Full text data of SLC40A1
SLC40A1
(FPN1, IREG1, SLC11A3)
[Confidence: high (present in two of the MS resources)]
Solute carrier family 40 member 1 (Ferroportin-1; Iron-regulated transporter 1)
Solute carrier family 40 member 1 (Ferroportin-1; Iron-regulated transporter 1)
hRBCD
IPI00005547
IPI00005547 Solute carrier family 40, member 1 Solute carrier family 40, member 1 membrane n/a n/a 1 2 3 n/a n/a 2 n/a n/a 5 2 n/a 3 2 n/a n/a 2 n/a n/a integral membrane protein n/a found at its expected molecular weight found at molecular weight
IPI00005547 Solute carrier family 40, member 1 Solute carrier family 40, member 1 membrane n/a n/a 1 2 3 n/a n/a 2 n/a n/a 5 2 n/a 3 2 n/a n/a 2 n/a n/a integral membrane protein n/a found at its expected molecular weight found at molecular weight
UniProt
Q9NP59
ID S40A1_HUMAN Reviewed; 571 AA.
AC Q9NP59; Q6FI62; Q7Z4F8; Q8IVB2; Q9NRL0;
DT 07-JUN-2004, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-OCT-2000, sequence version 1.
DT 22-JAN-2014, entry version 114.
DE RecName: Full=Solute carrier family 40 member 1;
DE AltName: Full=Ferroportin-1;
DE AltName: Full=Iron-regulated transporter 1;
GN Name=SLC40A1; Synonyms=FPN1, IREG1, SLC11A3; ORFNames=MSTP079;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], TISSUE SPECIFICITY, AND VARIANT HFE4
RP ASP-77.
RX PubMed=10747949; DOI=10.1074/jbc.M000713200;
RA Abboud S., Haile D.J.;
RT "A novel mammalian iron-regulated protein involved in intracellular
RT iron metabolism.";
RL J. Biol. Chem. 275:19906-19912(2000).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA], AND SUBCELLULAR LOCATION.
RX PubMed=10882071; DOI=10.1016/S1097-2765(00)80425-6;
RA McKie A.T., Marciani P., Rolfs A., Brennan K., Wehr K., Barrow D.,
RA Miret S., Bomford A., Peters T.J., Farzaneh F., Hediger M.A.,
RA Hentze M.W., Simpson R.J.;
RT "A novel duodenal iron-regulated transporter, IREG1, implicated in the
RT basolateral transfer of iron to the circulation.";
RL Mol. Cell 5:299-309(2000).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Placenta;
RX PubMed=10693807; DOI=10.1038/35001596;
RA Donovan A., Brownlie A., Zhou Y., Shepard J., Pratt S.J., Moynihan J.,
RA Paw B.H., Drejer A., Barut B., Zapata A., Law T.C., Brugnara C.,
RA Lux S.E. IV, Pinkus G.S., Pinkus J.L., Kingsley P.D., Palis J.,
RA Fleming M.D., Andrews N.C., Zon L.I.;
RT "Positional cloning of zebrafish ferroportin1 identifies a conserved
RT vertebrate iron exporter.";
RL Nature 403:776-781(2000).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Uterus;
RX PubMed=11230166; DOI=10.1101/gr.GR1547R;
RA Wiemann S., Weil B., Wellenreuther R., Gassenhuber J., Glassl S.,
RA Ansorge W., Boecher M., Bloecker H., Bauersachs S., Blum H.,
RA Lauber J., Duesterhoeft A., Beyer A., Koehrer K., Strack N.,
RA Mewes H.-W., Ottenwaelder B., Obermaier B., Tampe J., Heubner D.,
RA Wambutt R., Korn B., Klein M., Poustka A.;
RT "Towards a catalog of human genes and proteins: sequencing and
RT analysis of 500 novel complete protein coding human cDNAs.";
RL Genome Res. 11:422-435(2001).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Placenta;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RA Ebert L., Schick M., Neubert P., Schatten R., Henze S., Korn B.;
RT "Cloning of human full open reading frames in Gateway(TM) system entry
RT vector (pDONR201).";
RL Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15815621; DOI=10.1038/nature03466;
RA Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H.,
RA Minx P., Wagner-McPherson C., Layman D., Wylie K., Sekhon M.,
RA Becker M.C., Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E.,
RA Kremitzki C., Oddy L., Du H., Sun H., Bradshaw-Cordum H., Ali J.,
RA Carter J., Cordes M., Harris A., Isak A., van Brunt A., Nguyen C.,
RA Du F., Courtney L., Kalicki J., Ozersky P., Abbott S., Armstrong J.,
RA Belter E.A., Caruso L., Cedroni M., Cotton M., Davidson T., Desai A.,
RA Elliott G., Erb T., Fronick C., Gaige T., Haakenson W., Haglund K.,
RA Holmes A., Harkins R., Kim K., Kruchowski S.S., Strong C.M.,
RA Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K.,
RA McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C.,
RA Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N.,
RA Swearengen-Shahid S., Snider J., Strong J.T., Thompson J., Yoakum M.,
RA Leonard S., Pearman C., Trani L., Radionenko M., Waligorski J.E.,
RA Wang C., Rock S.M., Tin-Wollam A.-M., Maupin R., Latreille P.,
RA Wendl M.C., Yang S.-P., Pohl C., Wallis J.W., Spieth J., Bieri T.A.,
RA Berkowicz N., Nelson J.O., Osborne J., Ding L., Meyer R., Sabo A.,
RA Shotland Y., Sinha P., Wohldmann P.E., Cook L.L., Hickenbotham M.T.,
RA Eldred J., Williams D., Jones T.A., She X., Ciccarelli F.D.,
RA Izaurralde E., Taylor J., Schmutz J., Myers R.M., Cox D.R., Huang X.,
RA McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C.,
RA Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S.,
RA Miller W., Eichler E.E., Bork P., Suyama M., Torrents D.,
RA Waterston R.H., Wilson R.K.;
RT "Generation and annotation of the DNA sequences of human chromosomes 2
RT and 4.";
RL Nature 434:724-731(2005).
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [9]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Blood, and Testis;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [10]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 1-133.
RC TISSUE=Aorta;
RA Hui R.T., Zhao B., Sheng H., Qin B.M., Liu Y.Q., Liu B., Wang X.Y.,
RA Xu H.S., Zhang Q., Tong Y.K., Song L., Ji X.J., Liu B.H., Lu H.,
RA Chen J.Z., Cai M.Q., Zheng W.Y., Teng C.Y., Liu Q., Yu L.T., Lin J.,
RA Gong Q., Zhang A.M., Gao R.L.;
RL Submitted (JUL-1999) to the EMBL/GenBank/DDBJ databases.
RN [11]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-6; 16-129 AND 255-316, AND
RP VARIANT HFE4 VAL-270.
RX PubMed=15338274; DOI=10.1007/s00439-004-1166-y;
RA Zaahl M.G., Merryweather-Clarke A.T., Kotze M.J., van der Merwe S.,
RA Warnich L., Robson K.J.H.;
RT "Analysis of genes implicated in iron regulation in individuals
RT presenting with primary iron overload.";
RL Hum. Genet. 115:409-417(2004).
RN [12]
RP VARIANT HFE4 ASP-77.
RX PubMed=11518736;
RA Montosi G., Donovan A., Totaro A., Garuti C., Pignatti E.,
RA Cassanelli S., Trenor C.C., Gasparini P., Andrews N.C.,
RA Pietrangelo A.;
RT "Autosomal-dominant hemochromatosis is associated with a mutation in
RT the ferroportin (SLC11A3) gene.";
RL J. Clin. Invest. 108:619-623(2001).
RN [13]
RP VARIANT HFE4 HIS-144.
RX PubMed=11431687; DOI=10.1038/90038;
RA Njajou O.T., Vaessen N., Joosse M., Berghuis B., van Dongen J.W.F.,
RA Breuning M.H., Snijders P.J.L.M., Rutten W.P.F., Sandkuijl L.A.,
RA Oostra B.A., van Duijn C.M., Heutink P.;
RT "A mutation in SLC11A3 is associated with autosomal dominant
RT hemochromatosis.";
RL Nat. Genet. 28:213-214(2001).
RN [14]
RP VARIANT HFE4 VAL-162 DEL.
RX PubMed=12091366; DOI=10.1182/blood.V100.2.692;
RA Wallace D.F., Pedersen P., Dixon J.L., Stephenson P., Searle J.W.,
RA Powell L.W., Subramaniam V.N.;
RT "Novel mutation in ferroportin1 is associated with autosomal dominant
RT hemochromatosis.";
RL Blood 100:692-694(2002).
RN [15]
RP VARIANT HFE4 VAL-162 DEL.
RX PubMed=12091367; DOI=10.1182/blood-2001-11-0132;
RA Devalia V., Carter K., Walker A.P., Perkins S.J., Worwood M., May A.,
RA Dooley J.S.;
RT "Autosomal dominant reticuloendothelial iron overload associated with
RT a 3-base pair deletion in the ferroportin 1 gene (SLC11A3).";
RL Blood 100:695-697(2002).
RN [16]
RP VARIANT HFE4 VAL-162 DEL.
RX PubMed=12123233; DOI=10.1182/blood-2002-03-0693;
RA Roetto A., Merryweather-Clarke A.T., Daraio F., Livesey K.,
RA Pointon J.J., Barbabietola G., Piga A., Mackie P.H., Robson K.J.H.,
RA Camaschella C.;
RT "A valine deletion of ferroportin 1: a common mutation in
RT hemochromastosis type 4.";
RL Blood 100:733-734(2002).
RN [17]
RP VARIANT HFE4 VAL-162 DEL.
RX PubMed=12406098; DOI=10.1046/j.1365-2141.2002.03946.x;
RA Cazzola M., Cremonesi L., Papaioannou M., Soriani N., Kioumi A.,
RA Charalambidou A., Paroni R., Romtsou K., Levi S., Ferrari M.,
RA Arosio P., Christakis J.;
RT "Genetic hyperferritinaemia and reticuloendothelial iron overload
RT associated with a three base pair deletion in the coding region of the
RT ferroportin gene (SLC11A3).";
RL Br. J. Haematol. 119:539-546(2002).
RN [18]
RP VARIANTS HFE4 GLY-157; HIS-182 AND VAL-323.
RX PubMed=12730114; DOI=10.1182/blood-2003-02-0439;
RA Hetet G., Devaux I., Soufir N., Grandchamp B., Beaumont C.;
RT "Molecular analyses of patients with hyperferritinemia and normal
RT serum iron values reveal both L ferritin IRE and 3 new ferroportin
RT (SLC11A3) mutations.";
RL Blood 102:1904-1910(2003).
RN [19]
RP VARIANT HIS-248.
RX PubMed=14636642; DOI=10.1016/S1079-9796(03)00164-5;
RA Gordeuk V.R., Caleffi A., Corradini E., Ferrara F., Jones R.A.,
RA Castro O., Onyekwere O., Kittles R., Pignatti E., Montosi G.,
RA Garuti C., Gangaidzo I.T., Gomo Z.A.R., Moyo V.M., Rouault T.A.,
RA MacPhail P., Pietrangelo A.;
RT "Iron overload in Africans and African-Americans and a common mutation
RT in the SCL40A1 (ferroportin 1) gene.";
RL Blood Cells Mol. Dis. 31:299-304(2003).
RN [20]
RP VARIANT HFE4 THR-144.
RX PubMed=12865285; DOI=10.1136/gut.52.8.1215;
RA Arden K.E., Wallace D.F., Dixon J.L., Summerville L., Searle J.W.,
RA Anderson G.J., Ramm G.A., Powell L.W., Subramaniam V.N.;
RT "A novel mutation in ferroportin1 is associated with haemochromatosis
RT in a Solomon Islands patient.";
RL Gut 52:1215-1217(2003).
RN [21]
RP VARIANT HFE4 ASN-64.
RX PubMed=12857562;
RA Rivard S.R., Lanzara C., Grimard D., Carella M., Simard H.,
RA Ficarella R., Simard R., D'Adamo A.P., De Braekeleer M., Gasparini P.;
RT "Autosomal dominant reticuloendothelial iron overload (HFE type 4) due
RT to a new missense mutation in the FERROPORTIN 1 gene (SLC11A3) in a
RT large French-Canadian family.";
RL Haematologica 88:824-826(2003).
RN [22]
RP VARIANT IRON OVERLOAD ASP-490.
RX PubMed=12873829; DOI=10.1016/S0168-8278(03)00148-X;
RA Jouanolle A.-M., Douabin-Gicquel V., Halimi C., Loreal O.,
RA Fergelot P., Delacour T., de Lajarte-Thirouard A.-S., Turlin B.,
RA Le Gall J.-Y., Cadet E., Rochette J., David V., Brissot P.;
RT "Novel mutation in ferroportin 1 gene is associated with autosomal
RT dominant iron overload.";
RL J. Hepatol. 39:286-289(2003).
RN [23]
RP VARIANTS IRON OVERLOAD SER-80 AND ILE-174.
RX PubMed=14757427; DOI=10.1016/j.bcmd.2003.08.003;
RA Pietrangelo A.;
RT "The ferroportin disease.";
RL Blood Cells Mol. Dis. 32:131-138(2004).
RN [24]
RP VARIANTS HFE4 ASP-144 AND VAL-270, AND VARIANT IRON OVERLOAD TYR-326.
RX PubMed=15466004; DOI=10.1136/jmg.2004.020644;
RA Robson K.J.H., Merryweather-Clarke A.T., Cadet E., Viprakasit V.,
RA Zaahl M.G., Pointon J.J., Weatherall D.J., Rochette J.;
RT "Recent advances in understanding haemochromatosis: a transition
RT state.";
RL J. Med. Genet. 41:721-730(2004).
RN [25]
RP ERRATUM.
RA Robson K.J.H., Merryweather-Clarke A.T., Cadet E., Viprakasit V.,
RA Zaahl M.G., Pointon J.J., Weatherall D.J., Rochette J.;
RL J. Med. Genet. 41:959-959(2004).
RN [26]
RP VARIANTS HFE4 VAL-80; VAL-181 AND ASP-267.
RX PubMed=16351644; DOI=10.1111/j.1365-2141.2005.05815.x;
RA Cremonesi L., Forni G.L., Soriani N., Lamagna M., Fermo I., Daraio F.,
RA Galli A., Pietra D., Malcovati L., Ferrari M., Camaschella C.,
RA Cazzola M.;
RT "Genetic and clinical heterogeneity of ferroportin disease.";
RL Br. J. Haematol. 131:663-670(2005).
RN [27]
RP ERRATUM.
RA Cremonesi L., Forni G.L., Soriani N., Lamagna M., Fermo I., Daraio F.,
RA Galli A., Pietra D., Malcovati L., Ferrari M., Camaschella C.,
RA Cazzola M.;
RL Br. J. Haematol. 132:806-806(2006).
CC -!- FUNCTION: May be involved in iron export from duodenal epithelial
CC cell and also in transfer of iron between maternal and fetal
CC circulation. Mediates iron efflux in the presence of a ferroxidase
CC (hephaestin and/or ceruloplasmin).
CC -!- INTERACTION:
CC P05067:APP; NbExp=4; IntAct=EBI-725153, EBI-77613;
CC -!- SUBCELLULAR LOCATION: Cell membrane; Multi-pass membrane protein.
CC Note=Localized to the basolateral membrane of polarized epithelial
CC cells.
CC -!- TISSUE SPECIFICITY: Expressed in placenta, intestine, muscle and
CC spleen.
CC -!- DISEASE: Hemochromatosis 4 (HFE4) [MIM:606069]: A disorder of iron
CC metabolism characterized by iron overload. Excess iron is
CC deposited in a variety of organs leading to their failure, and
CC resulting in serious illnesses including cirrhosis, hepatomas,
CC diabetes, cardiomyopathy, arthritis, and hypogonadotropic
CC hypogonadism. Severe effects of the disease usually do not appear
CC until after decades of progressive iron loading. Note=The disease
CC is caused by mutations affecting the gene represented in this
CC entry.
CC -!- SIMILARITY: Belongs to the ferroportin (FP) (TC 2.A.100) family.
CC SLC40A subfamily.
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/SLC40A1";
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DR EMBL; AF215636; AAF80986.1; -; mRNA.
DR EMBL; AF231121; AAF44330.1; -; mRNA.
DR EMBL; AF226614; AAF36697.1; -; mRNA.
DR EMBL; AL136944; CAB66878.1; -; mRNA.
DR EMBL; AK314827; BAG37348.1; -; mRNA.
DR EMBL; CR533564; CAG38595.1; -; mRNA.
DR EMBL; AC013439; AAX93082.1; -; Genomic_DNA.
DR EMBL; CH471058; EAX10902.1; -; Genomic_DNA.
DR EMBL; BC035893; AAH35893.1; -; mRNA.
DR EMBL; BC037733; AAH37733.1; -; mRNA.
DR EMBL; AF171087; AAQ13603.1; -; mRNA.
DR EMBL; AJ604512; CAE53170.1; -; Genomic_DNA.
DR EMBL; AJ609539; CAE81347.1; -; Genomic_DNA.
DR EMBL; AJ609540; CAE81348.1; -; Genomic_DNA.
DR EMBL; AJ616848; CAE83578.1; -; Genomic_DNA.
DR EMBL; AJ616847; CAE83578.1; JOINED; Genomic_DNA.
DR RefSeq; NP_055400.1; NM_014585.5.
DR UniGene; Hs.643005; -.
DR ProteinModelPortal; Q9NP59; -.
DR IntAct; Q9NP59; 5.
DR MINT; MINT-1404238; -.
DR STRING; 9606.ENSP00000261024; -.
DR TCDB; 2.A.100.1.4; the ferroportin (fpn) family.
DR PhosphoSite; Q9NP59; -.
DR DMDM; 48428687; -.
DR PaxDb; Q9NP59; -.
DR PeptideAtlas; Q9NP59; -.
DR PRIDE; Q9NP59; -.
DR DNASU; 30061; -.
DR Ensembl; ENST00000261024; ENSP00000261024; ENSG00000138449.
DR GeneID; 30061; -.
DR KEGG; hsa:30061; -.
DR UCSC; uc002uqp.4; human.
DR CTD; 30061; -.
DR GeneCards; GC02M190389; -.
DR HGNC; HGNC:10909; SLC40A1.
DR MIM; 604653; gene.
DR MIM; 606069; phenotype.
DR neXtProt; NX_Q9NP59; -.
DR Orphanet; 139491; Hemochromatosis type 4.
DR PharmGKB; PA35805; -.
DR eggNOG; NOG273752; -.
DR HOGENOM; HOG000234273; -.
DR HOVERGEN; HBG055582; -.
DR InParanoid; Q9NP59; -.
DR KO; K14685; -.
DR OMA; LHKETEP; -.
DR OrthoDB; EOG72NRPT; -.
DR PhylomeDB; Q9NP59; -.
DR Reactome; REACT_15518; Transmembrane transport of small molecules.
DR GeneWiki; Ferroportin; -.
DR GenomeRNAi; 30061; -.
DR NextBio; 52848; -.
DR PRO; PR:Q9NP59; -.
DR ArrayExpress; Q9NP59; -.
DR Bgee; Q9NP59; -.
DR CleanEx; HS_SLC40A1; -.
DR Genevestigator; Q9NP59; -.
DR GO; GO:0005737; C:cytoplasm; TAS:ProtInc.
DR GO; GO:0005887; C:integral to plasma membrane; IC:BHF-UCL.
DR GO; GO:0005771; C:multivesicular body; IEA:Ensembl.
DR GO; GO:0008021; C:synaptic vesicle; IEA:Ensembl.
DR GO; GO:0005381; F:iron ion transmembrane transporter activity; IMP:BHF-UCL.
DR GO; GO:0009653; P:anatomical structure morphogenesis; TAS:ProtInc.
DR GO; GO:0006915; P:apoptotic process; IEA:Ensembl.
DR GO; GO:0006879; P:cellular iron ion homeostasis; IMP:BHF-UCL.
DR GO; GO:0003158; P:endothelium development; IEA:Ensembl.
DR GO; GO:0002260; P:lymphocyte homeostasis; IEA:Ensembl.
DR GO; GO:0060586; P:multicellular organismal iron ion homeostasis; IEA:Ensembl.
DR GO; GO:0060345; P:spleen trabecula formation; IEA:Ensembl.
DR InterPro; IPR009716; Ferroportin-1.
DR InterPro; IPR016196; MFS_dom_general_subst_transpt.
DR Pfam; PF06963; FPN1; 1.
DR SUPFAM; SSF103473; SSF103473; 3.
PE 1: Evidence at protein level;
KW Cell membrane; Complete proteome; Disease mutation; Glycoprotein;
KW Ion transport; Iron; Iron transport; Membrane; Polymorphism;
KW Reference proteome; Transmembrane; Transmembrane helix; Transport.
FT CHAIN 1 571 Solute carrier family 40 member 1.
FT /FTId=PRO_0000191310.
FT TRANSMEM 12 34 Helical; (Potential).
FT TRANSMEM 58 80 Helical; (Potential).
FT TRANSMEM 93 115 Helical; (Potential).
FT TRANSMEM 125 147 Helical; (Potential).
FT TRANSMEM 299 321 Helical; (Potential).
FT TRANSMEM 341 363 Helical; (Potential).
FT TRANSMEM 370 392 Helical; (Potential).
FT TRANSMEM 450 472 Helical; (Potential).
FT TRANSMEM 492 514 Helical; (Potential).
FT TRANSMEM 519 541 Helical; (Potential).
FT CARBOHYD 174 174 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 434 434 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 567 567 N-linked (GlcNAc...) (Potential).
FT VARIANT 64 64 Y -> N (in HFE4).
FT /FTId=VAR_030057.
FT VARIANT 77 77 A -> D (in HFE4).
FT /FTId=VAR_022594.
FT VARIANT 80 80 G -> S (in iron overload).
FT /FTId=VAR_030058.
FT VARIANT 80 80 G -> V (in HFE4).
FT /FTId=VAR_030059.
FT VARIANT 144 144 N -> D (in HFE4).
FT /FTId=VAR_030060.
FT VARIANT 144 144 N -> H (in HFE4).
FT /FTId=VAR_022595.
FT VARIANT 144 144 N -> T (in HFE4).
FT /FTId=VAR_030061.
FT VARIANT 157 157 D -> G (in HFE4).
FT /FTId=VAR_022596.
FT VARIANT 162 162 Missing (in HFE4).
FT /FTId=VAR_022597.
FT VARIANT 174 174 N -> I (in iron overload).
FT /FTId=VAR_030062.
FT VARIANT 181 181 D -> V (in HFE4).
FT /FTId=VAR_030063.
FT VARIANT 182 182 Q -> H (in HFE4).
FT /FTId=VAR_022598.
FT VARIANT 248 248 Q -> H (common polymorphism associated
FT with mild anemia and a tendency to iron
FT loading; dbSNP:rs11568350).
FT /FTId=VAR_020295.
FT VARIANT 267 267 G -> D (in HFE4).
FT /FTId=VAR_030064.
FT VARIANT 270 270 D -> V (in HFE4).
FT /FTId=VAR_030065.
FT VARIANT 323 323 G -> V (in HFE4).
FT /FTId=VAR_022599.
FT VARIANT 326 326 C -> Y (in iron overload).
FT /FTId=VAR_030066.
FT VARIANT 432 432 M -> V (in dbSNP:rs11568355).
FT /FTId=VAR_020296.
FT VARIANT 443 443 P -> L (in dbSNP:rs45606432).
FT /FTId=VAR_029299.
FT VARIANT 490 490 G -> D (in iron overload).
FT /FTId=VAR_030067.
FT VARIANT 561 561 R -> G (in dbSNP:rs11568346).
FT /FTId=VAR_018980.
FT CONFLICT 130 133 TSCY -> VSSQ (in Ref. 10; AAQ13603).
FT CONFLICT 324 324 F -> S (in Ref. 9; AAH35893).
FT CONFLICT 430 431 IY -> RD (in Ref. 1; AAF80986).
SQ SEQUENCE 571 AA; 62542 MW; E4D6B5594C904959 CRC64;
MTRAGDHNRQ RGCCGSLADY LTSAKFLLYL GHSLSTWGDR MWHFAVSVFL VELYGNSLLL
TAVYGLVVAG SVLVLGAIIG DWVDKNARLK VAQTSLVVQN VSVILCGIIL MMVFLHKHEL
LTMYHGWVLT SCYILIITIA NIANLASTAT AITIQRDWIV VVAGEDRSKL ANMNATIRRI
DQLTNILAPM AVGQIMTFGS PVIGCGFISG WNLVSMCVEY VLLWKVYQKT PALAVKAGLK
EEETELKQLN LHKDTEPKPL EGTHLMGVKD SNIHELEHEQ EPTCASQMAE PFRTFRDGWV
SYYNQPVFLA GMGLAFLYMT VLGFDCITTG YAYTQGLSGS ILSILMGASA ITGIMGTVAF
TWLRRKCGLV RTGLISGLAQ LSCLILCVIS VFMPGSPLDL SVSPFEDIRS RFIQGESITP
TKIPEITTEI YMSNGSNSAN IVPETSPESV PIISVSLLFA GVIAARIGLW SFDLTVTQLL
QENVIESERG IINGVQNSMN YLLDLLHFIM VILAPNPEAF GLLVLISVSF VAMGHIMYFR
FAQNTLGNKL FACGPDAKEV RKENQANTSV V
//
ID S40A1_HUMAN Reviewed; 571 AA.
AC Q9NP59; Q6FI62; Q7Z4F8; Q8IVB2; Q9NRL0;
DT 07-JUN-2004, integrated into UniProtKB/Swiss-Prot.
read moreDT 01-OCT-2000, sequence version 1.
DT 22-JAN-2014, entry version 114.
DE RecName: Full=Solute carrier family 40 member 1;
DE AltName: Full=Ferroportin-1;
DE AltName: Full=Iron-regulated transporter 1;
GN Name=SLC40A1; Synonyms=FPN1, IREG1, SLC11A3; ORFNames=MSTP079;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC Catarrhini; Hominidae; Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA], TISSUE SPECIFICITY, AND VARIANT HFE4
RP ASP-77.
RX PubMed=10747949; DOI=10.1074/jbc.M000713200;
RA Abboud S., Haile D.J.;
RT "A novel mammalian iron-regulated protein involved in intracellular
RT iron metabolism.";
RL J. Biol. Chem. 275:19906-19912(2000).
RN [2]
RP NUCLEOTIDE SEQUENCE [MRNA], AND SUBCELLULAR LOCATION.
RX PubMed=10882071; DOI=10.1016/S1097-2765(00)80425-6;
RA McKie A.T., Marciani P., Rolfs A., Brennan K., Wehr K., Barrow D.,
RA Miret S., Bomford A., Peters T.J., Farzaneh F., Hediger M.A.,
RA Hentze M.W., Simpson R.J.;
RT "A novel duodenal iron-regulated transporter, IREG1, implicated in the
RT basolateral transfer of iron to the circulation.";
RL Mol. Cell 5:299-309(2000).
RN [3]
RP NUCLEOTIDE SEQUENCE [MRNA].
RC TISSUE=Placenta;
RX PubMed=10693807; DOI=10.1038/35001596;
RA Donovan A., Brownlie A., Zhou Y., Shepard J., Pratt S.J., Moynihan J.,
RA Paw B.H., Drejer A., Barut B., Zapata A., Law T.C., Brugnara C.,
RA Lux S.E. IV, Pinkus G.S., Pinkus J.L., Kingsley P.D., Palis J.,
RA Fleming M.D., Andrews N.C., Zon L.I.;
RT "Positional cloning of zebrafish ferroportin1 identifies a conserved
RT vertebrate iron exporter.";
RL Nature 403:776-781(2000).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Uterus;
RX PubMed=11230166; DOI=10.1101/gr.GR1547R;
RA Wiemann S., Weil B., Wellenreuther R., Gassenhuber J., Glassl S.,
RA Ansorge W., Boecher M., Bloecker H., Bauersachs S., Blum H.,
RA Lauber J., Duesterhoeft A., Beyer A., Koehrer K., Strack N.,
RA Mewes H.-W., Ottenwaelder B., Obermaier B., Tampe J., Heubner D.,
RA Wambutt R., Korn B., Klein M., Poustka A.;
RT "Towards a catalog of human genes and proteins: sequencing and
RT analysis of 500 novel complete protein coding human cDNAs.";
RL Genome Res. 11:422-435(2001).
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Placenta;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A.,
RA Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M.,
RA Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y.,
RA Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M.,
RA Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K.,
RA Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S.,
RA Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J.,
RA Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y.,
RA Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N.,
RA Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S.,
RA Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y.,
RA Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T.,
RA Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y.,
RA Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S.,
RA Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T.,
RA Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M.,
RA Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T.,
RA Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K.,
RA Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R.,
RA Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [6]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RA Ebert L., Schick M., Neubert P., Schatten R., Henze S., Korn B.;
RT "Cloning of human full open reading frames in Gateway(TM) system entry
RT vector (pDONR201).";
RL Submitted (JUN-2004) to the EMBL/GenBank/DDBJ databases.
RN [7]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15815621; DOI=10.1038/nature03466;
RA Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H.,
RA Minx P., Wagner-McPherson C., Layman D., Wylie K., Sekhon M.,
RA Becker M.C., Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E.,
RA Kremitzki C., Oddy L., Du H., Sun H., Bradshaw-Cordum H., Ali J.,
RA Carter J., Cordes M., Harris A., Isak A., van Brunt A., Nguyen C.,
RA Du F., Courtney L., Kalicki J., Ozersky P., Abbott S., Armstrong J.,
RA Belter E.A., Caruso L., Cedroni M., Cotton M., Davidson T., Desai A.,
RA Elliott G., Erb T., Fronick C., Gaige T., Haakenson W., Haglund K.,
RA Holmes A., Harkins R., Kim K., Kruchowski S.S., Strong C.M.,
RA Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K.,
RA McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C.,
RA Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N.,
RA Swearengen-Shahid S., Snider J., Strong J.T., Thompson J., Yoakum M.,
RA Leonard S., Pearman C., Trani L., Radionenko M., Waligorski J.E.,
RA Wang C., Rock S.M., Tin-Wollam A.-M., Maupin R., Latreille P.,
RA Wendl M.C., Yang S.-P., Pohl C., Wallis J.W., Spieth J., Bieri T.A.,
RA Berkowicz N., Nelson J.O., Osborne J., Ding L., Meyer R., Sabo A.,
RA Shotland Y., Sinha P., Wohldmann P.E., Cook L.L., Hickenbotham M.T.,
RA Eldred J., Williams D., Jones T.A., She X., Ciccarelli F.D.,
RA Izaurralde E., Taylor J., Schmutz J., Myers R.M., Cox D.R., Huang X.,
RA McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C.,
RA Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S.,
RA Miller W., Eichler E.E., Bork P., Suyama M., Torrents D.,
RA Waterston R.H., Wilson R.K.;
RT "Generation and annotation of the DNA sequences of human chromosomes 2
RT and 4.";
RL Nature 434:724-731(2005).
RN [8]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G., Florea L., Halpern A.L.,
RA Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R.,
RA Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V.,
RA Hannenhalli S., Turner R., Yooseph S., Lu F., Nusskern D.R.,
RA Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H.,
RA Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G.,
RA Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W.,
RA Venter J.C.;
RL Submitted (SEP-2005) to the EMBL/GenBank/DDBJ databases.
RN [9]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC TISSUE=Blood, and Testis;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA
RT project: the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [10]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 1-133.
RC TISSUE=Aorta;
RA Hui R.T., Zhao B., Sheng H., Qin B.M., Liu Y.Q., Liu B., Wang X.Y.,
RA Xu H.S., Zhang Q., Tong Y.K., Song L., Ji X.J., Liu B.H., Lu H.,
RA Chen J.Z., Cai M.Q., Zheng W.Y., Teng C.Y., Liu Q., Yu L.T., Lin J.,
RA Gong Q., Zhang A.M., Gao R.L.;
RL Submitted (JUL-1999) to the EMBL/GenBank/DDBJ databases.
RN [11]
RP NUCLEOTIDE SEQUENCE [GENOMIC DNA] OF 1-6; 16-129 AND 255-316, AND
RP VARIANT HFE4 VAL-270.
RX PubMed=15338274; DOI=10.1007/s00439-004-1166-y;
RA Zaahl M.G., Merryweather-Clarke A.T., Kotze M.J., van der Merwe S.,
RA Warnich L., Robson K.J.H.;
RT "Analysis of genes implicated in iron regulation in individuals
RT presenting with primary iron overload.";
RL Hum. Genet. 115:409-417(2004).
RN [12]
RP VARIANT HFE4 ASP-77.
RX PubMed=11518736;
RA Montosi G., Donovan A., Totaro A., Garuti C., Pignatti E.,
RA Cassanelli S., Trenor C.C., Gasparini P., Andrews N.C.,
RA Pietrangelo A.;
RT "Autosomal-dominant hemochromatosis is associated with a mutation in
RT the ferroportin (SLC11A3) gene.";
RL J. Clin. Invest. 108:619-623(2001).
RN [13]
RP VARIANT HFE4 HIS-144.
RX PubMed=11431687; DOI=10.1038/90038;
RA Njajou O.T., Vaessen N., Joosse M., Berghuis B., van Dongen J.W.F.,
RA Breuning M.H., Snijders P.J.L.M., Rutten W.P.F., Sandkuijl L.A.,
RA Oostra B.A., van Duijn C.M., Heutink P.;
RT "A mutation in SLC11A3 is associated with autosomal dominant
RT hemochromatosis.";
RL Nat. Genet. 28:213-214(2001).
RN [14]
RP VARIANT HFE4 VAL-162 DEL.
RX PubMed=12091366; DOI=10.1182/blood.V100.2.692;
RA Wallace D.F., Pedersen P., Dixon J.L., Stephenson P., Searle J.W.,
RA Powell L.W., Subramaniam V.N.;
RT "Novel mutation in ferroportin1 is associated with autosomal dominant
RT hemochromatosis.";
RL Blood 100:692-694(2002).
RN [15]
RP VARIANT HFE4 VAL-162 DEL.
RX PubMed=12091367; DOI=10.1182/blood-2001-11-0132;
RA Devalia V., Carter K., Walker A.P., Perkins S.J., Worwood M., May A.,
RA Dooley J.S.;
RT "Autosomal dominant reticuloendothelial iron overload associated with
RT a 3-base pair deletion in the ferroportin 1 gene (SLC11A3).";
RL Blood 100:695-697(2002).
RN [16]
RP VARIANT HFE4 VAL-162 DEL.
RX PubMed=12123233; DOI=10.1182/blood-2002-03-0693;
RA Roetto A., Merryweather-Clarke A.T., Daraio F., Livesey K.,
RA Pointon J.J., Barbabietola G., Piga A., Mackie P.H., Robson K.J.H.,
RA Camaschella C.;
RT "A valine deletion of ferroportin 1: a common mutation in
RT hemochromastosis type 4.";
RL Blood 100:733-734(2002).
RN [17]
RP VARIANT HFE4 VAL-162 DEL.
RX PubMed=12406098; DOI=10.1046/j.1365-2141.2002.03946.x;
RA Cazzola M., Cremonesi L., Papaioannou M., Soriani N., Kioumi A.,
RA Charalambidou A., Paroni R., Romtsou K., Levi S., Ferrari M.,
RA Arosio P., Christakis J.;
RT "Genetic hyperferritinaemia and reticuloendothelial iron overload
RT associated with a three base pair deletion in the coding region of the
RT ferroportin gene (SLC11A3).";
RL Br. J. Haematol. 119:539-546(2002).
RN [18]
RP VARIANTS HFE4 GLY-157; HIS-182 AND VAL-323.
RX PubMed=12730114; DOI=10.1182/blood-2003-02-0439;
RA Hetet G., Devaux I., Soufir N., Grandchamp B., Beaumont C.;
RT "Molecular analyses of patients with hyperferritinemia and normal
RT serum iron values reveal both L ferritin IRE and 3 new ferroportin
RT (SLC11A3) mutations.";
RL Blood 102:1904-1910(2003).
RN [19]
RP VARIANT HIS-248.
RX PubMed=14636642; DOI=10.1016/S1079-9796(03)00164-5;
RA Gordeuk V.R., Caleffi A., Corradini E., Ferrara F., Jones R.A.,
RA Castro O., Onyekwere O., Kittles R., Pignatti E., Montosi G.,
RA Garuti C., Gangaidzo I.T., Gomo Z.A.R., Moyo V.M., Rouault T.A.,
RA MacPhail P., Pietrangelo A.;
RT "Iron overload in Africans and African-Americans and a common mutation
RT in the SCL40A1 (ferroportin 1) gene.";
RL Blood Cells Mol. Dis. 31:299-304(2003).
RN [20]
RP VARIANT HFE4 THR-144.
RX PubMed=12865285; DOI=10.1136/gut.52.8.1215;
RA Arden K.E., Wallace D.F., Dixon J.L., Summerville L., Searle J.W.,
RA Anderson G.J., Ramm G.A., Powell L.W., Subramaniam V.N.;
RT "A novel mutation in ferroportin1 is associated with haemochromatosis
RT in a Solomon Islands patient.";
RL Gut 52:1215-1217(2003).
RN [21]
RP VARIANT HFE4 ASN-64.
RX PubMed=12857562;
RA Rivard S.R., Lanzara C., Grimard D., Carella M., Simard H.,
RA Ficarella R., Simard R., D'Adamo A.P., De Braekeleer M., Gasparini P.;
RT "Autosomal dominant reticuloendothelial iron overload (HFE type 4) due
RT to a new missense mutation in the FERROPORTIN 1 gene (SLC11A3) in a
RT large French-Canadian family.";
RL Haematologica 88:824-826(2003).
RN [22]
RP VARIANT IRON OVERLOAD ASP-490.
RX PubMed=12873829; DOI=10.1016/S0168-8278(03)00148-X;
RA Jouanolle A.-M., Douabin-Gicquel V., Halimi C., Loreal O.,
RA Fergelot P., Delacour T., de Lajarte-Thirouard A.-S., Turlin B.,
RA Le Gall J.-Y., Cadet E., Rochette J., David V., Brissot P.;
RT "Novel mutation in ferroportin 1 gene is associated with autosomal
RT dominant iron overload.";
RL J. Hepatol. 39:286-289(2003).
RN [23]
RP VARIANTS IRON OVERLOAD SER-80 AND ILE-174.
RX PubMed=14757427; DOI=10.1016/j.bcmd.2003.08.003;
RA Pietrangelo A.;
RT "The ferroportin disease.";
RL Blood Cells Mol. Dis. 32:131-138(2004).
RN [24]
RP VARIANTS HFE4 ASP-144 AND VAL-270, AND VARIANT IRON OVERLOAD TYR-326.
RX PubMed=15466004; DOI=10.1136/jmg.2004.020644;
RA Robson K.J.H., Merryweather-Clarke A.T., Cadet E., Viprakasit V.,
RA Zaahl M.G., Pointon J.J., Weatherall D.J., Rochette J.;
RT "Recent advances in understanding haemochromatosis: a transition
RT state.";
RL J. Med. Genet. 41:721-730(2004).
RN [25]
RP ERRATUM.
RA Robson K.J.H., Merryweather-Clarke A.T., Cadet E., Viprakasit V.,
RA Zaahl M.G., Pointon J.J., Weatherall D.J., Rochette J.;
RL J. Med. Genet. 41:959-959(2004).
RN [26]
RP VARIANTS HFE4 VAL-80; VAL-181 AND ASP-267.
RX PubMed=16351644; DOI=10.1111/j.1365-2141.2005.05815.x;
RA Cremonesi L., Forni G.L., Soriani N., Lamagna M., Fermo I., Daraio F.,
RA Galli A., Pietra D., Malcovati L., Ferrari M., Camaschella C.,
RA Cazzola M.;
RT "Genetic and clinical heterogeneity of ferroportin disease.";
RL Br. J. Haematol. 131:663-670(2005).
RN [27]
RP ERRATUM.
RA Cremonesi L., Forni G.L., Soriani N., Lamagna M., Fermo I., Daraio F.,
RA Galli A., Pietra D., Malcovati L., Ferrari M., Camaschella C.,
RA Cazzola M.;
RL Br. J. Haematol. 132:806-806(2006).
CC -!- FUNCTION: May be involved in iron export from duodenal epithelial
CC cell and also in transfer of iron between maternal and fetal
CC circulation. Mediates iron efflux in the presence of a ferroxidase
CC (hephaestin and/or ceruloplasmin).
CC -!- INTERACTION:
CC P05067:APP; NbExp=4; IntAct=EBI-725153, EBI-77613;
CC -!- SUBCELLULAR LOCATION: Cell membrane; Multi-pass membrane protein.
CC Note=Localized to the basolateral membrane of polarized epithelial
CC cells.
CC -!- TISSUE SPECIFICITY: Expressed in placenta, intestine, muscle and
CC spleen.
CC -!- DISEASE: Hemochromatosis 4 (HFE4) [MIM:606069]: A disorder of iron
CC metabolism characterized by iron overload. Excess iron is
CC deposited in a variety of organs leading to their failure, and
CC resulting in serious illnesses including cirrhosis, hepatomas,
CC diabetes, cardiomyopathy, arthritis, and hypogonadotropic
CC hypogonadism. Severe effects of the disease usually do not appear
CC until after decades of progressive iron loading. Note=The disease
CC is caused by mutations affecting the gene represented in this
CC entry.
CC -!- SIMILARITY: Belongs to the ferroportin (FP) (TC 2.A.100) family.
CC SLC40A subfamily.
CC -!- WEB RESOURCE: Name=GeneReviews;
CC URL="http://www.ncbi.nlm.nih.gov/sites/GeneTests/lab/gene/SLC40A1";
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DR EMBL; AF215636; AAF80986.1; -; mRNA.
DR EMBL; AF231121; AAF44330.1; -; mRNA.
DR EMBL; AF226614; AAF36697.1; -; mRNA.
DR EMBL; AL136944; CAB66878.1; -; mRNA.
DR EMBL; AK314827; BAG37348.1; -; mRNA.
DR EMBL; CR533564; CAG38595.1; -; mRNA.
DR EMBL; AC013439; AAX93082.1; -; Genomic_DNA.
DR EMBL; CH471058; EAX10902.1; -; Genomic_DNA.
DR EMBL; BC035893; AAH35893.1; -; mRNA.
DR EMBL; BC037733; AAH37733.1; -; mRNA.
DR EMBL; AF171087; AAQ13603.1; -; mRNA.
DR EMBL; AJ604512; CAE53170.1; -; Genomic_DNA.
DR EMBL; AJ609539; CAE81347.1; -; Genomic_DNA.
DR EMBL; AJ609540; CAE81348.1; -; Genomic_DNA.
DR EMBL; AJ616848; CAE83578.1; -; Genomic_DNA.
DR EMBL; AJ616847; CAE83578.1; JOINED; Genomic_DNA.
DR RefSeq; NP_055400.1; NM_014585.5.
DR UniGene; Hs.643005; -.
DR ProteinModelPortal; Q9NP59; -.
DR IntAct; Q9NP59; 5.
DR MINT; MINT-1404238; -.
DR STRING; 9606.ENSP00000261024; -.
DR TCDB; 2.A.100.1.4; the ferroportin (fpn) family.
DR PhosphoSite; Q9NP59; -.
DR DMDM; 48428687; -.
DR PaxDb; Q9NP59; -.
DR PeptideAtlas; Q9NP59; -.
DR PRIDE; Q9NP59; -.
DR DNASU; 30061; -.
DR Ensembl; ENST00000261024; ENSP00000261024; ENSG00000138449.
DR GeneID; 30061; -.
DR KEGG; hsa:30061; -.
DR UCSC; uc002uqp.4; human.
DR CTD; 30061; -.
DR GeneCards; GC02M190389; -.
DR HGNC; HGNC:10909; SLC40A1.
DR MIM; 604653; gene.
DR MIM; 606069; phenotype.
DR neXtProt; NX_Q9NP59; -.
DR Orphanet; 139491; Hemochromatosis type 4.
DR PharmGKB; PA35805; -.
DR eggNOG; NOG273752; -.
DR HOGENOM; HOG000234273; -.
DR HOVERGEN; HBG055582; -.
DR InParanoid; Q9NP59; -.
DR KO; K14685; -.
DR OMA; LHKETEP; -.
DR OrthoDB; EOG72NRPT; -.
DR PhylomeDB; Q9NP59; -.
DR Reactome; REACT_15518; Transmembrane transport of small molecules.
DR GeneWiki; Ferroportin; -.
DR GenomeRNAi; 30061; -.
DR NextBio; 52848; -.
DR PRO; PR:Q9NP59; -.
DR ArrayExpress; Q9NP59; -.
DR Bgee; Q9NP59; -.
DR CleanEx; HS_SLC40A1; -.
DR Genevestigator; Q9NP59; -.
DR GO; GO:0005737; C:cytoplasm; TAS:ProtInc.
DR GO; GO:0005887; C:integral to plasma membrane; IC:BHF-UCL.
DR GO; GO:0005771; C:multivesicular body; IEA:Ensembl.
DR GO; GO:0008021; C:synaptic vesicle; IEA:Ensembl.
DR GO; GO:0005381; F:iron ion transmembrane transporter activity; IMP:BHF-UCL.
DR GO; GO:0009653; P:anatomical structure morphogenesis; TAS:ProtInc.
DR GO; GO:0006915; P:apoptotic process; IEA:Ensembl.
DR GO; GO:0006879; P:cellular iron ion homeostasis; IMP:BHF-UCL.
DR GO; GO:0003158; P:endothelium development; IEA:Ensembl.
DR GO; GO:0002260; P:lymphocyte homeostasis; IEA:Ensembl.
DR GO; GO:0060586; P:multicellular organismal iron ion homeostasis; IEA:Ensembl.
DR GO; GO:0060345; P:spleen trabecula formation; IEA:Ensembl.
DR InterPro; IPR009716; Ferroportin-1.
DR InterPro; IPR016196; MFS_dom_general_subst_transpt.
DR Pfam; PF06963; FPN1; 1.
DR SUPFAM; SSF103473; SSF103473; 3.
PE 1: Evidence at protein level;
KW Cell membrane; Complete proteome; Disease mutation; Glycoprotein;
KW Ion transport; Iron; Iron transport; Membrane; Polymorphism;
KW Reference proteome; Transmembrane; Transmembrane helix; Transport.
FT CHAIN 1 571 Solute carrier family 40 member 1.
FT /FTId=PRO_0000191310.
FT TRANSMEM 12 34 Helical; (Potential).
FT TRANSMEM 58 80 Helical; (Potential).
FT TRANSMEM 93 115 Helical; (Potential).
FT TRANSMEM 125 147 Helical; (Potential).
FT TRANSMEM 299 321 Helical; (Potential).
FT TRANSMEM 341 363 Helical; (Potential).
FT TRANSMEM 370 392 Helical; (Potential).
FT TRANSMEM 450 472 Helical; (Potential).
FT TRANSMEM 492 514 Helical; (Potential).
FT TRANSMEM 519 541 Helical; (Potential).
FT CARBOHYD 174 174 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 434 434 N-linked (GlcNAc...) (Potential).
FT CARBOHYD 567 567 N-linked (GlcNAc...) (Potential).
FT VARIANT 64 64 Y -> N (in HFE4).
FT /FTId=VAR_030057.
FT VARIANT 77 77 A -> D (in HFE4).
FT /FTId=VAR_022594.
FT VARIANT 80 80 G -> S (in iron overload).
FT /FTId=VAR_030058.
FT VARIANT 80 80 G -> V (in HFE4).
FT /FTId=VAR_030059.
FT VARIANT 144 144 N -> D (in HFE4).
FT /FTId=VAR_030060.
FT VARIANT 144 144 N -> H (in HFE4).
FT /FTId=VAR_022595.
FT VARIANT 144 144 N -> T (in HFE4).
FT /FTId=VAR_030061.
FT VARIANT 157 157 D -> G (in HFE4).
FT /FTId=VAR_022596.
FT VARIANT 162 162 Missing (in HFE4).
FT /FTId=VAR_022597.
FT VARIANT 174 174 N -> I (in iron overload).
FT /FTId=VAR_030062.
FT VARIANT 181 181 D -> V (in HFE4).
FT /FTId=VAR_030063.
FT VARIANT 182 182 Q -> H (in HFE4).
FT /FTId=VAR_022598.
FT VARIANT 248 248 Q -> H (common polymorphism associated
FT with mild anemia and a tendency to iron
FT loading; dbSNP:rs11568350).
FT /FTId=VAR_020295.
FT VARIANT 267 267 G -> D (in HFE4).
FT /FTId=VAR_030064.
FT VARIANT 270 270 D -> V (in HFE4).
FT /FTId=VAR_030065.
FT VARIANT 323 323 G -> V (in HFE4).
FT /FTId=VAR_022599.
FT VARIANT 326 326 C -> Y (in iron overload).
FT /FTId=VAR_030066.
FT VARIANT 432 432 M -> V (in dbSNP:rs11568355).
FT /FTId=VAR_020296.
FT VARIANT 443 443 P -> L (in dbSNP:rs45606432).
FT /FTId=VAR_029299.
FT VARIANT 490 490 G -> D (in iron overload).
FT /FTId=VAR_030067.
FT VARIANT 561 561 R -> G (in dbSNP:rs11568346).
FT /FTId=VAR_018980.
FT CONFLICT 130 133 TSCY -> VSSQ (in Ref. 10; AAQ13603).
FT CONFLICT 324 324 F -> S (in Ref. 9; AAH35893).
FT CONFLICT 430 431 IY -> RD (in Ref. 1; AAF80986).
SQ SEQUENCE 571 AA; 62542 MW; E4D6B5594C904959 CRC64;
MTRAGDHNRQ RGCCGSLADY LTSAKFLLYL GHSLSTWGDR MWHFAVSVFL VELYGNSLLL
TAVYGLVVAG SVLVLGAIIG DWVDKNARLK VAQTSLVVQN VSVILCGIIL MMVFLHKHEL
LTMYHGWVLT SCYILIITIA NIANLASTAT AITIQRDWIV VVAGEDRSKL ANMNATIRRI
DQLTNILAPM AVGQIMTFGS PVIGCGFISG WNLVSMCVEY VLLWKVYQKT PALAVKAGLK
EEETELKQLN LHKDTEPKPL EGTHLMGVKD SNIHELEHEQ EPTCASQMAE PFRTFRDGWV
SYYNQPVFLA GMGLAFLYMT VLGFDCITTG YAYTQGLSGS ILSILMGASA ITGIMGTVAF
TWLRRKCGLV RTGLISGLAQ LSCLILCVIS VFMPGSPLDL SVSPFEDIRS RFIQGESITP
TKIPEITTEI YMSNGSNSAN IVPETSPESV PIISVSLLFA GVIAARIGLW SFDLTVTQLL
QENVIESERG IINGVQNSMN YLLDLLHFIM VILAPNPEAF GLLVLISVSF VAMGHIMYFR
FAQNTLGNKL FACGPDAKEV RKENQANTSV V
//
MIM
604653
*RECORD*
*FIELD* NO
604653
*FIELD* TI
*604653 SOLUTE CARRIER FAMILY 40 (IRON-REGULATED TRANSPORTER), MEMBER 1; SLC40A1
;;FERROPORTIN 1; FPN1;;
read moreIRON-REGULATED TRANSPORTER 1; IREG1;;
SOLUTE CARRIER FAMILY 11 (PROTON-COUPLED DIVALENT METAL ION TRANSPORTER),
MEMBER 3, FORMERLY; SLC11A3, FORMERLY
*FIELD* TX
CLONING
Defects in iron absorption and utilization lead to iron deficiency and
overload disorders. Adult mammals absorb iron through the duodenum,
whereas embryos obtain iron through placental transport. Iron uptake
from the intestinal lumen through the apical surface of the polarized
duodenal enterocytes is mediated by the divalent metal transporter, DMT1
(600523). A second transporter had been postulated to export iron across
the basolateral surface to the circulation. Donovan et al. (2000) used
positional cloning to identify the gene responsible for the hypochromic
anemia of the zebrafish mutant 'weissherbst.' The gene, which they
called ferroportin-1 (fpn1), encodes a multiple-transmembrane domain
protein expressed in the yolk sac that was a candidate for the elusive
iron transporter. Zebrafish ferroportin-1 is required for the transport
of iron from maternally-derived yolk stores to the circulation and
functions as an iron exporter when expressed in Xenopus oocytes.
Donovan et al. (2000) isolated mouse and human ferroportin-1 cDNAs by
RT-PCR of liver and placenta, respectively. Human ferroportin-1 is a
protein of 571 amino acids. A conserved sequence, predicted to form a
hairpin-loop structure typical of iron response elements (IREs), was
identified in the 5-prime untranslated region of the cDNAs from all 3
species. Northern blot analysis showed the highest level of expression
in human placenta, liver, spleen, and kidney. In mouse, primitive
erythroblasts derived from the blood islands do not express
ferroportin-1, whereas the trophoblast cells of the inner placenta
express high levels of ferroportin-1. In the human placenta,
ferroportin-1 protein was primarily expressed in a basal location within
the syncytiotrophoblasts, suggesting that it transports iron from mother
to embryo. Mammalian ferroportin-1 is also expressed at the basolateral
surface of duodenal enterocytes. On the basis of basolateral expression
pattern of ferroportin-1 in mammalian enterocytes and the implication
that ferroportin-1 is required for intestinal iron absorption and iron
transport in zebrafish, Donovan et al. (2000) suggested that the protein
is probably involved in iron export from enterocytes in mammals.
Iron absorption by the duodenal mucosa is initiated by uptake of ferrous
Fe(II) iron across the brush border membrane and culminates in transfer
of the metal across the basolateral membrane to the portal vein
circulation by an unknown mechanism. Using a subtractive cloning
strategy and PCR analysis, McKie et al. (2000) isolated mouse and human
duodenal cDNAs encoding FPN1, which they called iron-regulated
transporter-1 (IREG1). The IREG1 protein contains 10 transmembrane
domains and is localized to the basolateral membrane of polarized
epithelial cells. IREG1 mRNA and protein expression are increased under
conditions of increased iron absorption, and the 5-prime untranslated
region of the IREG1 mRNA contains a functional IRE.
MAPPING
By FISH, Haile (2000) mapped the SLC40A1 gene to human chromosome 2q32
and mouse chromosome 1B.
GENE FUNCTION
McKie et al. (2000) found that IREG1 stimulated iron efflux following
expression in Xenopus oocytes. They concluded that IREG1 represents the
long-sought duodenal iron export protein and is upregulated in the iron
overload disease hereditary hemochromatosis (235200).
Nemeth et al. (2004) reported that hepcidin (606464) bound to
ferroportin in tissue culture cells. After binding, ferroportin was
internalized and degraded, leading to decreased export of cellular iron.
Nemeth et al. (2004) postulated that the posttranslational regulation of
ferroportin by hepcidin may complete a homeostatic loop regulating iron
plasma levels and the tissue distribution of iron.
Sangokoya et al. (2013) stated that FPN expression is downregulated in
an iron-dependent manner by binding of iron regulatory protein (IRP; see
100880) to the IRE in the 5-prime UTR of the FPN transcript. Using a
reporter gene assay, they confirmed that FPN expression decreased during
iron depletion and increased significantly during iron supplementation
in human HepG2 hepatocytes. Sangokoya et al. (2013) also identified a
regulatory region in the 3-prime UTR of FPN that bound the microRNA
MIR485-3p (615385). MIR485-3p was induced during iron deficiency in
human cell lines, and MIR485-3p binding to the 3-prime UTR of the FPN
transcript repressed FPN translation, leading to increased cellular
ferritin (see 134790) levels and increased cellular iron. Inhibition of
MIR485-3p activity or mutation of the MIR485-3p-binding site in the FPN
3-prime UTR relieved FPN repression and led to cellular iron deficiency.
IRP and MIR485-3p downregulated FPN expression in an additive manner.
MOLECULAR GENETICS
By mutation analysis of all exons, intron-exon boundaries, and the
5-prime and 3-prime untranslated region (including the IRE) of the
SLC40A1 gene in a Dutch family with hemochromatosis type 4 (606069),
Njajou et al. (2001) identified a heterozygous A-to-C transversion at
nucleotide 734 in exon 5 in all affected individuals. The mutation
resulted in an asn144-to-his substitution (604653.0001). The substituted
asn is a highly conserved amino acid in vertebrates.
Independently, in an Italian family with autosomal dominant
hemochromatosis originally reported by Pietrangelo et al. (1999),
Montosi et al. (2001) mapped the disease locus responsible for autosomal
dominant hemochromatosis to 2q32 and recognized ferroportin as a
compelling positional candidate for the site of the mutation. They
identified a mutation in the SLC40A1 gene (604653.0002). They pointed
out that the distinguishing features of this disorder, in addition to
autosomal dominant inheritance, is early iron accumulation in
reticuloendothelial cells and a marked increase in serum ferritin before
elevation of the transferrin saturation. Fleming and Sly (2001)
commented that haploinsufficiency for ferroportin would (at least
initially) favor low serum iron by decreasing dietary iron absorption
and by impairing iron release from macrophages. This could explain the
low transferrin saturations, the anemia early in life, and the
sensitivity to phlebotomy observed in many of these patients. The
hepatocellular iron loading might be explained by the secondary effects
of the 'erythropoietic regulator' stimulating intestinal iron
absorption, or possibly by ferroportin-1 haploinsufficiency in
hepatocytes.
Unexplained hyperferritinemia is a common clinical finding, even in
asymptomatic persons. When early-onset bilateral cataracts are also
present, hereditary hyperferritinemia-cataract syndrome (600886),
resulting from a heterozygous point mutation in the L ferritin (FTL;
134790) IRE sequence, can be suspected. Hetet et al. (2003) sequenced
exon 1 of the FTL gene in 52 DNA samples from patients referred for
molecular diagnosis of hyperferritinemia-cataract syndrome. They
identified 24 samples with a point mutation or deletion in the IRE. For
the 28 samples in which no IRE mutation was present, they also genotyped
for mutations in the HFE gene (613609) and sequenced both the H ferritin
(FTH1; 134770) and SLC40A1 genes. They found an increased frequency (12
of 28) of heterozygotes for the HFE his63-to-asp mutation (H63D;
613609.0002), but no H ferritin mutations. They identified 3 novel
SLC40A1 mutations (604653.0004-604653.0006), suggesting that these
patients had dominant type 4 hemochromatosis. The study demonstrated
that both L ferritin IRE and SLC40A1 mutations can account for isolated
hyperferritinemia. The presence of cataract does not permit the
unambiguous identification of patients with hereditary
hyperferritinemia-cataract syndrome, although the existence of a family
history of cataract was only encountered in these patients. This raised
the possibility that lens ferritin accumulation may be a factor
contributing to age-related cataract in the general population.
In transfection experiments using HEK 293T cells, De Domenico et al.
(2005) showed that known human mutations introduced into the mouse
Slc40a1 gene generate proteins that either are defective in cell surface
localization or have a decreased ability to be internalized and degraded
in response to hepcidin. Coimmunoprecipitation studies revealed that
ferroportin is multimeric. Both wildtype and mutant ferroportin
participated in the multimer, and mutant ferroportin affected the
localization of wildtype ferroportin, its stability, and its response to
hepcidin. De Domenico et al. (2005) concluded that the behavior of
mutant ferroportin in cell culture and its ability to act as a dominant
negative explain the dominant inheritance of the disease as well as the
different patient phenotypes.
Cemonesi et al. (2005) studied 2 Italian families and 1 of Chinese
descent with elevated serum ferritin levels and identified
heterozygosity for 3 different mutations in the SLC40A1 gene,
respectively. The authors noted the variability in phenotypes between
the families and suggested that the mutation (604653.0007) in the first
Italian family, in which the proband had a liver biopsy showing heavy
iron deposition in both hepatocytes and Kupffer cells, likely caused
decreased responsiveness to hepcidin, whereas the mutations (604653.0008
and 604653.0009) in the latter 2 families likely caused defective
localization of the protein to the cell surface.
ANIMAL MODEL
Donovan et al. (2005) found that knockout of the ferroportin gene in
mice resulted in embryonic lethality, likely from a defect in iron
transfer from the mother. Heterozygous animals were viable and showed a
mild disruption of iron homeostasis. Mutant mice with ferroportin
deleted in all tissues except extraembryonic visceral endoderm and
placenta appeared normal at birth, but they developed anemia and
abnormal iron accumulation in duodenal enterocytes, Kupffer cells and
hepatocytes, and splenic macrophages. Mice with ferroportin deletion
restricted to the intestines developed severe iron deficiency anemia.
Donovan et al. (2005) concluded that ferroportin is essential for
prenatal and postnatal iron homeostasis, specifically in iron transfer
across extraembryonic visceral endoderm, and iron export from
enterocytes, macrophages, and hepatocytes.
Zohn et al. (2007) reported the mouse flatiron (ffe) mutation, a
his32-to-arg (H32R) substitution in Fpn that affected its localization
and iron export activity. Similar to human patients with classic
ferroportin disease, heterozygous ffe/+ mice exhibited iron loading on
Kupffer cells, high serum ferritin, and low transferrin saturation.
Using macrophages from ffe/+ mice and through expression of Fpn(ffe) in
human embryonic kidney cells, Zohn et al. (2007) showed that Fpn(ffe)
acted in a dominant-negative manner and prevented wildtype Fpn from
localizing on the cell surface and transporting iron.
*FIELD* AV
.0001
HEMOCHROMATOSIS, TYPE 4
SLC40A1, ASN144HIS
In a large Dutch family with autosomal dominant hemochromatosis
(606069), Njajou et al. (2001) identified an A-to-C transversion at
nucleotide 734 in exon 5 of the SLC40A1 gene, resulting in an
asn144-to-his substitution.
.0002
HEMOCHROMATOSIS, TYPE 4
SLC40A1, ALA77ASP
In an Italian family, Montosi et al. (2001) determined linkage of
autosomal dominant hemochromatosis (606069) to 2q32 and demonstrated a
nonconservative missense mutation in the ferroportin gene: a GCC-to-GAC
change resulting in an ala77-to-asp (A77D) substitution.
In 147 Indian patients with thalassemia major and 65 cirrhotic controls,
Agarwal et al. (2006) analyzed the SLC40A1 gene and other modifier genes
of iron hemostasis and identified the A77D mutation in 3 thalassemia
patients, 2 heterozygotes and 1 homozygote. The mutation was not found
in the control group. Agarwal et al. (2006) stated that this was the
first report of a ferroportin mutation in the Indian population.
.0003
HEMOCHROMATOSIS, TYPE 4
SLC40A1, 3-BP DEL, VAL162DEL
In an Australian family with autosomal dominant hemochromatosis
(606069), Wallace et al. (2002) found heterozygosity for a 3-bp (TTG)
deletion in exon 5 of the FPN1 gene, resulting in the deletion of valine
at position 162. They proposed that the deletion is a loss-of-function
mutation that results in impaired iron homeostasis and leads to iron
overload. The mutation was present in 2 brothers in whom the diagnosis
was made at ages 56 and 73 years and who had hepatic fibrosis. It was
also present in the first brother's children: his son, in whom the
diagnosis was made at age 20 years and who had mild fibrosis, and his
daughter, age 19 years, who had no hepatic abnormality.
In the United Kingdom, Devalia et al. (2002) found the same mutation in
members of a family with autosomal dominant hemochromatosis. The proband
was a 38-year-old woman who presented with fatigue and was found to have
a high serum ferritin concentration and, by liver biopsy, heavy iron
deposition in both hepatocytes and Kupffer cells. Venesection therapy
was poorly tolerated (i.e., anemia developed), suggesting a defect in
iron release from reticuloendothelial stores. The proband's sister
likewise had high serum ferritin concentration, and MRI suggested iron
accumulation in both the liver and spleen. Liver biopsy showed no
fibrosis but marked iron accumulation in Kupffer cells. The combination
of erythropoietin administration with phlebotomy permitted removal of
iron without anemia. Although details were not provided, other members
of the family were affected in a pedigree pattern consistent with
autosomal dominant inheritance.
The same heterozygous 3-bp deletion in the FPN1 gene was reported by
Roetto et al. (2002) in 2 related Italian patients and in 1 unrelated
British patient, suggesting that this is a particularly common mutation
in type 4 hemochromatosis. Roetto et al. (2002) suggested that
haploinsufficiency for ferroportin-1 would be more limiting to iron
transport in reticuloendothelial cells than in duodenal enterocytes,
because the flux of iron through the reticuloendothelial macrophages far
exceeds the flux of iron through the duodenal mucosa.
Cazzola et al. (2002) found the same mutation in a family with autosomal
dominant hyperferritinemia in whom the proband showed selective iron
accumulation in the Kupffer cells on liver biopsy. The mutation occurred
in the region of nucleotides 780-791, which comprises 4 TTG repeats; the
loss of 1 TTG unit was predicted to result in the deletion of 1 of 3
sequential valine residues, codons 160-162. This is a recurrent
mutation, presumably due to slippage mispairing. Affected individuals
showed marginally low serum iron and transferrin saturation. Serum
ferritin levels were directly related to age, but were 10 to 20 times
higher than normal. Cazzola et al. (2002) suggested that heterozygosity
for this mutation represents the prototype of selective
reticuloendothelial iron overload, and should be taken into account in
the differential diagnosis of hereditary or congenital
hyperferritinemias, such as hyperferritinemia-cataract syndrome
(600886), which is due to mutations in the ferritin light chain gene
(FTL; 134790), or disorders of the ferritin heavy chain gene (FTH1;
134770).
.0004
HEMOCHROMATOSIS, TYPE 4
SLC40A1, ASP157GLY
In a patient with type 4 hemochromatosis (606069), Hetet et al. (2003)
identified an asp157-to-gly (D157G) mutation in the SLC40A1 gene.
.0005
HEMOCHROMATOSIS, TYPE 4
SLC40A1, GLN182HIS
In a patient with type 4 hemochromatosis (606069), Hetet et al. (2003)
identified a gln182-to-his (Q182H) mutation in the SLC40A1 gene. The
patient's daughter also had increased serum ferritin levels and was
found to carry the Q182H mutation.
.0006
HEMOCHROMATOSIS, TYPE 4
SLC40A1, GLY323VAL
In a patient with type 4 hemochromatosis (606069), Hetet et al. (2003)
identified a gly323-to-val (G323V) mutation in the SLC40A1 gene.
.0007
HEMOCHROMATOSIS, TYPE 4
SLC40A1, ASP181VAL
In affected members of an Italian family with elevated serum ferritin
and low hepcidin/ferritin ratios (HFE4; 606069), Cemonesi et al. (2005)
identified heterozygosity for an 846A-T transversion in exon 6 of the
SLC40A1 gene, resulting in an asp181-to-val (D181V) substitution. A
liver biopsy from the 34-year-old male proband revealed heavy iron
deposition in both hepatocytes and Kupffer cells.
.0008
HEMOCHROMATOSIS, TYPE 4
SLC40A1, GLY80VAL
In 3 affected members of an Italian family with elevated serum ferritin
(HFE4; 606069), Cemonesi et al. (2005) identified heterozygosity for a
543G-T transversion in exon 3 of the SLC40A1 gene, resulting in a
gly80-to-val (G80V) substitution.
.0009
HEMOCHROMATOSIS, TYPE 4
SLC40A1, GLY267ASP
In 6 affected members of family of Chinese descent with isolated
elevated serum ferritin (HFE4; 606069), Cemonesi et al. (2005)
identified heterozygosity for a 1104G-A transition in exon 7 of the
SLC40A1 gene, resulting in a gly267-to-asp (G267D) substitution.
*FIELD* RF
1. Agarwal, S.; Sankar, V. H.; Tewari, D.; Pradhan, M.: Ferroportin
(SLC40A1) gene in thalassemic patients of Indian descent. (Letter) Clin.
Genet. 70: 86-87, 2006.
2. Cazzola, M.; Cremonesi, L.; Papaioannou, M.; Soriani, N.; Kioumi,
A.; Charalambidou, A.; Paroni, R.; Romtsou, K.; Levi, S.; Ferrari,
M.; Arosio, P.; Christakis, J.: Genetic hyperferritinaemia and reticuloendothelial
iron overload associated with a three base pair deletion in the coding
region of the ferroportin gene (SLC11A3). Brit. J. Haemat. 119:
539-546, 2002.
3. Cemonesi, L.; Forni, G. L.; Soriani, N.; Lamagna, M.; Fermo, I.;
Daraio, F.; Galli, A.; Pietra, D.; Malcovati, L.; Ferrari, M.; Camaschella,
C.; Cazzola, M.: Genetic and clinical heterogeneity of ferroportin
disease. Brit. J. Haemat. 131: 663-670, 2005. Note: Erratum: Brit.
J. Haemat. 132: 806 only, 2006.
4. De Domenico, I.; Ward, D. M.; Nemeth, E.; Vaughn, M. B.; Musci,
G.; Ganz, T.; Kaplan, J.: The molecular basis of ferroportin-linked
hemochromatosis. Proc. Nat. Acad. Sci. 102: 8955-8960, 2005.
5. Devalia, V.; Carter, K.; Walker, A. P.; Perkins, S. J.; Worwood,
M.; May, A.; Dooley, J. S.: Autosomal dominant reticuloendothelial
iron overload associated with a 3-base pair deletion in the ferroportin
1 gene (SLC11A3). Blood 100: 695-697, 2002.
6. Donovan, A.; Brownlie, A.; Zhou, Y.; Shepard, J.; Pratt, S. J.;
Moynihan, J.; Paw, B. H.; Drejer, A.; Barut, B.; Zapata, Z.; Law,
T. C.; Brugnara, C.; Lux, S. E.; Pinkus, G. S.; Pinkus, J. L.; Kingsley,
P. D.; Palis, J.; Fleming, M. D.; Andrews, N. C.; Zon, L. I.: Positional
cloning of zebrafish ferroportin1 identifies a conserved vertebrate
iron exporter. Nature 403: 776-781, 2000.
7. Donovan, A.; Lima, C. A.; Pinkus, J. L.; Pinkus, G. S.; Zon, L.
I.; Robine, S.; Andrews, N. C.: The iron exporter ferroportin/Slc40a1
is essential for iron homeostasis. Cell Metab. 1: 191-200, 2005.
8. Fleming, R. E.; Sly, W. S.: Ferroportin mutation in autosomal
dominant hemochromatosis: loss of function, gain in understanding. J.
Clin. Invest. 108: 521-522, 2001.
9. Haile, D. J.: Assignment of Slc11a3 to mouse chromosome 1 band
1B and SLC11A3 to human chromosome 2q21 by in situ hybridization. Cytogenet.
Cell Genet. 88: 328-329, 2000.
10. Hetet, G.; Devaux, I.; Soufir, N.; Grandchamp, B.; Beaumont, C.
: Molecular analyses of patients with hyperferritinemia and normal
serum iron values reveal both L ferritin IRE and 3 new ferroportin
(slc11A3) mutations. Blood 102: 1904-1910, 2003.
11. McKie, A. T.; Marciani, P.; Rolfs, A.; Brennan, K.; Wehr, K.;
Barrow, D.; Miret, S.; Bomford, A.; Peters, T. J.; Farzaneh, F.; Hediger,
M. A.; Hentze, M. W.; Simpson, R. J.: A novel duodenal iron-regulated
transporter, IREG1, implicated in the basolateral transfer of iron
to the circulation. Molec. Cell 5: 299-309, 2000.
12. Montosi, G.; Donovan, A.; Totaro, A.; Garuti, C.; Pignatti, E.;
Cassanelli, S.; Trenor, C. C.; Gasparini, P.; Andrews, N. C.; Pietrangelo,
A.: Autosomal-dominant hemochromatosis is associated with a mutation
in the ferroportin (SLC11A3) gene. J. Clin. Invest. 108: 619-623,
2001.
13. Nemeth, E.; Tuttle, M. S.; Powelson, J.; Vaughn, M. B.; Donovan,
A.; Ward, D. M.; Ganz, T.; Kaplan, J.: Hepcidin regulates cellular
iron efflux by binding to ferroportin and inducing its internalization. Science 306:
2090-2093, 2004.
14. Njajou, O. T.; Vaessen, N.; Joosse, M.; Berghuis, B.; van Dongen,
J. W. F.; Breuning, M. H.; Snijders, P. J. L. M.; Rutten, W. P. F.;
Sandkuijl, L. A.; Oostra, B. A.; van Duijn, C. M.; Heutink, P.: A
mutation in SLC11A3 is associated with autosomal dominant hemochromatosis. Nature
Genet. 28: 213-214, 2001.
15. Pietrangelo, A.; Montosi, G.; Totaro, A.; Garuti, C.; Conte, D.;
Cassanelli, S.; Fraquelli, M.; Sardini, C.; Vasta, F.; Gasparini,
P.: Hereditary hemochromatosis in adults without pathogenic mutations
in the hemochromatosis gene. New Eng. J. Med. 341: 725-732, 1999.
16. Roetto, A.; Merryweather-Clarke, A. T.; Daraio, F.; Livesey, K.;
Pointon, J. J.; Barbabietola, G.; Piga, A.; Mackie, P. H.; Robson,
K. J. H.; Camaschella, C.: A valine deletion of ferroportin 1: a
common mutation in hemochromatosis type 4? (Letter) Blood 100: 733-734,
2002.
17. Sangokoya, C.; Doss, J. F.; Chi, J.-T.: Iron-responsive miR-485-3p
regulates cellular iron homeostasis by targeting ferroportin. PLoS
Genet. 9: e1003408, 2013. Note: Electronic Article.
18. Wallace, D. F.; Pedersen, P.; Dixon, J. L.; Stephenson, P.; Searle,
J. W.; Powell, L. W.; Subramaniam, V. N.: Novel mutation in ferroportin1
is associated with autosomal dominant hemochromatosis. Blood 100:
692-694, 2002.
19. Zohn, I. E.; De Domenico, I.; Pollock, A.; Ward, D. M.; Goodman,
J. F.; Liang, X.; Sanchez, A. J.; Niswander, L.; Kaplan, J.: The
flatiron mutation in mouse ferroportin acts as a dominant negative
to cause ferroportin disease. Blood 109: 4174-4180, 2007.
*FIELD* CN
Patricia A. Hartz - updated: 8/28/2013
Patricia A. Hartz - updated: 5/1/2008
Marla J. F. O'Neill - updated: 9/8/2006
Marla J. F. O'Neill - updated: 3/30/2006
Marla J. F. O'Neill - updated: 7/11/2005
Patricia A. Hartz - updated: 4/19/2005
Ada Hamosh - updated: 1/27/2005
Victor A. McKusick - updated: 11/26/2003
Victor A. McKusick - updated: 1/10/2003
Victor A. McKusick - updated: 9/26/2002
Victor A. McKusick - updated: 1/10/2002
Victor A. McKusick - updated: 6/22/2001
Joanna S. Amberger - updated: 8/7/2000
Stylianos E. Antonarakis - updated: 3/30/2000
*FIELD* CD
Ada Hamosh: 3/6/2000
*FIELD* ED
mgross: 08/28/2013
mgross: 8/28/2013
terry: 3/15/2013
carol: 10/21/2010
mgross: 5/1/2008
wwang: 9/12/2006
terry: 9/8/2006
wwang: 3/31/2006
terry: 3/30/2006
wwang: 7/20/2005
terry: 7/11/2005
mgross: 4/20/2005
terry: 4/19/2005
wwang: 2/2/2005
terry: 1/27/2005
tkritzer: 12/8/2003
tkritzer: 12/3/2003
terry: 11/26/2003
carol: 3/13/2003
terry: 3/12/2003
tkritzer: 1/14/2003
terry: 1/10/2003
carol: 10/1/2002
tkritzer: 9/27/2002
tkritzer: 9/26/2002
carol: 1/14/2002
terry: 1/10/2002
mgross: 6/27/2001
terry: 6/22/2001
carol: 8/21/2000
carol: 8/8/2000
joanna: 8/7/2000
alopez: 4/4/2000
mgross: 3/30/2000
alopez: 3/6/2000
*RECORD*
*FIELD* NO
604653
*FIELD* TI
*604653 SOLUTE CARRIER FAMILY 40 (IRON-REGULATED TRANSPORTER), MEMBER 1; SLC40A1
;;FERROPORTIN 1; FPN1;;
read moreIRON-REGULATED TRANSPORTER 1; IREG1;;
SOLUTE CARRIER FAMILY 11 (PROTON-COUPLED DIVALENT METAL ION TRANSPORTER),
MEMBER 3, FORMERLY; SLC11A3, FORMERLY
*FIELD* TX
CLONING
Defects in iron absorption and utilization lead to iron deficiency and
overload disorders. Adult mammals absorb iron through the duodenum,
whereas embryos obtain iron through placental transport. Iron uptake
from the intestinal lumen through the apical surface of the polarized
duodenal enterocytes is mediated by the divalent metal transporter, DMT1
(600523). A second transporter had been postulated to export iron across
the basolateral surface to the circulation. Donovan et al. (2000) used
positional cloning to identify the gene responsible for the hypochromic
anemia of the zebrafish mutant 'weissherbst.' The gene, which they
called ferroportin-1 (fpn1), encodes a multiple-transmembrane domain
protein expressed in the yolk sac that was a candidate for the elusive
iron transporter. Zebrafish ferroportin-1 is required for the transport
of iron from maternally-derived yolk stores to the circulation and
functions as an iron exporter when expressed in Xenopus oocytes.
Donovan et al. (2000) isolated mouse and human ferroportin-1 cDNAs by
RT-PCR of liver and placenta, respectively. Human ferroportin-1 is a
protein of 571 amino acids. A conserved sequence, predicted to form a
hairpin-loop structure typical of iron response elements (IREs), was
identified in the 5-prime untranslated region of the cDNAs from all 3
species. Northern blot analysis showed the highest level of expression
in human placenta, liver, spleen, and kidney. In mouse, primitive
erythroblasts derived from the blood islands do not express
ferroportin-1, whereas the trophoblast cells of the inner placenta
express high levels of ferroportin-1. In the human placenta,
ferroportin-1 protein was primarily expressed in a basal location within
the syncytiotrophoblasts, suggesting that it transports iron from mother
to embryo. Mammalian ferroportin-1 is also expressed at the basolateral
surface of duodenal enterocytes. On the basis of basolateral expression
pattern of ferroportin-1 in mammalian enterocytes and the implication
that ferroportin-1 is required for intestinal iron absorption and iron
transport in zebrafish, Donovan et al. (2000) suggested that the protein
is probably involved in iron export from enterocytes in mammals.
Iron absorption by the duodenal mucosa is initiated by uptake of ferrous
Fe(II) iron across the brush border membrane and culminates in transfer
of the metal across the basolateral membrane to the portal vein
circulation by an unknown mechanism. Using a subtractive cloning
strategy and PCR analysis, McKie et al. (2000) isolated mouse and human
duodenal cDNAs encoding FPN1, which they called iron-regulated
transporter-1 (IREG1). The IREG1 protein contains 10 transmembrane
domains and is localized to the basolateral membrane of polarized
epithelial cells. IREG1 mRNA and protein expression are increased under
conditions of increased iron absorption, and the 5-prime untranslated
region of the IREG1 mRNA contains a functional IRE.
MAPPING
By FISH, Haile (2000) mapped the SLC40A1 gene to human chromosome 2q32
and mouse chromosome 1B.
GENE FUNCTION
McKie et al. (2000) found that IREG1 stimulated iron efflux following
expression in Xenopus oocytes. They concluded that IREG1 represents the
long-sought duodenal iron export protein and is upregulated in the iron
overload disease hereditary hemochromatosis (235200).
Nemeth et al. (2004) reported that hepcidin (606464) bound to
ferroportin in tissue culture cells. After binding, ferroportin was
internalized and degraded, leading to decreased export of cellular iron.
Nemeth et al. (2004) postulated that the posttranslational regulation of
ferroportin by hepcidin may complete a homeostatic loop regulating iron
plasma levels and the tissue distribution of iron.
Sangokoya et al. (2013) stated that FPN expression is downregulated in
an iron-dependent manner by binding of iron regulatory protein (IRP; see
100880) to the IRE in the 5-prime UTR of the FPN transcript. Using a
reporter gene assay, they confirmed that FPN expression decreased during
iron depletion and increased significantly during iron supplementation
in human HepG2 hepatocytes. Sangokoya et al. (2013) also identified a
regulatory region in the 3-prime UTR of FPN that bound the microRNA
MIR485-3p (615385). MIR485-3p was induced during iron deficiency in
human cell lines, and MIR485-3p binding to the 3-prime UTR of the FPN
transcript repressed FPN translation, leading to increased cellular
ferritin (see 134790) levels and increased cellular iron. Inhibition of
MIR485-3p activity or mutation of the MIR485-3p-binding site in the FPN
3-prime UTR relieved FPN repression and led to cellular iron deficiency.
IRP and MIR485-3p downregulated FPN expression in an additive manner.
MOLECULAR GENETICS
By mutation analysis of all exons, intron-exon boundaries, and the
5-prime and 3-prime untranslated region (including the IRE) of the
SLC40A1 gene in a Dutch family with hemochromatosis type 4 (606069),
Njajou et al. (2001) identified a heterozygous A-to-C transversion at
nucleotide 734 in exon 5 in all affected individuals. The mutation
resulted in an asn144-to-his substitution (604653.0001). The substituted
asn is a highly conserved amino acid in vertebrates.
Independently, in an Italian family with autosomal dominant
hemochromatosis originally reported by Pietrangelo et al. (1999),
Montosi et al. (2001) mapped the disease locus responsible for autosomal
dominant hemochromatosis to 2q32 and recognized ferroportin as a
compelling positional candidate for the site of the mutation. They
identified a mutation in the SLC40A1 gene (604653.0002). They pointed
out that the distinguishing features of this disorder, in addition to
autosomal dominant inheritance, is early iron accumulation in
reticuloendothelial cells and a marked increase in serum ferritin before
elevation of the transferrin saturation. Fleming and Sly (2001)
commented that haploinsufficiency for ferroportin would (at least
initially) favor low serum iron by decreasing dietary iron absorption
and by impairing iron release from macrophages. This could explain the
low transferrin saturations, the anemia early in life, and the
sensitivity to phlebotomy observed in many of these patients. The
hepatocellular iron loading might be explained by the secondary effects
of the 'erythropoietic regulator' stimulating intestinal iron
absorption, or possibly by ferroportin-1 haploinsufficiency in
hepatocytes.
Unexplained hyperferritinemia is a common clinical finding, even in
asymptomatic persons. When early-onset bilateral cataracts are also
present, hereditary hyperferritinemia-cataract syndrome (600886),
resulting from a heterozygous point mutation in the L ferritin (FTL;
134790) IRE sequence, can be suspected. Hetet et al. (2003) sequenced
exon 1 of the FTL gene in 52 DNA samples from patients referred for
molecular diagnosis of hyperferritinemia-cataract syndrome. They
identified 24 samples with a point mutation or deletion in the IRE. For
the 28 samples in which no IRE mutation was present, they also genotyped
for mutations in the HFE gene (613609) and sequenced both the H ferritin
(FTH1; 134770) and SLC40A1 genes. They found an increased frequency (12
of 28) of heterozygotes for the HFE his63-to-asp mutation (H63D;
613609.0002), but no H ferritin mutations. They identified 3 novel
SLC40A1 mutations (604653.0004-604653.0006), suggesting that these
patients had dominant type 4 hemochromatosis. The study demonstrated
that both L ferritin IRE and SLC40A1 mutations can account for isolated
hyperferritinemia. The presence of cataract does not permit the
unambiguous identification of patients with hereditary
hyperferritinemia-cataract syndrome, although the existence of a family
history of cataract was only encountered in these patients. This raised
the possibility that lens ferritin accumulation may be a factor
contributing to age-related cataract in the general population.
In transfection experiments using HEK 293T cells, De Domenico et al.
(2005) showed that known human mutations introduced into the mouse
Slc40a1 gene generate proteins that either are defective in cell surface
localization or have a decreased ability to be internalized and degraded
in response to hepcidin. Coimmunoprecipitation studies revealed that
ferroportin is multimeric. Both wildtype and mutant ferroportin
participated in the multimer, and mutant ferroportin affected the
localization of wildtype ferroportin, its stability, and its response to
hepcidin. De Domenico et al. (2005) concluded that the behavior of
mutant ferroportin in cell culture and its ability to act as a dominant
negative explain the dominant inheritance of the disease as well as the
different patient phenotypes.
Cemonesi et al. (2005) studied 2 Italian families and 1 of Chinese
descent with elevated serum ferritin levels and identified
heterozygosity for 3 different mutations in the SLC40A1 gene,
respectively. The authors noted the variability in phenotypes between
the families and suggested that the mutation (604653.0007) in the first
Italian family, in which the proband had a liver biopsy showing heavy
iron deposition in both hepatocytes and Kupffer cells, likely caused
decreased responsiveness to hepcidin, whereas the mutations (604653.0008
and 604653.0009) in the latter 2 families likely caused defective
localization of the protein to the cell surface.
ANIMAL MODEL
Donovan et al. (2005) found that knockout of the ferroportin gene in
mice resulted in embryonic lethality, likely from a defect in iron
transfer from the mother. Heterozygous animals were viable and showed a
mild disruption of iron homeostasis. Mutant mice with ferroportin
deleted in all tissues except extraembryonic visceral endoderm and
placenta appeared normal at birth, but they developed anemia and
abnormal iron accumulation in duodenal enterocytes, Kupffer cells and
hepatocytes, and splenic macrophages. Mice with ferroportin deletion
restricted to the intestines developed severe iron deficiency anemia.
Donovan et al. (2005) concluded that ferroportin is essential for
prenatal and postnatal iron homeostasis, specifically in iron transfer
across extraembryonic visceral endoderm, and iron export from
enterocytes, macrophages, and hepatocytes.
Zohn et al. (2007) reported the mouse flatiron (ffe) mutation, a
his32-to-arg (H32R) substitution in Fpn that affected its localization
and iron export activity. Similar to human patients with classic
ferroportin disease, heterozygous ffe/+ mice exhibited iron loading on
Kupffer cells, high serum ferritin, and low transferrin saturation.
Using macrophages from ffe/+ mice and through expression of Fpn(ffe) in
human embryonic kidney cells, Zohn et al. (2007) showed that Fpn(ffe)
acted in a dominant-negative manner and prevented wildtype Fpn from
localizing on the cell surface and transporting iron.
*FIELD* AV
.0001
HEMOCHROMATOSIS, TYPE 4
SLC40A1, ASN144HIS
In a large Dutch family with autosomal dominant hemochromatosis
(606069), Njajou et al. (2001) identified an A-to-C transversion at
nucleotide 734 in exon 5 of the SLC40A1 gene, resulting in an
asn144-to-his substitution.
.0002
HEMOCHROMATOSIS, TYPE 4
SLC40A1, ALA77ASP
In an Italian family, Montosi et al. (2001) determined linkage of
autosomal dominant hemochromatosis (606069) to 2q32 and demonstrated a
nonconservative missense mutation in the ferroportin gene: a GCC-to-GAC
change resulting in an ala77-to-asp (A77D) substitution.
In 147 Indian patients with thalassemia major and 65 cirrhotic controls,
Agarwal et al. (2006) analyzed the SLC40A1 gene and other modifier genes
of iron hemostasis and identified the A77D mutation in 3 thalassemia
patients, 2 heterozygotes and 1 homozygote. The mutation was not found
in the control group. Agarwal et al. (2006) stated that this was the
first report of a ferroportin mutation in the Indian population.
.0003
HEMOCHROMATOSIS, TYPE 4
SLC40A1, 3-BP DEL, VAL162DEL
In an Australian family with autosomal dominant hemochromatosis
(606069), Wallace et al. (2002) found heterozygosity for a 3-bp (TTG)
deletion in exon 5 of the FPN1 gene, resulting in the deletion of valine
at position 162. They proposed that the deletion is a loss-of-function
mutation that results in impaired iron homeostasis and leads to iron
overload. The mutation was present in 2 brothers in whom the diagnosis
was made at ages 56 and 73 years and who had hepatic fibrosis. It was
also present in the first brother's children: his son, in whom the
diagnosis was made at age 20 years and who had mild fibrosis, and his
daughter, age 19 years, who had no hepatic abnormality.
In the United Kingdom, Devalia et al. (2002) found the same mutation in
members of a family with autosomal dominant hemochromatosis. The proband
was a 38-year-old woman who presented with fatigue and was found to have
a high serum ferritin concentration and, by liver biopsy, heavy iron
deposition in both hepatocytes and Kupffer cells. Venesection therapy
was poorly tolerated (i.e., anemia developed), suggesting a defect in
iron release from reticuloendothelial stores. The proband's sister
likewise had high serum ferritin concentration, and MRI suggested iron
accumulation in both the liver and spleen. Liver biopsy showed no
fibrosis but marked iron accumulation in Kupffer cells. The combination
of erythropoietin administration with phlebotomy permitted removal of
iron without anemia. Although details were not provided, other members
of the family were affected in a pedigree pattern consistent with
autosomal dominant inheritance.
The same heterozygous 3-bp deletion in the FPN1 gene was reported by
Roetto et al. (2002) in 2 related Italian patients and in 1 unrelated
British patient, suggesting that this is a particularly common mutation
in type 4 hemochromatosis. Roetto et al. (2002) suggested that
haploinsufficiency for ferroportin-1 would be more limiting to iron
transport in reticuloendothelial cells than in duodenal enterocytes,
because the flux of iron through the reticuloendothelial macrophages far
exceeds the flux of iron through the duodenal mucosa.
Cazzola et al. (2002) found the same mutation in a family with autosomal
dominant hyperferritinemia in whom the proband showed selective iron
accumulation in the Kupffer cells on liver biopsy. The mutation occurred
in the region of nucleotides 780-791, which comprises 4 TTG repeats; the
loss of 1 TTG unit was predicted to result in the deletion of 1 of 3
sequential valine residues, codons 160-162. This is a recurrent
mutation, presumably due to slippage mispairing. Affected individuals
showed marginally low serum iron and transferrin saturation. Serum
ferritin levels were directly related to age, but were 10 to 20 times
higher than normal. Cazzola et al. (2002) suggested that heterozygosity
for this mutation represents the prototype of selective
reticuloendothelial iron overload, and should be taken into account in
the differential diagnosis of hereditary or congenital
hyperferritinemias, such as hyperferritinemia-cataract syndrome
(600886), which is due to mutations in the ferritin light chain gene
(FTL; 134790), or disorders of the ferritin heavy chain gene (FTH1;
134770).
.0004
HEMOCHROMATOSIS, TYPE 4
SLC40A1, ASP157GLY
In a patient with type 4 hemochromatosis (606069), Hetet et al. (2003)
identified an asp157-to-gly (D157G) mutation in the SLC40A1 gene.
.0005
HEMOCHROMATOSIS, TYPE 4
SLC40A1, GLN182HIS
In a patient with type 4 hemochromatosis (606069), Hetet et al. (2003)
identified a gln182-to-his (Q182H) mutation in the SLC40A1 gene. The
patient's daughter also had increased serum ferritin levels and was
found to carry the Q182H mutation.
.0006
HEMOCHROMATOSIS, TYPE 4
SLC40A1, GLY323VAL
In a patient with type 4 hemochromatosis (606069), Hetet et al. (2003)
identified a gly323-to-val (G323V) mutation in the SLC40A1 gene.
.0007
HEMOCHROMATOSIS, TYPE 4
SLC40A1, ASP181VAL
In affected members of an Italian family with elevated serum ferritin
and low hepcidin/ferritin ratios (HFE4; 606069), Cemonesi et al. (2005)
identified heterozygosity for an 846A-T transversion in exon 6 of the
SLC40A1 gene, resulting in an asp181-to-val (D181V) substitution. A
liver biopsy from the 34-year-old male proband revealed heavy iron
deposition in both hepatocytes and Kupffer cells.
.0008
HEMOCHROMATOSIS, TYPE 4
SLC40A1, GLY80VAL
In 3 affected members of an Italian family with elevated serum ferritin
(HFE4; 606069), Cemonesi et al. (2005) identified heterozygosity for a
543G-T transversion in exon 3 of the SLC40A1 gene, resulting in a
gly80-to-val (G80V) substitution.
.0009
HEMOCHROMATOSIS, TYPE 4
SLC40A1, GLY267ASP
In 6 affected members of family of Chinese descent with isolated
elevated serum ferritin (HFE4; 606069), Cemonesi et al. (2005)
identified heterozygosity for a 1104G-A transition in exon 7 of the
SLC40A1 gene, resulting in a gly267-to-asp (G267D) substitution.
*FIELD* RF
1. Agarwal, S.; Sankar, V. H.; Tewari, D.; Pradhan, M.: Ferroportin
(SLC40A1) gene in thalassemic patients of Indian descent. (Letter) Clin.
Genet. 70: 86-87, 2006.
2. Cazzola, M.; Cremonesi, L.; Papaioannou, M.; Soriani, N.; Kioumi,
A.; Charalambidou, A.; Paroni, R.; Romtsou, K.; Levi, S.; Ferrari,
M.; Arosio, P.; Christakis, J.: Genetic hyperferritinaemia and reticuloendothelial
iron overload associated with a three base pair deletion in the coding
region of the ferroportin gene (SLC11A3). Brit. J. Haemat. 119:
539-546, 2002.
3. Cemonesi, L.; Forni, G. L.; Soriani, N.; Lamagna, M.; Fermo, I.;
Daraio, F.; Galli, A.; Pietra, D.; Malcovati, L.; Ferrari, M.; Camaschella,
C.; Cazzola, M.: Genetic and clinical heterogeneity of ferroportin
disease. Brit. J. Haemat. 131: 663-670, 2005. Note: Erratum: Brit.
J. Haemat. 132: 806 only, 2006.
4. De Domenico, I.; Ward, D. M.; Nemeth, E.; Vaughn, M. B.; Musci,
G.; Ganz, T.; Kaplan, J.: The molecular basis of ferroportin-linked
hemochromatosis. Proc. Nat. Acad. Sci. 102: 8955-8960, 2005.
5. Devalia, V.; Carter, K.; Walker, A. P.; Perkins, S. J.; Worwood,
M.; May, A.; Dooley, J. S.: Autosomal dominant reticuloendothelial
iron overload associated with a 3-base pair deletion in the ferroportin
1 gene (SLC11A3). Blood 100: 695-697, 2002.
6. Donovan, A.; Brownlie, A.; Zhou, Y.; Shepard, J.; Pratt, S. J.;
Moynihan, J.; Paw, B. H.; Drejer, A.; Barut, B.; Zapata, Z.; Law,
T. C.; Brugnara, C.; Lux, S. E.; Pinkus, G. S.; Pinkus, J. L.; Kingsley,
P. D.; Palis, J.; Fleming, M. D.; Andrews, N. C.; Zon, L. I.: Positional
cloning of zebrafish ferroportin1 identifies a conserved vertebrate
iron exporter. Nature 403: 776-781, 2000.
7. Donovan, A.; Lima, C. A.; Pinkus, J. L.; Pinkus, G. S.; Zon, L.
I.; Robine, S.; Andrews, N. C.: The iron exporter ferroportin/Slc40a1
is essential for iron homeostasis. Cell Metab. 1: 191-200, 2005.
8. Fleming, R. E.; Sly, W. S.: Ferroportin mutation in autosomal
dominant hemochromatosis: loss of function, gain in understanding. J.
Clin. Invest. 108: 521-522, 2001.
9. Haile, D. J.: Assignment of Slc11a3 to mouse chromosome 1 band
1B and SLC11A3 to human chromosome 2q21 by in situ hybridization. Cytogenet.
Cell Genet. 88: 328-329, 2000.
10. Hetet, G.; Devaux, I.; Soufir, N.; Grandchamp, B.; Beaumont, C.
: Molecular analyses of patients with hyperferritinemia and normal
serum iron values reveal both L ferritin IRE and 3 new ferroportin
(slc11A3) mutations. Blood 102: 1904-1910, 2003.
11. McKie, A. T.; Marciani, P.; Rolfs, A.; Brennan, K.; Wehr, K.;
Barrow, D.; Miret, S.; Bomford, A.; Peters, T. J.; Farzaneh, F.; Hediger,
M. A.; Hentze, M. W.; Simpson, R. J.: A novel duodenal iron-regulated
transporter, IREG1, implicated in the basolateral transfer of iron
to the circulation. Molec. Cell 5: 299-309, 2000.
12. Montosi, G.; Donovan, A.; Totaro, A.; Garuti, C.; Pignatti, E.;
Cassanelli, S.; Trenor, C. C.; Gasparini, P.; Andrews, N. C.; Pietrangelo,
A.: Autosomal-dominant hemochromatosis is associated with a mutation
in the ferroportin (SLC11A3) gene. J. Clin. Invest. 108: 619-623,
2001.
13. Nemeth, E.; Tuttle, M. S.; Powelson, J.; Vaughn, M. B.; Donovan,
A.; Ward, D. M.; Ganz, T.; Kaplan, J.: Hepcidin regulates cellular
iron efflux by binding to ferroportin and inducing its internalization. Science 306:
2090-2093, 2004.
14. Njajou, O. T.; Vaessen, N.; Joosse, M.; Berghuis, B.; van Dongen,
J. W. F.; Breuning, M. H.; Snijders, P. J. L. M.; Rutten, W. P. F.;
Sandkuijl, L. A.; Oostra, B. A.; van Duijn, C. M.; Heutink, P.: A
mutation in SLC11A3 is associated with autosomal dominant hemochromatosis. Nature
Genet. 28: 213-214, 2001.
15. Pietrangelo, A.; Montosi, G.; Totaro, A.; Garuti, C.; Conte, D.;
Cassanelli, S.; Fraquelli, M.; Sardini, C.; Vasta, F.; Gasparini,
P.: Hereditary hemochromatosis in adults without pathogenic mutations
in the hemochromatosis gene. New Eng. J. Med. 341: 725-732, 1999.
16. Roetto, A.; Merryweather-Clarke, A. T.; Daraio, F.; Livesey, K.;
Pointon, J. J.; Barbabietola, G.; Piga, A.; Mackie, P. H.; Robson,
K. J. H.; Camaschella, C.: A valine deletion of ferroportin 1: a
common mutation in hemochromatosis type 4? (Letter) Blood 100: 733-734,
2002.
17. Sangokoya, C.; Doss, J. F.; Chi, J.-T.: Iron-responsive miR-485-3p
regulates cellular iron homeostasis by targeting ferroportin. PLoS
Genet. 9: e1003408, 2013. Note: Electronic Article.
18. Wallace, D. F.; Pedersen, P.; Dixon, J. L.; Stephenson, P.; Searle,
J. W.; Powell, L. W.; Subramaniam, V. N.: Novel mutation in ferroportin1
is associated with autosomal dominant hemochromatosis. Blood 100:
692-694, 2002.
19. Zohn, I. E.; De Domenico, I.; Pollock, A.; Ward, D. M.; Goodman,
J. F.; Liang, X.; Sanchez, A. J.; Niswander, L.; Kaplan, J.: The
flatiron mutation in mouse ferroportin acts as a dominant negative
to cause ferroportin disease. Blood 109: 4174-4180, 2007.
*FIELD* CN
Patricia A. Hartz - updated: 8/28/2013
Patricia A. Hartz - updated: 5/1/2008
Marla J. F. O'Neill - updated: 9/8/2006
Marla J. F. O'Neill - updated: 3/30/2006
Marla J. F. O'Neill - updated: 7/11/2005
Patricia A. Hartz - updated: 4/19/2005
Ada Hamosh - updated: 1/27/2005
Victor A. McKusick - updated: 11/26/2003
Victor A. McKusick - updated: 1/10/2003
Victor A. McKusick - updated: 9/26/2002
Victor A. McKusick - updated: 1/10/2002
Victor A. McKusick - updated: 6/22/2001
Joanna S. Amberger - updated: 8/7/2000
Stylianos E. Antonarakis - updated: 3/30/2000
*FIELD* CD
Ada Hamosh: 3/6/2000
*FIELD* ED
mgross: 08/28/2013
mgross: 8/28/2013
terry: 3/15/2013
carol: 10/21/2010
mgross: 5/1/2008
wwang: 9/12/2006
terry: 9/8/2006
wwang: 3/31/2006
terry: 3/30/2006
wwang: 7/20/2005
terry: 7/11/2005
mgross: 4/20/2005
terry: 4/19/2005
wwang: 2/2/2005
terry: 1/27/2005
tkritzer: 12/8/2003
tkritzer: 12/3/2003
terry: 11/26/2003
carol: 3/13/2003
terry: 3/12/2003
tkritzer: 1/14/2003
terry: 1/10/2003
carol: 10/1/2002
tkritzer: 9/27/2002
tkritzer: 9/26/2002
carol: 1/14/2002
terry: 1/10/2002
mgross: 6/27/2001
terry: 6/22/2001
carol: 8/21/2000
carol: 8/8/2000
joanna: 8/7/2000
alopez: 4/4/2000
mgross: 3/30/2000
alopez: 3/6/2000
MIM
606069
*RECORD*
*FIELD* NO
606069
*FIELD* TI
#606069 HEMOCHROMATOSIS, TYPE 4; HFE4
;;HEMOCHROMATOSIS, AUTOSOMAL DOMINANT;;
HEMOCHROMATOSIS DUE TO DEFECT IN FERROPORTIN
read more*FIELD* TX
A number sign (#) is used with this entry because autosomal dominant
hemochromatosis (HFE4) is caused by mutation in the SLC40A1 gene
(604653), which encodes ferroportin.
For general background information and a discussion of genetic
heterogeneity of hereditary hemochromatosis, see 235200.
CLINICAL FEATURES
Pietrangelo et al. (1999) described an Italian family with an autosomal
dominant form of hemochromatosis not associated with mutations in the
HFE gene (613609) and not linked to 6p. Fifteen members of this pedigree
suffered from iron overload resulting in hepatic fibrosis, diabetes,
impotence, and arrhythmias. In addition to autosomal dominant
inheritance, features distinguishing this entity from classic
hemochromatosis included early iron accumulation in reticuloendothelial
cells and a marked increase in serum ferritin prior to elevation of the
transferrin saturation. Several patients showed a reduced tolerance to
phlebotomy and became anemic on therapy despite persistently elevated
serum ferritin values. In general, anemia early in life was a feature.
Njajou et al. (2001) studied a large Dutch family segregating an
autosomal dominant form of hemochromatosis. Individuals were considered
affected if they had serum ferritin levels exceeding 450 ng/ml and/or
transferrin saturation exceeding 50%. A final diagnosis of
hemochromatosis was made using results obtained by liver biopsy and/or
magnetic resonance imaging. Clinical symptoms of affected individuals
were similar to those of other patients with hemochromatosis and
included joint pains, osteoarthritis, fatigue, cardiomyopathies, and
endocrine disorders. The age of onset of the disorder was up to 60 years
in males and about 10 years later in females.
MAPPING
Njajou et al. (2001) carried out a genomewide scan for linkage in the
Dutch family with autosomal dominant hemochromatosis. The maximum lod
score (3.01 at theta of 0.0) was found with marker D2S389 on chromosome
2. In the critical region, the SLC40A1 gene was identified as the most
likely candidate.
In the Italian family with autosomal dominant hemochromatosis reported
by Pietrangelo et al. (1999), Montosi et al. (2001) mapped the disorder
to 2q32.
MOLECULAR GENETICS
Njajou et al. (2001) detected a missense mutation in the SLC40A1 gene
(604653.0001) in a large Dutch family with autosomal dominant
hemochromatosis.
Montosi et al. (2001) identified a missense mutation (604653.0002) in
the SLC40A1 gene in the Italian family with autosomal dominant
hemochromatosis reported by Pietrangelo et al. (1999).
De Domenico et al. (2005) demonstrated that ferroportin is multimeric
and that mutant ferroportin can be defective in cell surface
localization or have a decreased ability to be internalized and degraded
in response to hepcidin. The authors concluded that mutant ferroportin
can act as a dominant negative, thus providing a molecular basis for the
dominant inheritance of the disease as well as the different patient
phenotypes.
Cemonesi et al. (2005) studied 2 Italian families and 1 of Chinese
descent with elevated serum ferritin levels and identified
heterozygosity for 3 different mutations in the SLC40A1 gene,
respectively. The authors noted the variability in phenotypes between
the families and suggested that the mutation (604653.0007) in the first
Italian family, in which the proband had a liver biopsy showing heavy
iron deposition in both hepatocytes and Kupffer cells, likely caused
decreased responsiveness to hepcidin, whereas the mutations (604653.0008
and 604653.0009) in the latter 2 families likely caused defective
localization of the protein to the cell surface.
*FIELD* RF
1. Cemonesi, L.; Forni, G. L.; Soriani, N.; Lamagna, M.; Fermo, I.;
Daraio, F.; Galli, A.; Pietra, D.; Malcovati, L.; Ferrari, M.; Camaschella,
C.; Cazzola, M.: Genetic and clinical heterogeneity of ferroportin
disease. Brit. J. Haemat. 131: 663-670, 2005. Note: Erratum: Brit.
J. Haemat. 132: 806 only, 2006.
2. De Domenico, I.; Ward, D. M.; Nemeth, E.; Vaughn, M. B.; Musci,
G.; Ganz, T.; Kaplan, J.: The molecular basis of ferroportin-linked
hemochromatosis. Proc. Nat. Acad. Sci. 102: 8955-8960, 2005.
3. Montosi, G.; Donovan, A.; Totaro, A.; Garuti, C.; Pignatti, E.;
Cassanelli, S.; Trenor, C. C.; Gasparini, P.; Andrews, N. C.; Pietrangelo,
A.: Autosomal-dominant hemochromatosis is associated with a mutation
in the ferroportin (SLC11A3) gene. J. Clin. Invest. 108: 619-623,
2001.
4. Njajou, O. T.; Vaessen, N.; Joosse, M.; Berghuis, B.; van Dongen,
J. W. F.; Breuning, M. H.; Snijders, P. J. L. M.; Rutten, W. P. F.;
Sandkuijl, L. A.; Oostra, B. A.; van Duijn, C. M.; Heutink, P.: A
mutation in SLC11A3 is associated with autosomal dominant hemochromatosis. Nature
Genet. 28: 213-214, 2001.
5. Pietrangelo, A.; Montosi, G.; Totaro, A.; Garuti, C.; Conte, D.;
Cassanelli, S.; Fraquelli, M.; Sardini, C.; Vasta, F.; Gasparini,
P.: Hereditary hemochromatosis in adults without pathogenic mutations
in the hemochromatosis gene. New Eng. J. Med. 341: 725-732, 1999.
*FIELD* CN
Marla J. F. O'Neill - updated: 3/30/2006
Marla J. F. O'Neill - updated: 7/11/2005
Victor A. McKusick - updated: 2/6/2003
Victor A. McKusick - updated: 1/10/2002
*FIELD* CD
Victor A. McKusick: 6/27/2001
*FIELD* ED
terry: 03/15/2013
carol: 10/21/2010
alopez: 3/25/2010
wwang: 3/31/2006
terry: 3/30/2006
wwang: 7/20/2005
terry: 7/11/2005
mgross: 4/20/2005
tkritzer: 3/6/2003
carol: 2/13/2003
carol: 2/6/2003
terry: 2/6/2003
alopez: 12/11/2002
carol: 1/14/2002
terry: 1/10/2002
mgross: 6/27/2001
*RECORD*
*FIELD* NO
606069
*FIELD* TI
#606069 HEMOCHROMATOSIS, TYPE 4; HFE4
;;HEMOCHROMATOSIS, AUTOSOMAL DOMINANT;;
HEMOCHROMATOSIS DUE TO DEFECT IN FERROPORTIN
read more*FIELD* TX
A number sign (#) is used with this entry because autosomal dominant
hemochromatosis (HFE4) is caused by mutation in the SLC40A1 gene
(604653), which encodes ferroportin.
For general background information and a discussion of genetic
heterogeneity of hereditary hemochromatosis, see 235200.
CLINICAL FEATURES
Pietrangelo et al. (1999) described an Italian family with an autosomal
dominant form of hemochromatosis not associated with mutations in the
HFE gene (613609) and not linked to 6p. Fifteen members of this pedigree
suffered from iron overload resulting in hepatic fibrosis, diabetes,
impotence, and arrhythmias. In addition to autosomal dominant
inheritance, features distinguishing this entity from classic
hemochromatosis included early iron accumulation in reticuloendothelial
cells and a marked increase in serum ferritin prior to elevation of the
transferrin saturation. Several patients showed a reduced tolerance to
phlebotomy and became anemic on therapy despite persistently elevated
serum ferritin values. In general, anemia early in life was a feature.
Njajou et al. (2001) studied a large Dutch family segregating an
autosomal dominant form of hemochromatosis. Individuals were considered
affected if they had serum ferritin levels exceeding 450 ng/ml and/or
transferrin saturation exceeding 50%. A final diagnosis of
hemochromatosis was made using results obtained by liver biopsy and/or
magnetic resonance imaging. Clinical symptoms of affected individuals
were similar to those of other patients with hemochromatosis and
included joint pains, osteoarthritis, fatigue, cardiomyopathies, and
endocrine disorders. The age of onset of the disorder was up to 60 years
in males and about 10 years later in females.
MAPPING
Njajou et al. (2001) carried out a genomewide scan for linkage in the
Dutch family with autosomal dominant hemochromatosis. The maximum lod
score (3.01 at theta of 0.0) was found with marker D2S389 on chromosome
2. In the critical region, the SLC40A1 gene was identified as the most
likely candidate.
In the Italian family with autosomal dominant hemochromatosis reported
by Pietrangelo et al. (1999), Montosi et al. (2001) mapped the disorder
to 2q32.
MOLECULAR GENETICS
Njajou et al. (2001) detected a missense mutation in the SLC40A1 gene
(604653.0001) in a large Dutch family with autosomal dominant
hemochromatosis.
Montosi et al. (2001) identified a missense mutation (604653.0002) in
the SLC40A1 gene in the Italian family with autosomal dominant
hemochromatosis reported by Pietrangelo et al. (1999).
De Domenico et al. (2005) demonstrated that ferroportin is multimeric
and that mutant ferroportin can be defective in cell surface
localization or have a decreased ability to be internalized and degraded
in response to hepcidin. The authors concluded that mutant ferroportin
can act as a dominant negative, thus providing a molecular basis for the
dominant inheritance of the disease as well as the different patient
phenotypes.
Cemonesi et al. (2005) studied 2 Italian families and 1 of Chinese
descent with elevated serum ferritin levels and identified
heterozygosity for 3 different mutations in the SLC40A1 gene,
respectively. The authors noted the variability in phenotypes between
the families and suggested that the mutation (604653.0007) in the first
Italian family, in which the proband had a liver biopsy showing heavy
iron deposition in both hepatocytes and Kupffer cells, likely caused
decreased responsiveness to hepcidin, whereas the mutations (604653.0008
and 604653.0009) in the latter 2 families likely caused defective
localization of the protein to the cell surface.
*FIELD* RF
1. Cemonesi, L.; Forni, G. L.; Soriani, N.; Lamagna, M.; Fermo, I.;
Daraio, F.; Galli, A.; Pietra, D.; Malcovati, L.; Ferrari, M.; Camaschella,
C.; Cazzola, M.: Genetic and clinical heterogeneity of ferroportin
disease. Brit. J. Haemat. 131: 663-670, 2005. Note: Erratum: Brit.
J. Haemat. 132: 806 only, 2006.
2. De Domenico, I.; Ward, D. M.; Nemeth, E.; Vaughn, M. B.; Musci,
G.; Ganz, T.; Kaplan, J.: The molecular basis of ferroportin-linked
hemochromatosis. Proc. Nat. Acad. Sci. 102: 8955-8960, 2005.
3. Montosi, G.; Donovan, A.; Totaro, A.; Garuti, C.; Pignatti, E.;
Cassanelli, S.; Trenor, C. C.; Gasparini, P.; Andrews, N. C.; Pietrangelo,
A.: Autosomal-dominant hemochromatosis is associated with a mutation
in the ferroportin (SLC11A3) gene. J. Clin. Invest. 108: 619-623,
2001.
4. Njajou, O. T.; Vaessen, N.; Joosse, M.; Berghuis, B.; van Dongen,
J. W. F.; Breuning, M. H.; Snijders, P. J. L. M.; Rutten, W. P. F.;
Sandkuijl, L. A.; Oostra, B. A.; van Duijn, C. M.; Heutink, P.: A
mutation in SLC11A3 is associated with autosomal dominant hemochromatosis. Nature
Genet. 28: 213-214, 2001.
5. Pietrangelo, A.; Montosi, G.; Totaro, A.; Garuti, C.; Conte, D.;
Cassanelli, S.; Fraquelli, M.; Sardini, C.; Vasta, F.; Gasparini,
P.: Hereditary hemochromatosis in adults without pathogenic mutations
in the hemochromatosis gene. New Eng. J. Med. 341: 725-732, 1999.
*FIELD* CN
Marla J. F. O'Neill - updated: 3/30/2006
Marla J. F. O'Neill - updated: 7/11/2005
Victor A. McKusick - updated: 2/6/2003
Victor A. McKusick - updated: 1/10/2002
*FIELD* CD
Victor A. McKusick: 6/27/2001
*FIELD* ED
terry: 03/15/2013
carol: 10/21/2010
alopez: 3/25/2010
wwang: 3/31/2006
terry: 3/30/2006
wwang: 7/20/2005
terry: 7/11/2005
mgross: 4/20/2005
tkritzer: 3/6/2003
carol: 2/13/2003
carol: 2/6/2003
terry: 2/6/2003
alopez: 12/11/2002
carol: 1/14/2002
terry: 1/10/2002
mgross: 6/27/2001