1a6z

Structural highlights

Disease

HFE_HUMAN Defects in HFE are a cause of hemochromatosis (HFE) [MIM:235200. A disorder of iron metabolism characterized by iron overload. Excess iron is deposited in a variety of organs leading to their failure, and resulting in serious illnesses including cirrhosis, hepatomas, diabetes, cardiomyopathy, arthritis, and hypogonadotropic hypogonadism. Severe effects of the disease usually do not appear until after decades of progressive iron loading.^{[1] [2] [3] [4] [5] [6] [7] [8]} [:]^{[9] [10] [11] [12] [13] [14] [15] [16] [17]} Defects in HFE are associated with variegate porphyria (VP) [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. VP 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. Note=Iron overload due to HFE mutations is a precipitating or exacerbating factor in variegate porphyria. Defects in HFE are associated with susceptibility to microvascular complications of diabetes type 7 (MVCD7) [MIM:612635. These are pathological conditions that develop in numerous tissues and organs as a consequence of diabetes mellitus. They include diabetic retinopathy, diabetic nephropathy leading to end-stage renal disease, and diabetic neuropathy. Diabetic retinopathy remains the major cause of new-onset blindness among diabetic adults. It is characterized by vascular permeability and increased tissue ischemia and angiogenesis.

Function

HFE_HUMAN Binds to transferrin receptor (TFR) and reduces its affinity for iron-loaded transferrin.^[18]

Evolutionary Conservation

Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.

See Also

• Beta-2 microglobulin 3D structures
• Hemochromatosis protein

References

1. ↑ Feder JN, Gnirke A, Thomas W, Tsuchihashi Z, Ruddy DA, Basava A, Dormishian F, Domingo R Jr, Ellis MC, Fullan A, Hinton LM, Jones NL, Kimmel BE, Kronmal GS, Lauer P, Lee VK, Loeb DB, Mapa FA, McClelland E, Meyer NC, Mintier GA, Moeller N, Moore T, Morikang E, Prass CE, Quintana L, Starnes SM, Schatzman RC, Brunke KJ, Drayna DT, Risch NJ, Bacon BR, Wolff RK. A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis. Nat Genet. 1996 Aug;13(4):399-408. PMID:8696333 doi:10.1038/ng0896-399
2. ↑ Carella M, D'Ambrosio L, Totaro A, Grifa A, Valentino MA, Piperno A, Girelli D, Roetto A, Franco B, Gasparini P, Camaschella C. Mutation analysis of the HLA-H gene in Italian hemochromatosis patients. Am J Hum Genet. 1997 Apr;60(4):828-32. PMID:9106528
3. ↑ Roberts AG, Whatley SD, Morgan RR, Worwood M, Elder GH. Increased frequency of the haemochromatosis Cys282Tyr mutation in sporadic porphyria cutanea tarda. Lancet. 1997 Feb 1;349(9048):321-3. PMID:9024376 doi:S0140-6736(96)09436-6
4. ↑ Bonkovsky HL, Poh-Fitzpatrick M, Pimstone N, Obando J, Di Bisceglie A, Tattrie C, Tortorelli K, LeClair P, Mercurio MG, Lambrecht RW. Porphyria cutanea tarda, hepatitis C, and HFE gene mutations in North America. Hepatology. 1998 Jun;27(6):1661-9. PMID:9620340 doi:S0270913998002468
5. ↑ Mura C, Raguenes O, Ferec C. HFE mutations analysis in 711 hemochromatosis probands: evidence for S65C implication in mild form of hemochromatosis. Blood. 1999 Apr 15;93(8):2502-5. PMID:10194428
6. ↑ Barton JC, Sawada-Hirai R, Rothenberg BE, Acton RT. Two novel missense mutations of the HFE gene (I105T and G93R) and identification of the S65C mutation in Alabama hemochromatosis probands. Blood Cells Mol Dis. 1999 Jun-Aug;25(3-4):147-55. PMID:10575540
7. ↑ de Villiers JN, Hillermann R, Loubser L, Kotze MJ. Spectrum of mutations in the HFE gene implicated in haemochromatosis and porphyria. Hum Mol Genet. 1999 Aug;8(8):1517-22. PMID:10401000
8. ↑ Merryweather-Clarke AT, Simonsen H, Shearman JD, Pointon JJ, Norgaard-Pedersen B, Robson KJ. A retrospective anonymous pilot study in screening newborns for HFE mutations in Scandinavian populations. Hum Mutat. 1999;13(2):154-9. PMID:10094552 doi:<154::AID-HUMU8>3.0.CO;2-E 10.1002/(SICI)1098-1004(1999)13:2<154::AID-HUMU8>3.0.CO;2-E
9. ↑ Moczulski DK, Grzeszczak W, Gawlik B. Role of hemochromatosis C282Y and H63D mutations in HFE gene in development of type 2 diabetes and diabetic nephropathy. Diabetes Care. 2001 Jul;24(7):1187-91. PMID:11423500
10. ↑ Imanishi H, Liu W, Cheng J, Ikeda N, Amuro Y, Hada T. Idiopathic hemochromatosis with the mutation of Ala176Val heterozygous for HFE gene. Intern Med. 2001 Jun;40(6):479-83. PMID:11446670
11. ↑ Jones DC, Young NT, Pigott C, Fuggle SV, Barnardo MC, Marshall SE, Bunce M. Comprehensive hereditary hemochromatosis genotyping. Tissue Antigens. 2002 Dec;60(6):481-8. PMID:12542741
12. ↑ Le Gac G, Dupradeau FY, Mura C, Jacolot S, Scotet V, Esnault G, Mercier AY, Rochette J, Ferec C. Phenotypic expression of the C282Y/Q283P compound heterozygosity in HFE and molecular modeling of the Q283P mutation effect. Blood Cells Mol Dis. 2003 May-Jun;30(3):231-7. PMID:12737937
13. ↑ Biasiotto G, Belloli S, Ruggeri G, Zanella I, Gerardi G, Corrado M, Gobbi E, Albertini A, Arosio P. 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. Clin Chem. 2003 Dec;49(12):1981-8. PMID:14633868 doi:10.1373/clinchem.2003.023440
14. ↑ Wigg AJ, Harley H, Casey G. Heterozygous recipient and donor HFE mutations associated with a hereditary haemochromatosis phenotype after liver transplantation. Gut. 2003 Mar;52(3):433-5. PMID:12584229
15. ↑ Bento MC, Ribeiro ML, Relvas L. Gene symbol: HFE. Disease: Haemochromatosis. Hum Genet. 2004 Mar;114(4):405. PMID:15046077
16. ↑ Ka C, Le Gac G, Dupradeau FY, Rochette J, Ferec C. The Q283P amino-acid change in HFE leads to structural and functional consequences similar to those described for the mutated 282Y HFE protein. Hum Genet. 2005 Sep;117(5):467-75. Epub 2005 Jun 18. PMID:15965644 doi:10.1007/s00439-005-1307-y
17. ↑ Dupradeau FY, Pissard S, Coulhon MP, Cadet E, Foulon K, Fourcade C, Goossens M, Case DA, Rochette J. 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. Hum Mutat. 2008 Jan;29(1):206. PMID:18157833 doi:10.1002/humu.9517
18. ↑ Feder JN, Penny DM, Irrinki A, Lee VK, Lebron JA, Watson N, Tsuchihashi Z, Sigal E, Bjorkman PJ, Schatzman RC. The hemochromatosis gene product complexes with the transferrin receptor and lowers its affinity for ligand binding. Proc Natl Acad Sci U S A. 1998 Feb 17;95(4):1472-7. PMID:9465039
19. ↑ Lebron JA, Bennett MJ, Vaughn DE, Chirino AJ, Snow PM, Mintier GA, Feder JN, Bjorkman PJ. Crystal structure of the hemochromatosis protein HFE and characterization of its interaction with transferrin receptor. Cell. 1998 Apr 3;93(1):111-23. PMID:9546397