Non-HFE hemochromatosis: Genetics, pathogenesis, and clinical management

Current Gastroenterology Reports

Volumn 7, Issue 1, 2005, Pages 71-80

  Nelson, James E ^a   Kowdley, Kris V ^a  

^a UNIVERSITY OF WASHINGTON MEDICAL CENTER   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

HFE PROTEIN, HUMAN; HLA ANTIGEN CLASS 1; IRON; MEMBRANE PROTEIN;

ADOLESCENT; ADULT; AGE; BLOOD; CHILD; FEMALE; GENETIC PREDISPOSITION; GENETICS; HEMOCHROMATOSIS; HUMAN; IRON METABOLISM DISORDER; MALE; METHODOLOGY; MORTALITY; MUTATION; PATHOPHYSIOLOGY; PHENOTYPE; PHLEBOTOMY; PROGNOSIS; REVIEW; RISK ASSESSMENT; SEX DIFFERENCE; SURVIVAL; TREATMENT OUTCOME;

ADOLESCENT; ADULT; AGE FACTORS; CHILD; FEMALE; GENETIC PREDISPOSITION TO DISEASE; HEMOCHROMATOSIS; HISTOCOMPATIBILITY ANTIGENS CLASS I; HUMANS; IRON; IRON METABOLISM DISORDERS; MALE; MEMBRANE PROTEINS; MUTATION; PHENOTYPE; PHLEBOTOMY; PROGNOSIS; RISK ASSESSMENT; SEX FACTORS; SURVIVAL ANALYSIS; TREATMENT OUTCOME;

EID: 38849166859     PISSN: 15228037     EISSN: None     Source Type: Journal    
DOI: 10.1007/s11894-005-0069-y     Document Type: Review

References (73)

1. TroussDau A: Glycosurie: diabete sucre. In Clinique Medicale de l'Hotel-Dieu de Paris, vol 2. Paris: JB Bailliere, 1865:663-698.
2. von Recklinghausen FD: Uber Haemochromatose. Tageblatt Versammlung Dtsche Naturforscher Arzte Heidelberg 1889, 62: 324-325.
3. Simon M, Pawlotsky Y, Bourel M, et al.: [Letter: Idiopathic hemochromatosis associated with HL-A 3 tissular antigen]. Nouv Presse Med 1975, 4: 1432.
4. Simon M, Le Mignon L, Fauchet R, et al.: A study of 609 HLA haplotypes marking for the hemochromatosis gene: (1) mapping of the gene near the HLA-A locus and characters required to define a heterozygous population and (2) hypothesis concerning the underlying cause of hemochromatosis-HLA association. Am J Hum Genet 1987, 41: 89-105.
5. Feder JN, 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.
6. Donovan A, Brownlie A, Zhou Y, et al.: Positional cloning of zebrafish ferroportin1 identifies a conserved vertebrate iron exporter. Nature 2000, 403: 776-781. This study reported simultaneously with McKie et al. [11] the cloning of the human ferroportin gene along with the zebrafish and murine homologues.
7. 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. This extensive study reported the cloning, sequencing, and mapping of the human TFR2 gene. Expression and functionality studies, including Northern analysis, transient transfection, and ligand binding kinetics, were reported.
8. Papanikolaou G, Samuels ME, Ludwig EH, et al.: Mutations in HFE2 cause iron overload in chromosome 1q-linked juvenile hemochromatosis. Nat Genet 2004, 36: 77-82. These authors identified the gene responsible for the 1q-linked form of juvenile hemochromatosis by positional cloning. They identified six causative mutations in 12 different families from Greece, Canada, and France.
9. Park CH, Valore EV, Waring AJ, Ganz T: Hepcidin, a urinary antimicrobial peptide synthesized in the liver. J Biol Chem 2001, 276: 7806-7810.
10. Krause A, Neitz S, Magert HJ, et al.: LEAP-1, a novel highly disulfide-bonded human peptide, exhibits antimicrobial activity. FEBS Lett 2000, 480: 147-150.
11. McKie AT, Marciani P, Rolfs A, et al.: A novel duodenal ironregulated transporter, IREG1, implicated in the basolateral transfer of iron to the circulation. Mol Cell 2000, 5: 299-309. This study reported simultaneously with Donovan et al. [6̇] the cloning and expression of the human and murine ferroportin genes.
12. Pietrangelo A: Non-HFE hemochromatosis. Hepatology 2004, 39: 21-29.
13. Pietrangelo A: HereditAry hemochromatosis: a new look at an old disease N Engl J Med 2004, 350: 2383-2397. This is a very comprehensive review.
14. Pietrangelo A: The ferroportin disease. Blood Cells Mol Dis 2004, 32: 131-138.
15. Waalen J, Felitti V, Gelbart T, et al.: Penetrance of hemochromatosis. Blood Cells Mol Dis 2002, 29: 418-432.
16. Beutler E, Felitti VJ, Koziol JA, et al.: Penetrance of 845G→ A (C282Y) HFE hereditary haemochromatosis mutation in the USA. Lancet 2002, 359: 211-218.
17. Bomford A: Genetics of haemochromatosis. Lancet 2002, 360: 1673-1681.
18. Camaschella C, RoettG A, De Gobbi M: Genetic haemochromatosis: genes and mutations associated with iron loading. Best Pract Res Clin Haematol 2002, 15: 261-276.
19. Worwood M: HFE Mutations as risk factors in disease. Best Pract Res Clin Haematol 2002, 15: 295-314.
20. 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 U S A 2001, 98: 8780-8785. This was the first experiment to show that hepcidin is involved in iron metabolism.
21. Nicolas G, Chauvet C, Viatte L, et al.: The gene encoding the iron regulatory peptide hepcidin is regulated by anemia, hypoxia, and inflammation. J Clin Invest 2002, 110: 1037-1044.
22. Nicolas G, Viatte L, Lou DQ et al.: Constitutive hepcidin expression prevents iron overload in a mouse model of hemochromatosis. Nat Genet 2003, 34: 97-101.
23. Frazer DM, Wilkins SJ, Becker EM, et al.: Hepcidin expression inversely correlates with the expression of duodenal iron transporters and iron absorption in rats. Gastroenterology 2002, 123: 835-844.
24. 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.
25. Weinstein DA, Roy CN, Fleming MD, et al.: Inappropriate expression of hepcidin is associated with iron refractory anemia: Implications for the anemia of chronic disease. Blood 2002, 100: 3776-3781.
26. Kawabata H, Fleming RE, Gui D, et al.: Expression of hepcidin is down-regulated in TfR2 mutant mice manifesting a phenotype of hereditary hemochromatosis Blood 2004, Sep 2 [Epub ahead of print].
27. Muckenthaler M, Roy CN, Custodio AO, et al.: Regulatory defects in liver and intestine implicate abnormal hepcidin and Cybrd1 expression in mouse hemochromatosis. Nat Genet 2003, 34: 102-107.
28. Bridle KR, Frazer DM, Wilkins SJ, et al.: Disrupted hepcidin regulation in HFE-associated haemochromatosis and the liver as a regulator of body iron homoeostasis. Lancet 2003, 361: 669-673.
29. Nemeth E, Roetto A, Garozzo G, et al.: Hepcidin is decreased in TFR2-Hemochromatosis. Blood 2004, Oct 14 [Epub ahead of print].
30. Biasiotto G, Belloli S, Ruggeri G, et al.: 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, 49: 1981-1988.
31. 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.
32. Merryweather-Clarke AT, 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.
33. Le Gac G, Scotet V, Ka C, et al.: The recently identified type 2A juvenile haemochromatosis gene (HJV), a second candidate modifier of the C282Y homozygous phenotype. Hum Mol Genet 2004, 13: 1913-1918.
34. Delatycki MB, Allen KJ, Gow P, et al.: A homozygous HAMP mutation in a multiply consanguineous family with pseudo-dominant juvenile hemochromatosis. Clin Genet 2004, 65: 378-383.
35. Roetto A, Papanikolaou G, Politou M, et al.: Mutant antimicrobial peptide hepcidin is associated with severe juvenile hemochromatosis. Nat Genet 2003, 33: 21-22.
36. Matthes T, Aguilar-Martinez P, Pizzi-Bosman L, et al.: Severe hemochromatosis in a Portuguese family associated with a new mutation in the 5'-UTR of the HAMP gene. Blood 2004, 104: 2181-2183.
37. Majore S, Binni F, Pennese A, et al.: HAMP gene mutation c.208T> C (p.C70R) identified in an Italian patient with severe hereditary hemochromatosis. Hum Mutat 2004, 23: 400-408.
38. Roetto A, Daraio F, Porporato P, et al.: Screening hepcidin for mutations in juvenile hemochromatosis: Identification of a new mutation (C70R). Blood 2004, 103: 2407-2409.
39. Filali M, Le Jeunne C, Durand E et al.: Juvenile hemochromatosis HJV-related revealed by cardiogenic shock. Blood Cells Mol Dis 2004, 33: 120-124.
40. Huang FW, Rubio-Aliaga I, Kushner JP, et al.: Identification of a novel mutation (C321X) in HJV. Blood 2004, 104: 2176-2177.
41. Lanzara C, Roetto A, Daraio F, et al.: Spectrum of hemojuvelin gene mutations in 1q-linked juvenile hemochromatosis. Blood 2004, 103: 4317-4321.
42. Lee PL, Beutler E, Rao SV, Barton JC: Genetic abnormalities and juvenile hemochromatosis: Mutations of the HJV gene encoding hemojuvelin. Blood 2004, 103: 4669-4671.
43. Pissia M, Polonifi K, Politou M, et al.: Prevalence of the G320V mutation of the HJV gene, associated with juvenile hemochromatosis, in Greece. Haematologica 2004, 89: 742-743.
44. Fleming RE, Migas MC, Holden CC, et al.: Transferrin receptor 2: continued expression in mouse liver in the face of iron overload and in hereditary hemochromatosis. Proc Natl Acad Sci U S A 2000, 97: 2214-2219.
45. Kawabata H, Germain RS, Vuong PT, 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.
46. Camaschella C, Roetto A, Cali A, et al.: The gene TFR2 is mutated in a new type of haemochromatosis mapping to 7q2 2. Nat Genet 2000, 25: 14-15.
47. 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.
48. Piperno A, Roetto A, Mariani R, et al.: Homozygosity for transferrin receptor-2 Y250X mutation induces early iron overload. Haematologica 2004, 89: 359-360.
49. Roetto A, Totaro A, Piperno A et al.: New mutations inactivating transferrin receptor 2 in hemochromatosis type 3. Blood 2001, 97: 2555-2560.
50. 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.
51. Le Gac G, Mons F, Jacolot S, et al.: 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.
52. 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.
53. Hofmann WK, Tong XJ, Ajioka RS, et al.: Mutation analysis of transferrin-receptor 2 in patients with atypical hemochromatosis. Blood 2002, 100: 1099-1100.
54. Scotet V, Merour MC, Mercier AY, et al.: Hereditary hemochromatosis: genotype/phenotype correlations for the main HFE1 mutations. Am J Hum Genet 2003, 73: 384.
55. Fleming RE, Ahmann JR, Migas MC, et al.: Targeted mutagenesis of the murine transferrin receptor-2 gene produces hemochromatosis. Proc Natl Acad Sci U S A 2002, 99: 10653-10658.
56. Zhou XY, Tomatsu S, Fleming RE, et al.: HFE gene knockout produces mouse model of hereditary hemochromatosis. Proc Natl Acad Sci U S A 1998, 95: 2492-2497.
57. Piperno A, Mariani R, Arosio C, et al.: Haemochromatosis in patients with beta-thalassaemia trait. Br J Haematol 2000, 111: 908-914.
58. Beutler E, Barton JC, Felitti VJ, et al.: Ferroportin 1 (SCL40A1) variant associated with iron overload in African-Americans. Blood Cells Mol Dis 2003, 31: 305-309.
59. Gordeuk VR, 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.
60. 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.
61. Haile DJ: Assignment of Slc11a3 to mouse chromosome 1 band 1B and SLC11A3 to human chromosome 2q32 by in situ hybridization. Cytogenet Cell Genet 2000, 88: 328-329.
62. Njajou OT, Vaessen N, Joosse M, et al.: A mutation in SLC11A3 is associated with autosomal dominant hemochromatosis. Nat Genet 2001, 28: 213-214.
63. 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.
64. Devalia V, Carter K, Walker AP, 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.
65. Roetto A, Merryweather-Clarke AT, Daraio F, et al.: A valine deletion of ferroportin 1: A common mutation in hemochromastosis type 4. Blood 2002, 100: 733-734.
66. Wallace DF, Pedersen P, Dixon JL, et al.: Novel mutation in ferroportin1 is associated with autosomal dominant hemochromatosis. Blood 2002, 100: 692-694.
67. McLaren CE, McLachlan GJ, Halliday JW et al.: Distribution of transferrin saturation in an Australian population: Relevance to the early diagnosis of hemochromatosis. Gastroenterology 1998, 114: 543-549.
68. Lee PL, Barton JC, Brandhagen D, et al.: Hemojuvelin (HJV) mutations in persons of European, African-American and Asian ancestry with adult onset haemochromatosis. Br J Haematol 2004, 127: 224-229.
69. Rivard SR, 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.
70. Arden KE, Wallace DF, Dixon JL, et al.: A novel mutation in ferroportin1 is associated with haemochromatosis in a Solomon Islands patient. Gut 2003, 52: 1215-1217.
71. Hetet G, Devaux I, Soufir N, et al.: Molecular analyses of patients with hyperferritinemia and normal serum iron values reveal both L ferritin IRE and 3 new ferroportin (slc11A3) mutations. Blood 2003, 102: 1904-1910.
72. Jouanolle AM, 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.
73. Douabin-Gicquel V, Soriano N, Ferran H, et al.: Identification of 96 single nucleotide polymorphisms in eight genes involved in iron metabolism: Efficiency of bioinformatic extraction compared with a systematic sequencing approach. Hum Genet 2001, 109: 393-401.