Reviewed, UniProtKB/Swiss-Prot Q30201 (HFE_HUMAN)

Names and origin

Protein names

Recommended name:
    Hereditary hemochromatosis protein
Alternative name(s):
    HLA-H

Gene names

Name:	HFE
Synonyms:	HLAH

Organism

Homo sapiens (Human) [Complete proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	348 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is further processed into a mature form.
Protein existence	Evidence at protein level.

General annotation (Comments)

Function	Binds to transferrin receptor (TFR) and reduces its affinity for iron-loaded transferrin. Ref.9
Subunit structure	Binds TFR through the extracellular domain in a pH-dependent manner.
Subcellular location	Membrane; Single-pass type I membrane protein.
Tissue specificity	In all tissues tested except brain.
Involvement in disease	Defects in HFE are a cause of hereditary hemochromatosis (HH) [MIM:235200]. HH is an autosomal recessive inborn disorder of iron metabolism. It is the most common recessive disease in Caucasians. HH is characterized by abnormal intestinal iron absorption and progressive increase of total body iron, which results in midlife in clinical complications including cirrhosis, cardiopathy, diabetes, endocrine dysfunctions, arthropathy, and susceptibility to liver cancer. Since the disease complications can be effectively prevented by regular phlebotomies, early diagnosis is most important to provide a normal life expectancy to the affected subjects. Ref.1 Ref.14 Ref.15 Ref.16 Ref.17 Ref.18 Ref.19 Ref.20 Ref.21 Ref.22 Ref.25 Ref.26 Ref.27 Ref.28 Ref.29 Ref.30 Ref.31 Ref.32 Ref.33 Defects in HFE are a cause of porphyria variegata (PV) [MIM:176200]. Porphyrias are inherited defects in the biosynthesis of heme, resulting in the accumulation and increased excretion of porphyrins or porphyrin precursors. They are classified as erythropoietic or hepatic, depending on whether the enzyme deficiency occurs in red blood cells or in the liver. PV is the most common form of porphyria in South Africa. It is characterized by skin hyperpigmentation and hypertrichosis, abdominal pain, tachycardia, hypertension and neuromuscular disturbances. High fecal levels of protoporphyrin and coproporphyrin, increased urine uroporphyrins and iron overload are typical markers of the disease. Ref.20 Defects in HFE are associated with susceptibility to diabetic nephropathy [MIM:612635]; also called susceptibility to microvascular complications of diabetes type 7 (MVCD7) or susceptibility to diabetic proliferative retinopathy. Diabetic nephropathy is a kidney disease and resultant kidney function impairment due to the long standing effects of diabetes on the microvasculature (glomerulus) of the kidney. Features include increased urine protein and declining kidney function.
Sequence similarities	Belongs to the MHC class I family. Contains 1 Ig-like C1-type (immunoglobulin-like) domain.

Ontologies

Keywords
Biological process	Immune response Ion transport Iron transport Transport
Cellular component	MHC I Membrane
Coding sequence diversity	Alternative splicing Polymorphism
Disease	Disease mutation
Domain	Signal Transmembrane
Ligand	Iron
PTM	Disulfide bond Glycoprotein
Technical term	3D-structure Complete proteome
Gene Ontology (GO)
Biological process	antigen processing and presentation of peptide antigen via MHC class I Inferred from electronic annotation. Source: UniProtKB-KW cellular iron ion homeostasis Ref.12 Traceable author statement. Source: ProtInc immune response Inferred from electronic annotation. Source: UniProtKB-KW iron ion transport Traceable author statement. Source: ProtInc protein complex assembly Ref.12 Traceable author statement. Source: ProtInc receptor-mediated endocytosis Traceable author statement. Source: ProtInc
Cellular component	MHC class I protein complex Inferred from electronic annotation. Source: UniProtKB-KW apical part of cell Inferred from direct assay. Source: UniProtKB basal part of cell Inferred from direct assay. Source: UniProtKB cytoplasmic vesicle Inferred from direct assay. Source: UniProtKB early endosome Inferred from direct assay. Source: UniProtKB integral to plasma membrane Ref.12 Traceable author statement. Source: ProtInc perinuclear region of cytoplasm Inferred from direct assay. Source: UniProtKB recycling endosome Inferred from direct assay. Source: UniProtKB
Molecular function	iron ion binding Inferred from electronic annotation. Source: UniProtKB-KW protein binding Inferred from physical interaction. Source: UniProtKB
Complete GO annotation...

Alternative products

This entry describes 10 isoforms produced by alternative splicing. [Align] [Select]

Note: Additional isoforms seem to exist.

Isoform 1 (identifier: Q30201-1)

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

Note: May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay.

Isoform 2 (identifier: Q30201-2)

Also known as: delE2;

The sequence of this isoform differs from the canonical sequence as follows:
     26-114: RSHSLHYLFM...IMENHNHSKE → Q

Isoform 3 (identifier: Q30201-3)

Also known as: del14E4;

The sequence of this isoform differs from the canonical sequence as follows:
     207-220: Missing.

Isoform 4 (identifier: Q30201-4)

Also known as: delE214E4;

The sequence of this isoform differs from the canonical sequence as follows:
     26-114: RSHSLHYLFM...IMENHNHSKE → Q
     207-220: Missing.

Isoform 5 (identifier: Q30201-5)

The sequence of this isoform differs from the canonical sequence as follows:
     26-49: RSHSLHYLFMGASEQDLGLSLFEA → P

Isoform 6 (identifier: Q30201-6)

The sequence of this isoform differs from the canonical sequence as follows:
     27-206: Missing.

Isoform 7 (identifier: Q30201-7)

Also known as: delE3;

The sequence of this isoform differs from the canonical sequence as follows:
     114-205: Missing.

Isoform 8 (identifier: Q30201-8)

Also known as: 1043-2283del,intron6ins;

The sequence of this isoform differs from the canonical sequence as follows:
     275-276: GE → KY
     277-348: Missing.

Isoform 9 (identifier: Q30201-9)

Also known as: delE3-7;

The sequence of this isoform differs from the canonical sequence as follows:
     144-161: DHLEFCPDTLDWRAAEPR → VLQDTIYSSEVSSLGIKF
     162-348: Missing.

Isoform 10 (identifier: Q30201-10)

Also known as: 562-878del;

The sequence of this isoform differs from the canonical sequence as follows:
     114-219: Missing.

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Signal peptide

1 – 22

22

Chain

23 – 348

326

Hereditary hemochromatosis protein

PRO_0000018892

Regions

Topological domain

23 – 306

284

Extracellular Potential

Transmembrane

307 – 330

24

Potential

Topological domain

331 – 348

18

Cytoplasmic Potential

Domain

207 – 298

92

Ig-like C1-type

Region

23 – 114

92

Alpha-1

Region

115 – 205

91

Alpha-2

Region

206 – 297

92

Alpha-3

Region

298 – 306

9

Connecting peptide

Amino acid modifications

Glycosylation

110

1

N-linked (GlcNAc...) Potential

Glycosylation

130

1

N-linked (GlcNAc...) Potential

Glycosylation

234

1

N-linked (GlcNAc...) Potential

Disulfide bond

124 ↔ 187

Disulfide bond

225 ↔ 282

Natural variations

Alternative sequence

26 – 114

89

RSHSL…NHSKE → Q in isoform 2 and isoform 4.

VSP_003218

Alternative sequence

26 – 49

24

RSHSL…SLFEA → P in isoform 5.

VSP_003219

Alternative sequence

27 – 206

180

Missing in isoform 6.

VSP_003220

Alternative sequence

114 – 219

106

Missing in isoform 10.

VSP_003222

Alternative sequence

114 – 205

92

Missing in isoform 7.

VSP_003221

Alternative sequence

144 – 161

18

DHLEF…AAEPR → VLQDTIYSSEVSSLGIKF in isoform 9.

VSP_003223

Alternative sequence

162 – 348

187

Missing in isoform 9.

VSP_003224

Alternative sequence

207 – 220

14

Missing in isoform 3 and isoform 4.

VSP_003225

Alternative sequence

275 – 276

2

GE → KY in isoform 8.

VSP_003226

Alternative sequence

277 – 348

72

Missing in isoform 8.

VSP_003227

Natural variant

6

1

R → S in HH. Ref.30

VAR_042506

Natural variant

43

1

G → D in HH; located on the same allele as D-63. Ref.33

VAR_042507

Natural variant

53

1

V → M

VAR_008111

Natural variant

59

1

V → M

VAR_008112

Natural variant

63

1

H → D in HH and PV; increased frequency of the Asp-63 allele among patients with diabetic nephropathy. dbSNP rs1799945. Ref.1 Ref.14 Ref.16 Ref.17 Ref.18 Ref.20 Ref.21 Ref.25 Ref.27 Ref.29 Ref.33 Ref.24

VAR_004396

Natural variant

65

1

S → C in HH; mild form. dbSNP rs1800730. Ref.18 Ref.19 Ref.22 Ref.27 Ref.29

VAR_004397

Natural variant

66

1

R → C in HH. Ref.29

VAR_042508

Natural variant

93

1

G → R in HH. dbSNP rs28934597. Ref.19

VAR_008729

Natural variant

105

1

I → T in HH. dbSNP rs28934596. Ref.19

VAR_008730

Natural variant

127

1

Q → H in HH and PV. dbSNP rs28934595. Ref.20

VAR_008113

Natural variant

176

1

A → V in HH; uncertain pathological significance. Ref.26

VAR_042509

Natural variant

217

1

T → I: dbSNP rs4986950.

VAR_020270

Natural variant

224

1

R → G in HH. Ref.29

VAR_042510

Natural variant

277

1

E → K Rare polymorphism. Ref.23

VAR_008731

Natural variant

282

1

C → Y in HH; the frequency of the Tyr-282 mutation is higher in patients with type 2 diabetes than it is in the general population of healthy subjects. dbSNP rs1800562. Ref.1 Ref.14 Ref.15 Ref.17 Ref.18 Ref.21 Ref.25 Ref.27 Ref.29 Ref.33 Ref.24

VAR_004398

Natural variant

283

1

Q → P in HH; destabilizing effect on the tertiary structure of the protein; prevents the normal interaction between HFE and B2M and between HFE and TFRC; decreases the capacity of HFE to reduce transferrin-mediated iron uptake. Ref.28 Ref.32

VAR_037304

Natural variant

295

1

V → A in HH. Ref.27 Ref.31

VAR_042511

Natural variant

330

1

R → M in HH. Ref.20

VAR_008114

Experimental info

Sequence conflict

26

1

R → L in CAC80805. Ref.6

Sequence conflict

230

1

Y → H in AAG29342. Ref.7

Sequence conflict

248

1

A → T in AAG29575. Ref.7

Sequence conflict

256

1

V → A in AAG29577. Ref.7

Sequence conflict

275

1

G → E in AAG29342. Ref.7

Sequence conflict

311

1

S → R in AAG29342. Ref.7

Sequence conflict

339

1

M → V in AAG29577. Ref.7

Secondary structure

1

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348

Helix Strand Turn

Details...

Beta strand

28 – 38

11

Beta strand

43 – 45

3

Beta strand

48 – 53

6

Beta strand

56 – 65

10

Beta strand

68 – 70

3

Turn

79 – 82

4

Helix

83 – 107

25

Turn

108 – 110

3

Beta strand

112 – 114

3

Beta strand

117 – 126

10

Beta strand

132 – 140

9

Beta strand

143 – 149

7

Helix

150 – 152

3

Beta strand

154 – 159

6

Helix

160 – 162

3

Helix

163 – 170

8

Helix

174 – 184

11

Helix

186 – 198

13

Turn

199 – 201

3

Beta strand

209 – 216

8

Beta strand

221 – 233

13

Beta strand

236 – 241

6

Helix

248 – 250

3

Beta strand

255 – 258

4

Beta strand

264 – 272

9

Helix

276 – 279

4

Beta strand

280 – 285

6

Beta strand

289 – 291

3

Beta strand

293 – 296

4

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified November 1, 1997. Version 1. Checksum: 432EB9A314A55BEA	FASTA	348	40,108
	10 20 30 40 50 60 MGPRARPALL LLMLLQTAVL QGRLLRSHSL HYLFMGASEQ DLGLSLFEAL GYVDDQLFVF 70 80 90 100 110 120 YDHESRRVEP RTPWVSSRIS SQMWLQLSQS LKGWDHMFTV DFWTIMENHN HSKESHTLQV 130 140 150 160 170 180 ILGCEMQEDN STEGYWKYGY DGQDHLEFCP DTLDWRAAEP RAWPTKLEWE RHKIRARQNR 190 200 210 220 230 240 AYLERDCPAQ LQQLLELGRG VLDQQVPPLV KVTHHVTSSV TTLRCRALNY YPQNITMKWL 250 260 270 280 290 300 KDKQPMDAKE FEPKDVLPNG DGTYQGWITL AVPPGEEQRY TCQVEHPGLD QPLIVIWEPS 310 320 330 340 PSGTLVIGVI SGIAVFVVIL FIGILFIILR KRQGSRGAMG HYVLAERE
	Isoform 2 (delE2). Checksum: C30AC94F06A81AAA	FASTA	260	29,633
	10 20 30 40 50 60 MGPRARPALL LLMLLQTAVL QGRLLQSHTL QVILGCEMQE DNSTEGYWKY GYDGQDHLEF 70 80 90 100 110 120 CPDTLDWRAA EPRAWPTKLE WERHKIRARQ NRAYLERDCP AQLQQLLELG RGVLDQQVPP 130 140 150 160 170 180 LVKVTHHVTS SVTTLRCRAL NYYPQNITMK WLKDKQPMDA KEFEPKDVLP NGDGTYQGWI 190 200 210 220 230 240 TLAVPPGEEQ RYTCQVEHPG LDQPLIVIWE PSPSGTLVIG VISGIAVFVV ILFIGILFII 250 260 LRKRQGSRGA MGHYVLAERE
	Isoform 3 (del14E4). Checksum: 811D9D68BB9D7F3A	FASTA	334	38,625
	10 20 30 40 50 60 MGPRARPALL LLMLLQTAVL QGRLLRSHSL HYLFMGASEQ DLGLSLFEAL GYVDDQLFVF 70 80 90 100 110 120 YDHESRRVEP RTPWVSSRIS SQMWLQLSQS LKGWDHMFTV DFWTIMENHN HSKESHTLQV 130 140 150 160 170 180 ILGCEMQEDN STEGYWKYGY DGQDHLEFCP DTLDWRAAEP RAWPTKLEWE RHKIRARQNR 190 200 210 220 230 240 AYLERDCPAQ LQQLLELGRG VLDQQVTTLR CRALNYYPQN ITMKWLKDKQ PMDAKEFEPK 250 260 270 280 290 300 DVLPNGDGTY QGWITLAVPP GEEQRYTCQV EHPGLDQPLI VIWEPSPSGT LVIGVISGIA 310 320 330 VFVVILFIGI LFIILRKRQG SRGAMGHYVL AERE
	Isoform 4 (delE214E4). Checksum: 47B79FE7B8B49A0A	FASTA	246	28,151
	10 20 30 40 50 60 MGPRARPALL LLMLLQTAVL QGRLLQSHTL QVILGCEMQE DNSTEGYWKY GYDGQDHLEF 70 80 90 100 110 120 CPDTLDWRAA EPRAWPTKLE WERHKIRARQ NRAYLERDCP AQLQQLLELG RGVLDQQVTT 130 140 150 160 170 180 LRCRALNYYP QNITMKWLKD KQPMDAKEFE PKDVLPNGDG TYQGWITLAV PPGEEQRYTC 190 200 210 220 230 240 QVEHPGLDQP LIVIWEPSPS GTLVIGVISG IAVFVVILFI GILFIILRKR QGSRGAMGHY VLAERE
	Isoform 5. Checksum: 626343ACFAA862EF	FASTA	325	37,514
	10 20 30 40 50 60 MGPRARPALL LLMLLQTAVL QGRLLPLGYV DDQLFVFYDH ESRRVEPRTP WVSSRISSQM 70 80 90 100 110 120 WLQLSQSLKG WDHMFTVDFW TIMENHNHSK ESHTLQVILG CEMQEDNSTE GYWKYGYDGQ 130 140 150 160 170 180 DHLEFCPDTL DWRAAEPRAW PTKLEWERHK IRARQNRAYL ERDCPAQLQQ LLELGRGVLD 190 200 210 220 230 240 QQVPPLVKVT HHVTSSVTTL RCRALNYYPQ NITMKWLKDK QPMDAKEFEP KDVLPNGDGT 250 260 270 280 290 300 YQGWITLAVP PGEEQRYTCQ VEHPGLDQPL IVIWEPSPSG TLVIGVISGI AVFVVILFIG 310 320 ILFIILRKRQ GSRGAMGHYV LAERE
	Isoform 6. Checksum: ABEBD094D95FFEA8	FASTA	168	18,777
	10 20 30 40 50 60 MGPRARPALL LLMLLQTAVL QGRLLRPPLV KVTHHVTSSV TTLRCRALNY YPQNITMKWL 70 80 90 100 110 120 KDKQPMDAKE FEPKDVLPNG DGTYQGWITL AVPPGEEQRY TCQVEHPGLD QPLIVIWEPS 130 140 150 160 PSGTLVIGVI SGIAVFVVIL FIGILFIILR KRQGSRGAMG HYVLAERE
	Isoform 7 (delE3). Checksum: 0E810B1BBACDF0BF	FASTA	256	29,194
	10 20 30 40 50 60 MGPRARPALL LLMLLQTAVL QGRLLRSHSL HYLFMGASEQ DLGLSLFEAL GYVDDQLFVF 70 80 90 100 110 120 YDHESRRVEP RTPWVSSRIS SQMWLQLSQS LKGWDHMFTV DFWTIMENHN HSKVPPLVKV 130 140 150 160 170 180 THHVTSSVTT LRCRALNYYP QNITMKWLKD KQPMDAKEFE PKDVLPNGDG TYQGWITLAV 190 200 210 220 230 240 PPGEEQRYTC QVEHPGLDQP LIVIWEPSPS GTLVIGVISG IAVFVVILFI GILFIILRKR 250 QGSRGAMGHY VLAERE
	Isoform 8 (1043-2283del,intron6ins). Checksum: 3E0D2762D7476B82	FASTA	276	32,243
	10 20 30 40 50 60 MGPRARPALL LLMLLQTAVL QGRLLRSHSL HYLFMGASEQ DLGLSLFEAL GYVDDQLFVF 70 80 90 100 110 120 YDHESRRVEP RTPWVSSRIS SQMWLQLSQS LKGWDHMFTV DFWTIMENHN HSKESHTLQV 130 140 150 160 170 180 ILGCEMQEDN STEGYWKYGY DGQDHLEFCP DTLDWRAAEP RAWPTKLEWE RHKIRARQNR 190 200 210 220 230 240 AYLERDCPAQ LQQLLELGRG VLDQQVPPLV KVTHHVTSSV TTLRCRALNY YPQNITMKWL 250 260 270 KDKQPMDAKE FEPKDVLPNG DGTYQGWITL AVPPKY
	Isoform 9 (delE3-7). Checksum: 5E288C5835DC3784	FASTA	161	18,651
	10 20 30 40 50 60 MGPRARPALL LLMLLQTAVL QGRLLRSHSL HYLFMGASEQ DLGLSLFEAL GYVDDQLFVF 70 80 90 100 110 120 YDHESRRVEP RTPWVSSRIS SQMWLQLSQS LKGWDHMFTV DFWTIMENHN HSKESHTLQV 130 140 150 160 ILGCEMQEDN STEGYWKYGY DGQVLQDTIY SSEVSSLGIK F
	Isoform 10 (562-878del). Checksum: E423FF903128DB74	FASTA	242	27,711
	10 20 30 40 50 60 MGPRARPALL LLMLLQTAVL QGRLLRSHSL HYLFMGASEQ DLGLSLFEAL GYVDDQLFVF 70 80 90 100 110 120 YDHESRRVEP RTPWVSSRIS SQMWLQLSQS LKGWDHMFTV DFWTIMENHN HSKVTTLRCR 130 140 150 160 170 180 ALNYYPQNIT MKWLKDKQPM DAKEFEPKDV LPNGDGTYQG WITLAVPPGE EQRYTCQVEH 190 200 210 220 230 240 PGLDQPLIVI WEPSPSGTLV IGVISGIAVF VVILFIGILF IILRKRQGSR GAMGHYVLAE RE

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis." Feder J.N., Gnirke A., Thomas W., Tsuchihashi Z., Ruddy D.A., Basava A., Dormishian F., Domingo R. Jr., Ellis M.C. Jr., Fullan A., Hinton L.M., Jones N.L., Kimmel B.E., Kronmal G.S., Lauer P., Lee V.K., Loeb D.B., Mapa F.A. , McClelland E., Meyer N.C., Mintier G.A., Moeller N., Moore T., Morikang E., Prass C.E., Quintana L., Starnes S.M., Schatzman R.C., Brunke K.J., Drayna D.T., Risch N.J., Bacon B.R., Wolff R.K. Nat. Genet. 13:399-409(1996) [PubMed: 8696333] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), VARIANTS HH ASP-63 AND TYR-282.
[2]	"A 1.1-Mb transcript map of the hereditary hemochromatosis locus." Ruddy D.A., Kronmal G.S., Lee V.K., Mintier G.A., Quintana L., Domingo R. Jr., Meyer N.C., Irrinki A., McClelland E.E., Fullan A., Mapa F.A., Moore T., Thomas W., Loeb D.B., Harmon C., Tsuchihashi Z., Wolff R.K., Schatzman R.C., Feder J.N. Genome Res. 7:441-456(1997) [PubMed: 9149941] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA / MRNA] (ISOFORM 1).
[3]	"The haemochromatosis candidate gene HFE (HLA-H) of man and mouse is located in syntenic regions within the histone gene." Albig W., Drabent B., Burmester N., Bode C., Doenecke D. J. Cell. Biochem. 69:117-126(1998) [PubMed: 9548560] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORM 1).
[4]	"Hereditary hemochromatosis genomic structure and organization of HLA-H gene." Gasparini P. Submitted (SEP-1997) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [GENOMIC DNA] (ISOFORM 1).
[5]	"Alternate splice variants of the hemochromatosis gene Hfe." Rhodes D.A., Trowsdale J. Immunogenetics 49:357-359(1999) [PubMed: 10079302] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 2; 3 AND 4).
[6]	"Identification of different alternative splicing forms of the HFE gene." Oliva R., Sanchez M. Submitted (SEP-2001) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 2; 5; 6 AND 7).
[7]	"The HFE gene undergoes alternate splicing processes." Thenie A., Orhant M., Gicquel I., Fergelot P., Le Gall J.-Y., David V., Mosser J. Blood Cells Mol. Dis. 26:155-162(2000) [PubMed: 11001625] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORMS 1; 7; 8; 9 AND 10).
[8]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). Tissue: Colon.
[9]	"The hemochromatosis gene product complexes with the transferrin receptor and lowers its affinity for ligand binding." Feder J.N., Penny D.M., Irrinki A., Lee V.K., Lebron J.A., Watson N., Tsuchihashi Z., Sigal E., Bjorkman P.J., Schatzman R.C. Proc. Natl. Acad. Sci. U.S.A. 95:1472-1477(1998) [PubMed: 9465039] [Abstract] Cited for: FUNCTION.
[10]	"Crystal structure of the hemochromatosis protein HFE and characterization of its interaction with transferrin receptor." Lebron J.A., Bennett M.J., Vaughn D.E., Chirino A.J., Snow P.M., Mintier G.A., Feder J.N., Bjorkman P.J. Cell 93:111-123(1998) [PubMed: 9546397] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.6 ANGSTROMS) OF 23-297 IN COMPLEX WITH TFR.
[11]	"A 3-dimensional model building by homology of the HFE protein: molecular consequences and application to antibody development." Dupradeau F., Altenberg-Greulich B., Warin R., Fuentes V., Monti J., Rochette J. Biochim. Biophys. Acta 1481:213-221(2000) [PubMed: 11018711] [Abstract] Cited for: 3D-STRUCTURE MODELING OF 26-293 IN COMPLEX WITH B2MG.
[12]	"Crystal structure of the hereditary haemochromatosis protein HFE complexed with transferrin receptor." Bennett M.J., Lebron J.A., Bjorkman P.J. Nature 403:46-53(2000) [PubMed: 10638746] [Abstract] Cited for: X-RAY CRYSTALLOGRAPHY (2.8 ANGSTROMS) OF 26-297 IN COMPLEX WITH TFR.
[13]	"An unappreciated role for RNA surveillance." Hillman R.T., Green R.E., Brenner S.E. Genome Biol. 5:RESEARCH008.1-RESEARCH008.16(2004) [PubMed: 14759258] [Abstract] Cited for: SPLICE ISOFORM(S) THAT ARE POTENTIAL NMD TARGET(S).
[14]	"Mutation analysis of the HLA-H gene in Italian hemochromatosis patients." Carella M., D'Ambrosio L., Totaro A., Grifa A., Valentino M.A., Piperno A., Girelli D., Roetto A., Franco B., Gasparini P., Camaschella C. Am. J. Hum. Genet. 60:828-832(1997) [PubMed: 9106528] [Abstract] Cited for: VARIANTS HH ASP-63 AND TYR-282.
[15]	"Increased frequency of the haemochromatosis Cys282Tyr mutation in sporadic porphyria cutanea tarda." Roberts A.G., Whatley S.D., Morgan R.R., Worwood M., Elder G.H. Lancet 349:321-323(1997) [PubMed: 9024376] [Abstract] Cited for: VARIANT HH/PCT TYR-282.
[16]	"High prevalence of the His63Asp HFE mutation in Italian patients with porphyria cutanea tarda." Sampietro M., Piperno A., Lupica L., Arosio C., Vergani A., Corbetta N., Malosio I., Mattioli M., Fracanzani A.L., Cappellini M.D., Fiorelli G., Fargion S. Hepatology 27:181-184(1998) [PubMed: 9425935] [Abstract] Cited for: VARIANT HH/PCT ASP-63.
[17]	"Porphyria cutanea tarda, hepatitis C, and HFE gene mutations in North America." Bonkovsky H.L., Poh-Fitzpatrick M., Pimstone N., Obando J., Di Bisceglie A., Tattrie C., Tortorelli K., LeClair P., Mercurio M.G., Lambrecht R.W. Hepatology 27:1661-1669(1998) [PubMed: 9620340] [Abstract] Cited for: VARIANTS HH/PCT ASP-63 AND TYR-282.
[18]	"HFE mutations analysis in 711 hemochromatosis probands: evidence for S65C implication in mild form of hemochromatosis." Mura C., Raguenes O., Ferec C. Blood 93:2502-2505(1999) [PubMed: 10194428] [Abstract] Cited for: VARIANTS HH ASP-63; CYS-65 AND TYR-282.
[19]	"Two novel missense mutations of the HFE gene (I105T and G93R) and identification of the S65C mutation in Alabama hemochromatosis probands." Barton J.C., Sawada-Hirai R., Rothenberg B.E., Acton R.T. Blood Cells Mol. Dis. 25:147-155(1999) [PubMed: 10575540] [Abstract] Cited for: VARIANTS HH CYS-65; ARG-93 AND THR-105.
[20]	"Spectrum of mutations in the HFE gene implicated in haemochromatosis and porphyria." de Villiers J.N.P., Hillermann R., Loubser L., Kotze M.J. Hum. Mol. Genet. 8:1517-1522(1999) [PubMed: 10401000] [Abstract] Cited for: VARIANTS PV ASP-63 AND HIS-127, VARIANT HH MET-330, VARIANTS MET-53 AND MET-59.
[21]	"A retrospective anonymous pilot study in screening newborns for HFE mutations in Scandinavian populations." Merryweather-Clarke A.T., Simonsen H., Shearman J.D., Pointon J.J., Norgaard-Pedersen B., Robson K.J.H. Hum. Mutat. 13:154-159(1999) [PubMed: 10094552] [Abstract] Cited for: VARIANTS HH ASP-63 AND TYR-282.
[22]	"A novel missense mutation S65C in the HFE gene with a possible role in hereditary haemochromatosis." Fagan E., Payne S.J. Hum. Mutat. 13:507-508(1999) Cited for: VARIANT HH CYS-65.
[23]	"Two novel polymorphisms (E277K and V212V) in the haemochromatosis gene HFE." Bradbury R., Fagan E., Payne S.J. Hum. Mutat. 15:120-120(2000) [PubMed: 10612845] [Abstract] Cited for: VARIANT LYS-277.
[24]	"Co-inheritance of mutations in the uroporphyrinogen decarboxylase and hemochromatosis genes accelerates the onset of porphyria cutanea tarda." Brady J.J., Jackson H.A., Roberts A.G., Morgan R.R., Whatley S.D., Rowlands G.L., Darby C., Shudell E., Watson R., Paiker J., Worwood M.W., Elder G.H. J. Invest. Dermatol. 115:868-874(2000) [PubMed: 11069625] [Abstract] Cited for: VARIANTS ASP-63 AND TYR-282.
[25]	"Role of hemochromatosis C282Y and H63D mutations in HFE gene in development of type 2 diabetes and diabetic nephropathy." Moczulski D.K., Grzeszczak W., Gawlik B. Diabetes Care 24:1187-1191(2001) [PubMed: 11423500] [Abstract] Cited for: VARIANTS HH ASP-63 AND TYR-282, ASSOCIATION WITH DIABETIC NEPHROPATHY SUSCEPTIBILITY.
[26]	"Idiopathic hemochromatosis with the mutation of Ala176Val heterozygous for HFE gene." Imanishi H., Liu W., Cheng J., Ikeda N., Amuro Y., Hada T. Intern. Med. 40:479-483(2001) [PubMed: 11446670] [Abstract] Cited for: VARIANT HH VAL-176.
[27]	"Comprehensive hereditary hemochromatosis genotyping." Jones D.C., Young N.T., Pigott C., Fuggle S.V., Barnardo M.C.N.M., Marshall S.E., Bunce M. Tissue Antigens 60:481-488(2002) [PubMed: 12542741] [Abstract] Cited for: VARIANTS HH ASP-63; CYS-65; TYR-282 AND ALA-295.
[28]	"Phenotypic expression of the C282Y/Q283P compound heterozygosity in HFE and molecular modeling of the Q283P mutation effect." Le Gac G., Dupradeau F.-Y., Mura C., Jacolot S., Scotet V., Esnault G., Mercier A.-Y., Rochette J., Ferec C. Blood Cells Mol. Dis. 30:231-237(2003) [PubMed: 12737937] [Abstract] Cited for: VARIANT HH PRO-283, CHARACTERIZATION OF VARIANT HH PRO-283.
[29]	"Identification of new mutations of the HFE, hepcidin, and transferrin receptor 2 genes by denaturing HPLC analysis of individuals with biochemical indications of iron overload." Biasiotto G., Belloli S., Ruggeri G., Zanella I., Gerardi G., Corrado M., Gobbi E., Albertini A., Arosio P. Clin. Chem. 49:1981-1988(2003) [PubMed: 14633868] [Abstract] Cited for: VARIANTS HH ASP-63; CYS-65; CYS-66; GLY-224 AND TYR-282.
[30]	"Heterozygous recipient and donor HFE mutations associated with a hereditary haemochromatosis phenotype after liver transplantation." Wigg A.J., Harley H., Casey G. Gut 52:433-435(2003) [PubMed: 12584229] [Abstract] Cited for: VARIANT HH SER-6.
[31]	"Gene symbol: HFE. Disease: haemochromatosis." Bento M.C., Ribeiro M.L., Relvas L. Hum. Genet. 114:405-405(2004) [PubMed: 15046077] [Abstract] Cited for: VARIANT HH ALA-295.
[32]	"The Q283P amino-acid change in HFE leads to structural and functional consequences similar to those described for the mutated 282Y HFE protein." Ka C., Le Gac G., Dupradeau F.-Y., Rochette J., Ferec C. Hum. Genet. 117:467-475(2005) [PubMed: 15965644] [Abstract] Cited for: CHARACTERIZATION OF VARIANT HH PRO-283.
[33]	"An unusual case of hemochromatosis due to a new compound heterozygosity in HFE (p.[Gly43Asp;His63Asp]+[Cys282Tyr]): structural implications with respect to binding with transferrin receptor 1." Dupradeau F.-Y., Pissard S., Coulhon M.-P., Cadet E., Foulon K., Fourcade C., Goossens M., Case D.A., Rochette J. Hum. Mutat. 29:206-206(2008) [PubMed: 18157833] [Abstract] Cited for: VARIANTS HH ASP-43; ASP-63 AND TYR-282.
+	Additional computationally mapped references.

Web resources

Atlas of Genetics and Cytogenetics in Oncology and Haematology

GeneReviews

Cross-references

Sequence databases

EMBLGenBankDDBJ

U60319 mRNA. Translation: AAC51823.1.
U91328 Genomic DNA. Translation: AAB82083.1.
Z92910 Genomic DNA. Translation: CAB07442.1.
Y09801 , Y09800, Y09803, Y09799 Genomic DNA. Translation: CAA70934.1.
AF079407 mRNA. Translation: AAC62646.1.
AF079408 mRNA. Translation: AAC62647.1.
AF079409 mRNA. Translation: AAC62648.1.
AJ249335 mRNA. Translation: CAC67792.1.
AJ249336 mRNA. Translation: CAC67793.1.
AJ249337 mRNA. Translation: CAC67794.1.
AJ250635 mRNA. Translation: CAC80805.1.
AF115264 mRNA. Translation: AAG29571.1.
AF115265 mRNA. Translation: AAG29572.1.
AF144240 mRNA. Translation: AAG29575.1.
AF144242 mRNA. Translation: AAG29577.1.
AF149804 mRNA. Translation: AAG29342.1.
BC117201 mRNA. Translation: AAI17202.1.
BC117203 mRNA. Translation: AAI17204.1.

IPI

IPI00029419.
IPI00215955.
IPI00218211.
IPI00218212.
IPI00218213.
IPI00218215.
IPI00218218.
IPI00218221.
IPI00294375.

RefSeq

NP_000401.1.
NP_620572.1.
NP_620573.1.
NP_620575.1.
NP_620576.1.
NP_620577.1.
NP_620578.1.
NP_620579.1.

UniGene

Hs.233325

3D structure databases

PDBPDBe

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1A6Z	X-ray	2.60	A/C	23-297	[»]
1C42	model	-	A	26-293	[»]
1DE4	X-ray	2.80	A/D/G	23-297	[»]

ModBase

Search...

Protein-protein interaction databases

DIP

DIP:2737N.

STRING

Q30201.

Proteomic databases

PRIDE

Q30201.

Genome annotation databases

Ensembl

ENST00000309234; ENSP00000311698; ENSG00000010704; Homo sapiens. [Genome view]
ENST00000317896; ENSP00000313776; ENSG00000010704; Homo sapiens. [Genome view]
ENST00000336625; ENSP00000337819; ENSG00000010704; Homo sapiens. [Genome view]
ENST00000349999; ENSP00000259699; ENSG00000010704; Homo sapiens. [Genome view]
ENST00000352392; ENSP00000315936; ENSG00000010704; Homo sapiens. [Genome view]
ENST00000353147; ENSP00000312342; ENSG00000010704; Homo sapiens. [Genome view]
ENST00000397022; ENSP00000380217; ENSG00000010704; Homo sapiens. [Genome view]

GeneID

3077.

KEGG

hsa:3077.

UCSC

uc003nfx.1. human.
uc003nfz.1. human.
uc003nga.1. human.
uc003ngb.1. human.
uc003ngc.1. human.
uc003ngd.1. human.

Organism-specific databases

CTD

3077.

GeneCards

GC06P026195.

H-InvDB

HIX0025100.
HIX0032768.

HGNC

HGNC:4886. HFE.

HPA

HPA017276.

MIM

176200. phenotype.
235200. gene+phenotype.
612635. phenotype.

Orphanet

445. Hemochromatosis.
139498. Hemochromatosis, adult form.
79230. Hemochromatosis, juvenile form.
738. Porphyria.
79473. Porphyria, Variegata.

PharmGKB

PA29263.

GenAtlas

Search...

Phylogenomic databases

HOVERGEN

Q30201.

OMA

CQALNFY.

Gene expression databases

ArrayExpress

Q30201.

Bgee

Q30201.

Genevestigator

Q30201.

GermOnline

ENSG00000010704. Homo sapiens.

Family and domain databases

InterPro

IPR007110. Ig-like.
IPR013783. Ig-like_fold.
IPR003006. Ig/MHC_CS.
IPR003597. Ig_C1-set.
IPR011161. MHC_I-like_Ag-recog.
IPR001039. MHC_I_a_a1/a2.
[Graphical view]

Gene3D

G3DSA:2.60.40.10. Ig-like_fold. 1 hit.
G3DSA:3.30.500.10. MHC_I-like_Ag-recog. 1 hit.

Pfam

PF07654. C1-set. 1 hit.
PF00129. MHC_I. 1 hit.
[Graphical view]

PRINTS

PR01638. MHCCLASSI.

SMART

SM00407. IGc1. 1 hit.
[Graphical view]

PROSITE

PS50835. IG_LIKE. 1 hit.
PS00290. IG_MHC. 1 hit.
[Graphical view]

ProtoNet

Search...

Other Resources

NextBio

12169.

SOURCE

Search...

Entry information

Entry name

HFE_HUMAN

Accession

Primary (citable) accession number: Q30201
Secondary accession number(s): O75929 , O75930, O75931, Q17RT0, Q96KU5, Q96KU7, Q96KU8, Q9HC64, Q9HC68, Q9HC70, Q9HC83

Entry history

Integrated into UniProtKB/Swiss-Prot:	November 1, 1997
Last sequence update:	November 1, 1997
Last modified:	November 3, 2009
This is version 114 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)

Disclaimer

Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.