[uredi | uredi izvor]Greška: Imena
pokazatelja stanja stranice ne smiju biti prazna.
Reference
[uredi | uredi izvor]- ^ a b c GRCh38: Ensembl release 89: ENSG00000010704 - Ensembl, maj 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000006611 - 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.
- ^ "HGNC: HFE". Pristupljeno 30. 8. 2019.
- ^ "UniProt, Q30201" (jezik: engleski). Pristupljeno 3. 10. 2021.
- ^ "NCBI Gene: HFE homeostatic iron regulator". National Center for Biotechnology Information. Pristupljeno 30. 11. 2020.
Ovaj članak sadrži tekst iz ovog izvora, koji je u javnom vlasništvu.
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- ^ Dorak, M.T. (mart 2008). "HFE (hemochromatosis)". Atlas of Genetics and Cytogenetics in Oncology and Haematology. Arhivirano s originala, 29. 9. 2017. Pristupljeno 17. 6. 2020.
- ^ a b Martins, R; Silva, B; Proença, D; Faustino, P (3. 3. 2011). "Differential HFE gene expression is regulated by alternative splicing in human tissues". PLOS ONE. 6 (3): e17542. Bibcode:2011PLoSO...617542M. doi:10.1371/journal.pone.0017542. PMC 3048171. PMID 21407826.
- ^ Waheed, A; Parkkila, S; Saarnio, J; Fleming, RE; Zhou, XY; Tomatsu, S; Britton, RS; Bacon, BR; Sly, WS (16. 2. 1999). "Association of HFE protein with transferrin receptor in crypt enterocytes of human duodenum". Proceedings of the National Academy of Sciences of the United States of America. 96 (4): 1579–84. Bibcode:1999PNAS...96.1579W. doi:10.1073/pnas.96.4.1579. PMC 15523. PMID 9990067.
- ^ a b Griffiths, WJ; Kelly, AL; Smith, SJ; Cox, TM (septembar 2000). "Localization of iron transport and regulatory proteins in human cells". QJM : Monthly Journal of the Association of Physicians. 93 (9): 575–87. doi:10.1093/qjmed/93.9.575. PMID 10984552.
- ^ Parkkila, S; Parkkila, AK; Waheed, A; Britton, RS; Zhou, XY; Fleming, RE; Tomatsu, S; Bacon, BR; Sly, WS (april 2000). "Cell surface expression of HFE protein in epithelial cells, macrophages, and monocytes". Haematologica. 85 (4): 340–5. PMID 10756356.
- ^ Parkkila, S; Waheed, A; Britton, RS; Bacon, BR; Zhou, XY; Tomatsu, S; Fleming, RE; Sly, WS (25. 11. 1997). "Association of the transferrin receptor in human placenta with HFE, the protein defective in hereditary hemochromatosis". Proceedings of the National Academy of Sciences of the United States of America. 94 (24): 13198–202. Bibcode:1997PNAS...9413198P. doi:10.1073/pnas.94.24.13198. PMC 24286. PMID 9371823.
- ^ "Hemochromatosis". Arhivirano s originala, 18. 3. 2007. Pristupljeno 20. 8. 2009.
- ^ Gromadzka G, Wierzbicka DW, Przybyłkowski A, Litwin T (novembar 2020). "Effect of homeostatic iron regulator protein gene mutation on Wilson's disease clinical manifestation: original data and literature review". The International Journal of Neuroscience: 1–11. doi:10.1080/00207454.2020.1849190. PMID 33175593.
- ^ Porto, Graca; de Sousa, Maria (2000). Barton, James C.; Edwards, Corwin Q. (ured.). Variation of hemochromatosis prevalence and genotype in national groups. In: Hemochromatosis: Genetics, pathophysiology, diagnosis and treatment: Cambridge University Press. str. 51–62. ISBN 978-0521593809.
- ^ Ryan, E; O'Keane, C; Crowe, J (decembar 1998). "Hemochromatosis in Ireland and HFE". Blood Cells, Molecules & Diseases. 24 (4): 428–32. doi:10.1006/bcmd.1998.0211. PMID 9851896.
- ^ Acton, RT; Barton, JC; Snively, BM; McLaren, CE; Adams, PC; Harris, EL; Speechley, MR; McLaren, GD; Dawkins, FW; Leiendecker-Foster, C; Holup, JL; Balasubramanyam, A; Hemochromatosis and Iron Overload Screening Study Research Investigators (2006). "Geographic and racial/ethnic differences in HFE mutation frequencies in the Hemochromatosis and Iron Overload Screening (HEIRS) Study". Ethnicity & Disease. 16 (4): 815–21. PMID 17061732.
- ^ Rochette, J; Pointon, JJ; Fisher, CA; Perera, G; Arambepola, M; Arichchi, DS; De Silva, S; Vandwalle, JL; Monti, JP; Old, JM; Merryweather-Clarke, AT; Weatherall, DJ; Robson, KJ (april 1999). "Multicentric origin of hemochromatosis gene (HFE) mutations". American Journal of Human Genetics. 64 (4): 1056–62. doi:10.1086/302318. PMC 1377829. PMID 10090890.
- ^ Merryweather-Clarke, AT; Pointon, JJ; Shearman, JD; Robson, KJ (april 1997). "Global prevalence of putative haemochromatosis mutations". Journal of Medical Genetics. 34 (4): 275–8. doi:10.1136/jmg.34.4.275. PMC 1050911. PMID 9138148.
- ^ Merryweather-Clarke, AT; Pointon, JJ; Jouanolle, AM; Rochette, J; Robson, KJ (2000). "Geography of HFE C282Y and H63D mutations". Genetic Testing. 4 (2): 183–98. doi:10.1089/10906570050114902. PMID 10953959.
- ^ Fairbanks, Virgil F. (2000). Barton, James C.; Edwards, Corwin Q. (ured.). Hemochromatosis: population genetics. In: Hemochromatosis: Genetics, pathophysiology, diagnosis and treatment. Cambridge University Press. str. 42–50. ISBN 978-0521593809.
- ^ Acton, RT; Barton, JC; Snively, BM; McLaren, CE; Adams, PC; Harris, EL; Speechley, MR; McLaren, GD; Dawkins, FW; Leiendecker-Foster, C; Holup, JL; Balasubramanyam, A; Hemochromatosis and Iron Overload Screening Study Research Investigators (2000). "Geographic and racial/ethnic differences in HFE mutation frequencies in the Hemochromatosis and Iron Overload Screening (HEIRS) Study". Ethnicity & Disease. 16 (4): 815–21. PMID 17061732.
- ^ a b Edwards, Corwin Q.; Barton, James C. (2014). Greer, John P.; Arber, Daniel A.; Glader, Bertil; List, Alan F.; Means, Robert T., Jr.; Paraskevas, Frixos; Rodgers, George M. (ured.). Hemochromatosis. In: Wintrobe's Clinical Hematology. Wolters Kluwer/Lippincott Williams & Wilkins. str. 662–681. ISBN 9781451172683.
- ^ Feder JN, Penny DM, Irrinki A, Lee VK, Lebrón JA, Watson N, Tsuchihashi Z, Sigal E, Bjorkman PJ, Schatzman RC (februar 1998). "The hemochromatosis gene product complexes with the transferrin receptor and lowers its affinity for ligand binding". Proceedings of the National Academy of Sciences of the United States of America. 95 (4): 1472–7. Bibcode:1998PNAS...95.1472F. doi:10.1073/pnas.95.4.1472. PMC 19050. PMID 9465039.
- ^ West AP, Bennett MJ, Sellers VM, Andrews NC, Enns CA, Bjorkman PJ (decembar 2000). "Comparison of the interactions of transferrin receptor and transferrin receptor 2 with transferrin and the hereditary hemochromatosis protein HFE". The Journal of Biological Chemistry. 275 (49): 38135–8. doi:10.1074/jbc.C000664200. PMID 11027676.
- ^ Nemeth E, Ganz T (2006). "Regulation of iron metabolism by hepcidin". Annual Review of Nutrition. 26: 323–342. doi:10.1146/annurev.nutr.26.061505.111303. PMID 16848710.
- ^ a b Zhou, XY; Tomatsu, S; Fleming, RE; Parkkila, S; Waheed, A; Jiang, J; Fei, Y; Brunt, EM; Ruddy, DA; Prass, CE; Schatzman, RC; O'Neill, R; Britton, RS; Bacon, BR; Sly, WS (3. 3. 1998). "HFE gene knockout produces mouse model of hereditary hemochromatosis". Proceedings of the National Academy of Sciences of the United States of America. 95 (5): 2492–7. Bibcode:1998PNAS...95.2492Z. doi:10.1073/pnas.95.5.2492. PMC 19387. PMID 9482913.
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- ^ Levy, JE; Montross, LK; Cohen, DE; Fleming, MD; Andrews, NC (1. 7. 1999). "The C282Y mutation causing hereditary hemochromatosis does not produce a null allele". Blood. 94 (1): 9–11. doi:10.1182/blood.V94.1.9.413a43_9_11. PMID 10381492.
- ^ Beutler, E; West, C; Speir, JA; Wilson, IA; Worley, M (2001). "The hHFE gene of browsing and grazing rhinoceroses: a possible site of adaptation to a low-iron diet". Blood Cells, Molecules & Diseases. 27 (1): 342–50. doi:10.1006/bcmd.2001.0386. PMID 11358396.
Dopunska literatura
[uredi | uredi izvor]- Dorak MT, Burnett AK, Worwood M (mart 2002). "Hemochromatosis gene in leukemia and lymphoma". Leukemia & Lymphoma. 43 (3): 467–77. doi:10.1080/10428190290011930. PMID 12002748. S2CID 26047470.
- 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 | uredi izvor]- HFE protein, human na US National Library of Medicine Medical Subject Headings (MeSH)
- Q30201
Šablon:Metabolizam gvožđa
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Membrane-spanning 4A |
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Myelin |
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Pulmonary surfactant |
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Tetraspanin |
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Ostali/negrupisani |
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također pogledati other cell membrane protein disorders |
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