2005-2006 > Academic research: refereed > Publication in refereed journalVersion of RecordPublishe

Chang, YZ

Kang, YM

Qian, ZM

2005-2006 > Academic research: refereed > Publication in refereed journalVersion of RecordPublishedVoR allowe

PolyU Institutional Repository

　[ ????] 2005-08-25　　　[ ????] 2005-12-02＊[ ????] ???? UGC ????(PolyU5270/01M/ B-Q445), ??????????????(G-YX14 , A256 , G-YD78 , A-PD92 , G-T616 , and G-T856);?????????????????????????■???? E-mail:bcyake@polyu.edu.hk[ ????] 　1000-4718(2006)02-0408-04HFE?????????＊钱忠明1 , 2 ,3 , 　康友敏3 , 　常彦忠1 , 　柯　亚1■(1??????????????????????? , ?? , ?? ??;2????????????????? , ?? ?? 518060;3??????????????????? , ?? ??? 050016)HFE protein and hereditary haemochromatosisQIAN Zhong-ming1 ,2 , 3 , KANG You-min3 , CHANG Yan-zhong1 , KE Ya1■(1 Iron Metabolism Laboratory , Department of Applied Biology and Chemical Technology , Hong Kong PloytechnicUniversity , Kowloon , Hong Kong , China;2National Key Laboratory of Chinese Medicine and MolecularPharmacology , Shenzhen 518060 , China;3 Institue of Neurobiology &Neuropharmacology , HebeiNormal University , Shijiazhuang 050016 , China)　　【A Review】　Hereditary haemochromatosis is an iron-overload disease , which mainly induced by the hemochromatosis gene(HFE)mutation.Proximately 10% the whites have mutations in the HFE gene that has been identified in points of C282Y , H63Dand S65C.About 85% of HH cases are caused by a mutation of amino acid 282(C282Y)in the HFE gene.HFE protein is not on-ly involved in regulation of transferrin-bound iron uptake but also a key component in the regulation of intestinal iron absorption.Inaddition , other gene mutation such as transferrin receptor 2 also can cause HH disease.　　[ ???] 　??????;?? ,HFE;???;?? , ????　　[ KEY WORDS] 　Hereditary haemochromatosis;Genes , HFE;Iron metabolism;Receptors , transferrin　　[ ?????] 　R363　　　　　[ ?????] 　A　　??????(hereditary haemochromatosis , HH)???????????。?????? ,???????? , ?????????? 1/200。??1/10 ?????? HFE ???????[ 1] 。???HH???????????? ,???????????[ 2] 。HH?????????????? ,???? 、? 、???????????????? ,???????? 、??? 、???? 、??? 、???????????? 。?????????1865? ,???? HH ???????????。???????????????(pigment cirrho-sis),???????(bronzed diabetes)。?????????????????????? ,??????(haemochromatose)。???????????? ,????????? ,??????????。?? HH ????? 100????? ,?????????????????。1996? ,Feder ?[ 3]??HFE(hemochromatosis gene)??? HH ???????。1998? ,Lebron?[ 4] ??? HFE????????? HFE?????????(transferrin receptor ,TfR)???????。??????????????????????? HH ???????????? ,??????????????????????。1　HFE?? 、???????　　HFE(? HLA-H)??(12 kb)??? 6?????? ,? 1 029 bp?????????????。?????? 343 ?????????????HFE?? 。HFE???MHC-Ⅰ???(major histo-compatibility complex Ⅰ)???????? 。? MHC-Ⅰ????? ,HFE??????????? ,?N-???? 、?????(α1 、α2)、???????·408· ????????　Chinese Journal of Pathophysiology　2006 , 22(2):408-411???(α3)、?????????????[ 4] 。HFE?????????? ,??????????MHC????????? ,?????????????? 282 ????????????(helicaldomain)????????[ 3] 。??????????????? 、??????????????。α2?α3???2??????????? ,?α3????? 225? 282????????? 2??????????????? ,?α3?? β2????????????。?HFE??α1?α2??????。? MHC-Ⅰ??????? HFE ?????T ???????? ,??? T ???????? ,????????[ 5] 。HFE ??? MHC-Ⅰ????????????? HFE???α1?α2????MHC-Ⅰ???? 4 ,?HFE??????????????????? 415 ,?? MHC-Ⅰ????? 760 [ 4] 。?????? HFE???????????????。HFE???????????α1??????? 4??????(???pKa??? 6.5)。HFE ????????????????? ,????????????????????? ,????????????????????????????????? ,??????????????。HFE ??????????????? ,?????????????????????????????。2　HFE-TfR????????????　　????HFE??????????? TfR???? 2.8 ??????[ 4 ,6] ,???? HFE???????? TfR???。TfR??????? ,??pH(7.4)?????????(iron-bound trans-ferrin , Fe-Tf?? diferric Tf)???? 。??? TfR??????Fe-Tf。??????????。?????? pH ????????????????6.5?? ,???? Tf???????? Tf????[ 7 ,8] ,????????????(divalent metaltransporter , DMT1)??????? 。??????????????????????。HFE???Tf-Fe ???? TfR??????????? ,???HFE?????Fe-Tf?????? TfR???????[ 5] 。???? HFE ??????? TfR?? Fe-Tf? TfR???????? ,?????TfR? Fe -Tf ????? ,???????????。??? TfR??? TfR-HFE???????????????????。?? ,Lebron?[ 5]??????? HFE-TfR??????。?????????? HFE?????? TfR??? 。??????????????????????????? ,??????? TfR??????????1/2???HFE?? 。????????? TfR?HFE?????????????????? ,??? T?????MHC-Ⅰ??????????????????? 。??HFE?????????? 1? TfR??????? ,?TfR?????????????。HFE ? TfR?????? ,??2 000  ,??HFE???α1?α2???TfR?1?3????? ,????????? 3???? ,(??HFE ???α1 ??? TfR?????),?? 3?????α1??? 3????????? 5????????。???? HFE?? 、TfR??????????? HFE??? TfR????[ 4 , 9] ,??????????? TfR????????? ,?HFE???????? ,????? HFE-TfR?????? TfR??????????????? ,??????HFE??? 4???????????[ 5] 。3　HFE????　　???? ,HFE????????????? ,?? C282Y , H63D? S65C ?。?? C282Y???HFE???????? 12%, ? H63D ?? 25%。?? H63D?????? HFE ??????? ,?????HH 。C282Y?????? ,C282Y? HFE????????? 282?????????????(???Cys282Tyr? C282Y)。??? HH????????? 。??????????????????? 85%[ 3] 。??? HFE ?? C282Y ????????????(founder effect)。?????HFE????????????? β2-????????? ,????????????????。?? HFE???????????? ,???????????? ,??????????????????????????? ,??????????????????(???)。HFE ??????????? 63?????????????(??? His63Asp ? H63D)。H63D ???????HFE???????????? ,??? C282Y???????????? ,???????HH????。?? H63D??????????????·409·?[ 10] 。? 3?HFE???????? 65?????????????????(??? S65C)。?420???????? PCR-SSCP ??? 13 ?S65C?。?????? S65C????????????????????? ,?? S65C ???????????[ 11] 。?? ,Peuschel[ 12]?? 20???????????HH?? ,?????????????? ,?????????????????????????? 。? 20??????????? 4???? C282Y??? 、C282Y/H63D????? H63D ????????? ,???????HFE??? 2 、3 、4 、5???? 2 、4 、5????????[ 13] 。????????HH ??????HFE???? ,??HH ????????? 。???????? ???? ? 2 (transferrin receptor 2 ,TfR2)[ 13] ,??????????HH???TfR2???????。Fleming ?[ 6]??????????? ,TfR2???????????????????????? ,??? TfR2?????????????。Mattman?[ 15] ????? HH ??????4??? ,?? TfR2?????? 17??? , 690??????????? ,????????????????? 。??????????? 1(ferro-portin 1 , FP1)??? HH ??[ 17] 。?????????????????????? ,???? FP1?mRNA?????????? 3 ?。Njajou?[ 10]??????????????????? ,???? 2?????? SLCIIA3??(?? FP1??)?? 5?????734?????A??? C ,???????????? ,???????????。Wallace ?[ 16]???????HH?????FP1????(V162del),?????????? FP1????? ,???????? 。?????? FP1 ???????? HH???[ 10] ,??????? 。4　HFE???????? HFE?????????　　??HFE ???????? HFE ??????????????。?????? ,HFE ???????????? 2??? ,?????????????????????? ,???????????????? ,???????????。???????????? ,HFE?????????? ,????? TfR???????? TfR???Tf-Fe??。? HFE ????? ,HFE ? TfR???? ,???? Tf-Fe ?? ,???? 。? HFE????????????????????。??????????????????? hep-cidin[ 17 , 18] 。???TfR? HFE?????????? ,????? β -???????????????????????????????????? ,???????????????????。??????????????????? 4??????:????? B(duodenal cytochromeb ,Dcytb)、DMT1 、FP1 ?????????(hephaestin ,Hp)[ 19] 。DMT1? Dcytb?????????(???????????),FP1 ? Hp ??????????????????。?????????(Fe3+)??? Dcytb ??????(Fe2+),???DMT1????????? 。???????????????????????????? ,???(Fe2+)?FP1??????? ,?? Hp? Fe2+??? Fe3+ ,???????Tf??[ 19] 。　　??????????? 4??????? ,???? ,????[ 19] 。??? 4??????????????????。????? ,?????????????? 4??????????。???????????? ,????????????????? ,?????? ,????。?????????????? HFE(? TfR? β-????),????????????? hepcidin ??[ 20] 。???? hepcidin????????????? TfR2??????????。????? ,?????????? ,?????? 。???????? TfR2???? ,??? TfR2 ??????? ,??????????? hepcidin ?? 。Hep-cidin??????????? ,??? HFE-TfR1-β-??????? ,????????? ,????????? ,?????? 4?????????? , ????? , ????????????[ 20] 。????????(TfR2※hepcidin※HFE/TfR/β2 ???????※???????※4???????※?????※?????※TfR2)。???? ,HFE????????????????? ,????????????????????????? ,????? ,???????????HH[ 14 ,20] 。???? ,?? HH ???? HFE ?? ,??? TfR2???? 。TfR2????????????? 。TfR2???????????? TfR2·410·???????? ,???? ,?????HFE?????????? ,???HH 。5　??　　HFE??????????????????HH???????????????????。??????????????????????????。?? ,?? HFE? HH ??????????????? ,???????????????? 。?? ,HFE???? ,????????????????????? ,???????????????????????? ,????????? 。?? ,?? HH ??????? ,?????????????????????? 。?????HH?????????????????? ,???????????????????? HH??????????????? ,??????????????? 。[ ?　?　?　?][ 1] 　Burke W , Tjhomson E , Khoury MJ , et al.Hereditaryhemochromatosis:gene discovery and its implications for popu-lation-based screening[ J] .JAMA , 1998 , 280(2):172-178.[ 2] 　???.????[ A] .?:??? ??.????????[ M] .? 1 ?.??:????? , 2000.210-233.[ 3] 　Feder JN , Gnirke A , Thomas W , et al.A novel MHC class I-like gene is mutated in patients with hereditary haemochro-matosis[ J] .Nature Genet , 1996 , 13(4):399-408.[ 4] 　Lebron JA , Bennett MJ , Vaughn DE , et al.Crystal structureof the hemochromatosis protein HFE and characterization of itsinteraction with transferrin receptor[ J] .Cell , 1998 , 93(1):111-123.[ 5] 　Lebron JA , Bjorkman PJ.The transferrin receptor binding siteon HFE , the class I MHC-related protein mutated in heredi-tary hemochromatosis[ J] .J Mol Biol , 1999 , 289(4):1109-1118.[ 6] 　Fleming RE , Sly WS.Mechanisms of iron accumulation inhereditary hemochromatosis[ J] .Annu Rev Physiol , 2002 ,64:663-680.[ 7] 　Qian ZM , Tang PL.Mechanisms of iron uptake by mammaliancells[ J] .Biochim Biophys Acta , 1995 , 1269(3):205-214.[ 8] 　Qian ZM , Tang PL , Wang Q.Iron crosses the endosomalmembrane by a carrier-mediated process[ J] .Prog BiophysMol Biol , 1997 , 67(1):1-15.[ 9] 　Lawrence CM , Ray S , Babyonyshev M , et al.Crystal struc-ture of the ectodomain of human transferrin receptor[ J] .Sci-ence, 1999 , 286(5440):779-782.[ 10] Njajou OT , Vaessen N , Joosse M , et al.A mutation inSLC11A3 is associated with autosomal dominant hemochro-matosis[ J] .Nature Genet , 2001 , 28(3):213-214.[ 11] Powell LW.Hereditary hemochromatosis and iron overloaddiseases[ J] .J Gastroenterol Hepatol , 2002 , 17(Suppl):S191-S519.[ 12] Peuschel KE.A genetic defect of an iron pump on chromo-some 20 is postulated to cause human hemochromatosis[ J] .MedHypotheses , 1997 , 49(5):417-419.[ 13] Barton JC , Rothenberg EB , Bertoli LF , et al.Diagnosis ofhemochromatosis in family members of probands:a comparisonof phenotyping and HFE genotyping[ J] .Genet Med , 1999 , 1(3):89-93.[ 14] ??? , ??? , ???.?????? 2 ?????????[ J] .??????????? , 2003 , 30(4):533-537.[ 15] Mattman A , Huntsman D , Lockitch G , et al.Transferrin re-ceptor 2(TfR2)and HFE mutational analysis in non-C282Yiron overload:identification of a novel TfR2 mutation[ J] .Blood , 2002 , 100(3):1075-1077.[ 16] Wallace DF , Pedersen P , Dixon JL, et al.Novel mutation inferroportin1 is associated with autosomal dominant hemochro-matosis[ J] .Blood , 2002 , 100(2):692-694.[ 17] Nicolas G , Bennoun M , Devaux I , et al.Lack of hepcidingene expression and severe tissue iron overload in upstreamstimulatory factor 2(USF2)knockout mice[ J] .Proc Natl A-cad Sci USA , 2001 , 98(15):8780-8785.[ 18] Fleming RE , Sly WS.Hepcidin:a putative iron-regulatoryhormone relevant to hereditary hemochromatosis and the ane-mia of chronic disease[ J] .Proc Natl Acad Sci USA , 2001 ,98(15):8160-8162.[ 19] ??? ,???.????????????????[ J] .?????? , 2010 , 81(24):1533-1535.[ 20] ??? ,???.Hepcidin????[ J] .????????? , 2003 , 19(6):501-504.·411·

HFE protein and hereditary haemochromatosis

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