Non-HFE Hemochromatosis

ABSTRACT

The term “non-HFE hemochromatosis” (non-HFE HC) refers to several phenotypically similar but genetically distinct forms of hereditary hemochromatosis affecting individuals without pathogenic mutations of HFE. The involved genes are, sinsu strictu, transferrin receptor 2 (TfR2), hemojuvelin (HJV), and hepcidin (HAMP). Non-HFE HC share common pathogenic and clinical features with HFE HC. However, depending on the role of the affected gene in iron trafficking, the clinical onset may be earlier and phenotypic expressivity more severe than classic HC. Other forms of hereditary iron overload have distinct pathogenesis and phenotype. The most prevalent of these forms is “ferroportin disease,” characterized by autosomal dominant trait, predominant reticuloendothelial cell iron overload, and mild organ damage. Non-HFE HC gene products, while responsible for rarer cases of HC as compared with HFE, are much more central than HFE in human iron homeostasis and understanding their function will greatly advance our comprehension of iron trafficking in health and disease.

Hemochromatosis - transferrin receptor 2 - hemojuvelin - hepcidin

REFERENCES

• 1 Feder J N, Gnirke A, Thomas W et al.. A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis.  Nat Genet. 1996;  13 399-408
• 2 Piperno A, Sampietro M, Pietrangelo A et al.. Heterogeneity of hemochromatosis in Italy.  Gastroenterology. 1998;  114 996-1002
• 3 Borot N, Roth M, Malfroy L et al.. Mutations in the MHC class I-like candidate gene for hemochromatosis in French patients.  Immunogenetics. 1997;  45 320-324
• 4 Pietrangelo A. Hemochromatosis 1998: is one gene enough?.  J Hepatol. 1998;  29 502-509
• 5 Pietrangelo A. Hereditary hemochromatosis-a new look at an old disease.  N Engl J Med. 2004;  350 2383-2397
• 6 Pietrangelo A. The ferroportin disease.  Blood Cells Mol Dis. 2004;  32 131-138
• 7 Harris Z L, Takahashi Y, Miyajima H et al.. Aceruloplasminemia: molecular characterization of this disorder of iron metabolism.  Proc Natl Acad Sci USA. 1995;  92 2539-2543
• 8 Hayashi A, Wada Y, Suzuki T, Shimizu A. Studies on familial hypotransferrinemia-unique clinical course and molecular pathology.  Am J Hum Genet. 1993;  53 201-213
• 9 Camaschella C, Roetto A, Cali A et al.. The gene TFR2 is mutated in a new type of haemochromatosis mapping to 7q22.  Nat Genet. 2000;  25 14-15
• 10 Kawabata H, Yang R, Hirama T et al.. Molecular cloning of transferrin receptor 2. A new member of the transferrin receptor-like family.  J Biol Chem. 1999;  274 20826-20832
• 11 Roetto A, Totaro A, Piperno A et al.. New mutations inactivating transferrin receptor 2 in hemochromatosis type 3.  Blood. 2001;  97 2555-2560
• 12 Mattman A, Huntsman D, Lockitch G et al.. Transferrin receptor 2 (TfR2) and HFE mutational analysis in non-C282Y iron overload: identification of a novel TfR2 mutation.  Blood. 2002;  100 1075-1077
• 13 Hattori A, Wakusawa S, Hayashi H et al.. AVAQ 594-597 deletion of the TfR2 gene in a Japanese family with hemochromatosis.  Hepatol Res. 2003;  26 154-156
• 14 Le Gac G, Mons F, Jacolot S, Scotet V, Ferec C, Frebourg T. Early onset hereditary hemochromatosis resulting from a novel TFR2 gene nonsense mutation (R105X) in two siblings of north French descent.  Br J Haematol. 2004;  125 674-678
• 15 Kawabata H, Nakamaki T, Ikonomi P et al.. Expression of transferrin receptor 2 in normal and neoplastic hematopoietic cells.  Blood. 2001;  98 2714-2719
• 16 Cairo G, Pietrangelo A. Iron regulatory proteins in pathobiology.  Biochem J. 2000;  352(Pt 2) 241-250
• 17 Kawabata H, Germain R S, Vuong P T et al.. Transferrin receptor 2-alpha supports cell growth both in iron-chelated cultured cells and in vivo.  J Biol Chem. 2000;  275 16618-16625
• 18 Trinder D, Baker E. Transferrin receptor 2: a new molecule in iron metabolism.  Int J Biochem Cell Biol. 2003;  35 292-296
• 19 West Jr A P, Bennett M J, Sellers V M, Andrews N C, Enns C A, Bjorkman P J. Comparison of the interactions of transferrin receptor and transferrin receptor 2 with transferrin and the hereditary hemochromatosis protein HFE.  J Biol Chem. 2000;  275 38135-38138
• 20 Richardson D R, Baker E. Two saturable mechanisms of iron uptake from transferrin in human melanoma cells: the effect of transferrin concentration, chelators, and metabolic probes on transferrin and iron uptake.  J Cell Physiol. 1994;  161 160-168
• 21 Lamon J M, Marynick S P, Roseblatt R, Donnelly S. Idiopathic hemochromatosis in a young female. A case study and review of the syndrome in young people.  Gastroenterology. 1979;  76 178-183
• 22 Roetto A, Papanikolaou G, Politou M et al.. Mutant antimicrobial peptide hepcidin is associated with severe juvenile hemochromatosis.  Nat Genet. 2003;  33 21-22
• 23 Krause A, Neitz S, Magert H J et al.. LEAP-1, a novel highly disulfide-bonded human peptide, exhibits antimicrobial activity.  FEBS Lett. 2000;  480 147-150
• 24 Park C H, Valore E V, Waring A J, Ganz T. Hepcidin, a urinary antimicrobial peptide synthesized in the liver.  J Biol Chem. 2001;  276 7806-7810
• 25 Pigeon C, Ilyin G, Courselaud B et al.. A new mouse liver-specific gene, encoding a protein homologous to human antimicrobial peptide hepcidin, is overexpressed during iron overload.  J Biol Chem. 2001;  276 7811-7819
• 26 Nemeth E, Tuttle M S, Powelson J et al.. Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization.  Science. 2004;  306 2090-2093
• 27 Nicolas G, Bennoun M, Devaux I et al.. Lack of hepcidin gene expression and severe tissue iron overload in upstream stimulatory factor 2 (USF2) knockout mice.  Proc Natl Acad Sci USA. 2001;  98 8780-8785
• 28 Courselaud B, Pigeon C, Inoue Y et al.. C/EBPalpha regulates hepatic transcription of hepcidin, an antimicrobial peptide and regulator of iron metabolism. Cross-talk between C/EBP pathway and iron metabolism.  J Biol Chem. 2002;  277 41163-41170
• 29 Roetto A, Totaro A, Cazzola M et al.. Juvenile hemochromatosis locus maps to chromosome 1q.  Am J Hum Genet. 1999;  64 1388-1393
• 30 Papanikolaou G, Samuels M E, Ludwig E H et al.. Mutations in HFE2 cause iron overload in chromosome 1q-linked juvenile hemochromatosis.  Nat Genet. 2004;  36 77-82
• 31 Lanzara C, Roetto A, Daraio F et al.. The spectrum of hemojuvelin gene mutations in 1q-linked juvenile hemochromatosis.  Blood. 2004;  103 4317-4321
• 32 Lee P L, Beutler E, Rao S V, Barton J C. Genetic abnormalities and juvenile hemochromatosis: mutations of the HJV gene encoding hemojuvelin.  Blood. 2004;  103 4669-4671
• 33 Gehrke S, Pietrangelo A, Kascak M et al.. HJV gene mutations in European patients with juvenile hemochromatosis.  Clin Genet. 2005;  67 425-428
• 34 Girelli D, Bozzini C, Roetto A et al.. Clinical and pathologic findings in hemochromatosis type 3 due to a novel mutation in transferrin receptor 2 gene.  Gastroenterology. 2002;  122 1295-1302
• 35 Cazzola M, Ascari E, Barosi G et al.. Juvenile idiopathic haemochromatosis: a life-threatening disorder presenting as hypogonadotropic hypogonadism.  Hum Genet. 1983;  65 149-154
• 36 Rivard S R, Mura C, Simard H et al.. Clinical and molecular aspects of juvenile hemochromatosis in Saguenay-Lac-Saint-Jean (Quebec, Canada).  Blood Cells Mol Dis. 2000;  26 10-14
• 37 De Gobbi M, Roetto A, Piperno A et al.. Natural history of juvenile haemochromatosis.  Br J Haematol. 2002;  117 973-979
• 38 Bridle K R, Frazer D M, Wilkins S J et al.. Disrupted hepcidin regulation in HFE-associated haemochromatosis and the liver as a regulator of body iron homoeostasis.  Lancet. 2003;  361 669-673
• 39 Gehrke S G, Kulaksiz H, Herrmann T et al.. Expression of hepcidin in hereditary hemochromatosis: evidence for a regulation in response to serum transferrin saturation and non-transferrin-bound iron.  Blood. 2003;  102 371-376
• 40 Muckenthaler M, Roy C N, Custodio A O et al.. Regulatory defects in liver and intestine implicate abnormal hepcidin and Cybrd1 expression in mouse hemochromatosis.  Nat Genet. 2003;  34 102-107
• 41 Nicolas G, Viatte L, Lou D Q et al.. Constitutive hepcidin expression prevents iron overload in a mouse model of hemochromatosis.  Nat Genet. 2003;  34 97-101
• 42 Fleming R E, Ahmann J R, Migas M C et al.. Targeted mutagenesis of the murine transferrin receptor-2 gene produces hemochromatosis.  Proc Natl Acad Sci USA. 2002;  99 10653-10658
• 43 Nemeth E, Roetto A, Garozzo G, Ganz T, Camaschella C. Hepcidin is decreased in TFR2-Hemochromatosis.  Blood. 2005;  105 1083-1806
• 44 Kawabata H, Fleming R E, Gui D et al.. Expression of hepcidin is down-regulated in TfR2 mutant mice manifesting a phenotype of hereditary hemochromatosis.  Blood. 2005;  105 376-381
• 45 Pietrangelo A, Caleffi A, Henrion J et al.. Juvenile hemochromatosis associated with pathogenic mutations of adult hemochromatosis genes.  Gastroenterology. 2005;  128 470-479
• 46 Merryweather-Clarke A T, Cadet E, Bomford A et al.. Digenic inheritance of mutations in HAMP and HFE results in different types of haemochromatosis.  Hum Mol Genet. 2003;  12 2241-2247
• 47 Jacolot S, Le Gac G, Scotet V et al.. HAMP as a modifier gene that increases the phenotypic expression of the HFE pC282Y homozygous genotype.  Blood. 2004;  103 2835-2840
• 48 Hofmann W K, Tong X J, Ajioka R S et al.. Mutation analysis of transferrin-receptor 2 in patients with atypical hemochromatosis.  Blood. 2002;  100 1099-1100
• 49 Pietrangelo A, Montosi G, Totaro A et al.. Hereditary hemochromatosis in adults without pathogenic mutations in the hemochromatosis gene.  N Engl J Med. 1999;  341 725-732
• 50 Montosi G, Donovan A, Totaro A et al.. Autosomal-dominant hemochromatosis is associated with a mutation in the ferroportin (SLC11A3) gene.  J Clin Invest. 2001;  108 619-623
• 51 Njajou O T, Vaessen N, Joosse M et al.. A mutation in SLC11A3 is associated with autosomal dominant hemochromatosis.  Nat Genet. 2001;  28 213-214
• 52 Devalia V, Carter K, Walker A P et al.. Autosomal dominant reticuloendothelial iron overload associated with a 3-base pair deletion in the ferroportin 1 gene (SLC11A3).  Blood. 2002;  100 695-697
• 53 Wallace D F, Pedersen P, Dixon J L et al.. Novel mutation in ferroportin1 is associated with autosomal dominant hemochromatosis.  Blood. 2002;  100 692-694
• 54 Roetto A, Merryweather-Clarke A T, Daraio F et al.. A valine deletion of ferroportin 1: a common mutation in hemochromastosis type 4.  Blood. 2002;  100 733-734
• 55 Cazzola M, Cremonesi L, Papaioannou M et al.. Genetic hyperferritinaemia and reticuloendothelial iron overload associated with a three base pair deletion in the coding region of the ferroportin gene (SLC11A3).  Br J Haematol. 2002;  119 539-546
• 56 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 three new ferroportin (slc11A3) mutations.  Blood. 2003;  102 1904-1910
• 57 Rivard S R, Lanzara C, Grimard D et al.. Autosomal dominant reticuloendothelial iron overload (HFE type 4) due to a new missense mutation in the FERROPORTIN 1 gene (SLC11A3) in a large French-Canadian family.  Haematologica. 2003;  88 824-826
• 58 Jouanolle A M, Douabin-Gicquel V, Halimi C et al.. Novel mutation in ferroportin 1 gene is associated with autosomal dominant iron overload.  J Hepatol. 2003;  39 286-289
• 59 Sham R L, Phatak P D, West C et al.. Autosomal dominant hereditary hemochromatosis associated with a novel ferroportin mutation and unique clinical features.  Blood Cells Mol Dis. 2005;  34 157-161
• 60 Liu W, Shimomura S, Imanishi H et al.. Hemochromatosis with mutation of the ferroportin 1 (IREG1) gene.  Intern Med. 2005;  44 285-289
• 61 Wallace D F, Clark R M, Harley H A, Subramaniam V N. Autosomal dominant iron overload due to a novel mutation of ferroportin1 associated with parenchymal iron loading and cirrhosis.  J Hepatol. 2004;  40 710-713
• 62 Donovan A, Brownlie A, Zhou Y et al.. Positional cloning of zebrafish ferroportin1 identifies a conserved vertebrate iron exporter.  Nature. 2000;  403 776-781
• 63 McKie A T, Marciani P, Rolfs A et al.. A novel duodenal iron-regulated transporter, IREG1, implicated in the basolateral transfer of iron to the circulation.  Mol Cell. 2000;  5 299-309
• 64 Abboud S, Haile D J. A novel mammalian iron-regulated protein involved in intracellular iron metabolism.  J Biol Chem. 2000;  275 19906-19912
• 65 Zoller H, Koch R O, Theurl I et al.. Expression of the duodenal iron transporters divalent-metal transporter 1 and ferroportin 1 in iron deficiency and iron overload.  Gastroenterology. 2001;  120 1412-1419
• 66 Zoller H, Pietrangelo A, Vogel W, Weiss G. Duodenal metal-transporter (DMT-1, NRAMP-2) expression in patients with hereditary haemochromatosis.  Lancet. 1999;  353 2120-2123
• 67 Yang F, Liu X B, Quinones M et al.. Regulation of reticuloendothelial iron transporter MTP1 (Slc11a3) by inflammation.  J Biol Chem. 2002;  277 39786-39791
• 68 Yamaji S, Tennant J, Tandy S et al.. Zinc regulates the function and expression of the iron transporters DMT1 and IREG1 in human intestinal Caco-2 cells.  FEBS Lett. 2001;  507 137-141
• 69 Yang F, Wang X, Haile D J et al.. Iron increases expression of iron-export protein MTP1 in lung cells.  Am J Physiol Lung Cell Mol Physiol. 2002;  283 L932-L939
• 70 Martini L A, Tchack L, Wood R J. Iron treatment downregulates DMT1 and IREG1 mRNA expression in Caco-2 cells.  J Nutr. 2002;  132 693-696
• 71 Lymboussaki A, Pignatti E, Montosi G et al.. The role of the iron responsive element in the control of ferroportin1/IREG1/MTP1 gene expression.  J Hepatol. 2003;  39 710-715
• 72 Frazer D M, Wilkins S J, Becker E M et al.. Hepcidin expression inversely correlates with the expression of duodenal iron transporters and iron absorption in rats.  Gastroenterology. 2002;  123 835-844
• 73 Schimanski L M, Drakesmith H, Merryweather-Clarke A T et al.. In vitro functional analysis of human ferroportin (FPN) and hemochromatosis-associated FPN mutations.  Blood. 2005;  105 4096-4102
• 74 Drakesmith H, Schimanski L M, Ormerod E et al.. Resistance to hepcidin is conferred by hemochromatosis-associated mutations of ferroportin.  Blood. 2005;  106 1092-1097
• 75 Gualdi R, Casalgrandi G, Montosi G et al.. Excess iron into hepatocytes is required for activation of collagen type I gene during experimental siderosis.  Gastroenterology. 1994;  107 1118-1124
• 76 Jouanolle A M, Douabin-Gicquel V, Halimi C et al.. Novel mutation in ferroportin 1 gene is associated with autosomal dominant iron overload.  J Hepatol. 2003;  39 286-289
• 77 Beaumont C, Leneuve P, Devaux I et al.. Mutation in the iron responsive element of the L ferritin mRNA in a family with dominant hyperferritinaemia and cataract.  Nat Genet. 1995;  11 444-446
• 78 Girelli D, Corrocher R, Bisceglia L et al.. Molecular basis for the recently described hereditary hyperferritinemia-cataract syndrome: a mutation in the iron-responsive element of ferritin L-subunit gene (the “Verona mutation”).  Blood. 1995;  86 4050-4053
• 79 Yoshida K, Furihata K, Takeda S et al.. A mutation in the ceruloplasmin gene is associated with systemic hemosiderosis in humans.  Nat Genet. 1995;  9 267-272
• 80 Moirand R, Mortaji A M, Loreal O et al.. A new syndrome of liver iron overload with normal transferrin saturation.  Lancet. 1997;  349 95-97
• 81 Bothwell T H, Abrahams C, Bradlow B A, Charlton R W. Idiopathic and Bantu hemochromatosis.  Arch Pathol. 1965;  79 163-168
• 82 Gordeuk V, Mukiibi J, Hasstedt S J et al.. Iron overload in Africa. Interaction between a gene and dietary iron content.  N Engl J Med. 1992;  326 95-100
• 83 Moyo V M, Mandishona E, Hasstedt S J et al.. Evidence of genetic transmission in African iron overload.  Blood. 1998;  91 1076-1082
• 84 Gordeuk V R, Caleffi A, Corradini E et al.. Iron overload in Africans and African-Americans and a common mutation in the scl40a1 (ferroportin 1) gene.  Blood Cells Mol Dis. 2003;  31 299-304
• 85 Beutler E, Barton J C, Felitti V J et al.. Ferroportin (SLC11A3) variant associated with iron overload in African-Americans.  Blood Cells Mol Dis. 2003;  31 305-309
• 86 Eason R J, Adams P C, Aston C E, Searle J. Familial iron overload with possible autosomal dominant inheritance.  Aust N Z J Med. 1990;  20 226-230
• 87 Arden K E, Wallace D F, Dixon J L et al.. A novel mutation in ferroportin1 is associated with haemochromatosis in a Solomon Islands patient.  Gut. 2003;  52 1215-1217
• 88 Goode C A, Dinh C T, Linder M C. Mechanism of copper transport and delivery in mammals: review and recent findings.  Adv Exp Med Biol. 1989;  258 131-144
• 89 Miyajima H, Takahashi Y, Kamata T et al.. Use of desferrioxamine in the treatment of aceruloplasminemia.  Ann Neurol. 1997;  41 404-407
• 90 Kato J, Fujikawa K, Kanda M et al.. A mutation, in the iron-responsive element of H ferritin mRNA, causing autosomal dominant iron overload.  Am J Hum Genet. 2001;  69 191-197
• 91 Cox T M, Halsall D J. Hemochromatosis-neonatal and young subjects.  Blood Cells Mol Dis. 2002;  29 411-417
• 92 OMIM .Online Mendelian Inheritance in Man. Available at: http://www.ncbi.nlm.nih.gov/omim October 13, 2005