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  • Print publication year: 2010
  • Online publication date: June 2011

8 - Classical and atypical HFE hemochromatosis

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Summary

Hemochromatosis and HFE mutations

The “classical” type of familial hemochromatosis that is transmitted as an autosomal recessive disorder is usually due to homozygosity for the C282Y mutation of the HFE gene. It is expected that mutations of HFE cause the great majority of the cases of heritable iron overload in humans. There are at least 37 known mutations of the HFE gene (Table 8.1) (Chapter 4). Some individuals who are homozygous for any of the known mutations may develop heavy iron overload. At least six mutations are associated with mild iron accumulation; and at least six mutations were discovered in patients who did not have iron overload. There is insufficient reported information in the literature to determine if six of the mutations are sufficiently deleterious to result in iron overload. Approximately 1500 mutations of the cystic fibrosis gene (CF) are known, and the gene encodes a 1480 amino acid protein. In contrast, HFE is much smaller than CF, and encodes a protein of only 343 amino acids. Thus, it is expected that fewer mutations of HFE than mutations of CF will be eventually discovered.

Molecular genetics

Although the autosomal recessive inheritance pattern of “classical” hemochromatosis had long been recognized, identification of the responsible gene remained elusive for many years (Table 8.1). An important breakthrough in the search for the gene occurred in 1976 when hemochromatosis was found to be linked closely to the human leukocyte antigen (HLA)-A*03 region of the short arm of chromosome 6.

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Handbook of Iron Overload Disorders
  • Online ISBN: 9780511777035
  • Book DOI: https://doi.org/10.1017/CBO9780511777035
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References
Simon, M, Bourel, M, Fauchet, R, Genetet, B. Association of HLA-A3 and HLA-B14 antigens with idiopathic haemochromatosis. Gut 1976; 17: 332–4.
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.
Zhou, XY, Tomatsu, S, Fleming, RE, et al. HFE gene knockout produces mouse model of hereditary hemochromatosis. Proc Natl Acad Sci USA 1998; 95: 2492.
Levy, JE, Montross, LK, Cohen, , Fleming, MD, Andrews, NC. The C282Y mutation causing hereditary hemochromatosis does not produce a null allele. Blood 1999; 94: 9–11.
Feder, JN, Tsuchihashi, Z, Irrinki, A, et al. The hemochromatosis founder mutation in HLA-H disrupts beta2-microglobulin interaction and cell surface expression. J Biol Chem 1997; 272: 14025–8.
Waheed, A, Parkkila, S, Zhou, XY, et al. Hereditary hemochromatosis: effects of C282Y and H63D mutations on association with beta2-microglobulin, intracellular processing, and cell surface expression of the HFE protein in COS-7 cells. Proc Natl Acad Sci USA 1997; 94: 12384–9.
Santos, M, Schilham, MW, Rademakers, LH, Marx, JJ, Sousa, M, Clevers, H. Defective iron homeostasis in beta2-microglobulin knockout mice recapitulates hereditary hemochromatosis in man. J Exp Med 1996; 184: 1975–85.
Fleming, RE, Britton, RS, Waheed, A, Sly, WS, Bacon, BR. Pathogenesis of hereditary hemochromatosis. Clin Liver Dis 2004; 8: 7553, vii.
Beckman, , Saha, N, Spitsyn, V, Landeghem, G, Beckman, L. Ethnic differences in the HFE codon 282 (Cys/Tyr) polymorphism. Hum Hered 1997; 47: 263.
Rochette, J, Pointon, JJ, Fisher, CA, et al. Multicentric origin of hemochromatosis gene (HFE) mutations. Am J Hum Genet 1999; 64: 1056–62.
Beutler, E, Felitti, VJ, Koziol, JA, Ho, NJ, Gelbart, T. Penetrance of 845G–> A (C282Y) HFE hereditary haemochromatosis mutation in the USA. Lancet 2002; 359: 211–18.
Jacolot, S, Gac, G, Scotet, V, Quere, I, Mura, C, Ferec, C. HAMP as a modifier gene that increases the phenotypic expression of the HFE pC282Y homozygous genotype. Blood 2004; 103: 2835–40.
Steinberg, KK, Cogswell, ME, Chang, JC, et al. Prevalence of C282Y and H63D mutations in the hemochromatosis (HFE) gene in the United States. JAMA 2001; 285: 2216–22.
Gochee, PA, Powell, LW, Cullen, DJ, Du, SD, Rossi, E, Olynyk, JK. A population-based study of the biochemical and clinical expression of the H63D hemochromatosis mutation. Gastroenterology 2002; 122: 6461.
Barton, JC, Shih, WW, Sawada-Hirai, R, et al. Genetic and clinical description of hemochromatosis probands and heterozygotes: evidence that multiple genes linked to the major histocompatibility complex are responsible for hemochromatosis. Blood Cells Mol Dis 1997; 23: 135–45.
Pointon, JJ, Wallace, D, Merryweather-Clarke, AT, Robson, KJ. Uncommon mutations and polymorphisms in the hemochromatosis gene. Genet Test 2000; 4: 151–61.
Beutler, E, Griffin, MJ, Gelbart, T, West, C. A previously undescribed nonsense mutation of the HFE gene. Clin Genet 2002; 61: 40–2.
Barton, JC, West, C, Lee, PL, Beutler, E. A previously undescribed frameshift deletion mutation of HFE (c.del277; G93fs) associated with hemochromatosis and iron overload in a C282Y heterozygote. Clin Genet 2004; 66: 214–16.
Human Gene Mutation Database at the Institute of Medical Genetics in Cardiff. 01–23–2010.
Fleming, RE, Britton, RS.Iron Imports. VI. HFE and regulation of intestinal iron absorption. Am J Physiol Gastrointest Liver Physiol 2006; 290: G590–4.
Goswami, T, Andrews, NC.Hereditary hemochromatosis protein, HFE, interaction with transferrin receptor 2 suggests a molecular mechanism for mammalian iron sensing. J Biol Chem 2006; 281: 28 494–8.
Schmidt, PJ, Toran, PT, Giannetti, AM, Bjorkman, PJ, Andrews, NC. The transferrin receptor modulates Hfe-dependent regulation of hepcidin expression. Cell Metab 2008; 7: 205–14.
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: 6693.
Vujic Spasic, M, Kiss, J, Herrmann, T, et al. Hfe acts in hepatocytes to prevent hemochromatosis. Cell Metab 2008; 7: 173–8.
Stuart, KA, Anderson, GJ, Frazer, DM, et al. Duodenal expression of iron transport molecules in untreated haemochromatosis subjects. Gut 2003; 52: 953–9.
Bezwoda, WR, Disler, PB, Lynch, SR, et al. Patterns of food iron absorption in iron-deficient white and Indian subjects and in venesected haemochromatotic patients. Br J Haematol 1976; 33: 425–36.
Lynch, SR, Skikne, BS, Cook, JD. Food iron absorption in idiopathic hemochromatosis. Blood 1989; 74: 2187–93.
Parmley, RT, Barton, JC, Conrad, ME. Ultrastructural localization of transferrin, transferrin receptor, and iron-binding sites on human placental and duodenal microvilli. Br J Haematol 1985; 60: 81–9.
Whittaker, P, Skikne, BS, Covell, AM, et al. Duodenal iron proteins in idiopathic hemochromatosis. J Clin Invest 1989; 83: 261.
Feder, JN, Penny, DM, Irrinki, A, et al. The hemochromatosis gene product complexes with the transferrin receptor and lowers its affinity for ligand binding. Proc Natl Acad Sci USA 1998; 95: 1472.
Lebron, JA, Bennett, MJ, Vaughn, , et al. Crystal structure of the hemochromatosis protein HFE and characterization of its interaction with transferrin receptor. Cell 1998; 93: 111–23.
Kelleher, T, Ryan, E, Barrett, S, et al. Increased DMT1 but not IREG1 or HFE mRNA following iron depletion therapy in hereditary haemochromatosis. Gut 2004; 53: 1174–9.
Turnbull, A, Giblett, ER. The binding and transport of iron by transferrin variants. J Lab Clin Med 1961; 57: 450–9.
Bothwell, TH, Jacobs, P, Torrance, JD. Studies on the behavior of transferrin in idiopathic haemochromatosis. S Afr J Med Sci 1962; 27: 35–9.
Wheby, MS, Balcerzak, SP, Anderson, P, Crosby, WH. Clearance of iron from hemochromatotic and normal transferin in vivo. Blood 1964; 24: 765–9.
Batey, RG, Lai Chung, FP, Shamir, S, Sherlock, S. A non-transferrin-bound serum iron in idiopathic hemochromatosis. Dig Dis Sci 1980; 25: 340–6.
Cairo, G, Conte, D, Bianchi, L, Fraquelli, M, Recalcati, S. Reduced serum ceruloplasmin levels in hereditary haemochromatosis. Br J Haematol 2001; 114: 226–9.
Laine, F, Ropert, M, Lan, CL, et al. Serum ceruloplasmin and ferroxidase activity are decreased in HFE C282Y homozygote male iron overloaded patients. J Hepatol 2002; 36: 60.
Sciot, R, Paterson, AC, Oord, JJ, Desmet, VJ. Lack of hepatic transferrin receptor expression in hemochromatosis. Hepatology 1987; 7: 831.
Lombard, M, Bomford, A, Hynes, M, et al. Regulation of the hepatic transferrin receptor in hereditary hemochromatosis. Hepatology 1989; 9: 1.
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: 20826–32.
Chua, ACG, Delima, RD, Morgan, EH, et al. Iron uptake from plasma transferrin by a transferrin receptor 2 mutant mouse model of haemachromatosis, J Hepatol (in press).
Merle, U, Theilig, F, Fein, E, et al. Localization of the iron-regulatory proteins hemojuvelin and transferrin receptor 2 to the basolateral membrane domain of hepatocytes. Histochem Cell Biol 2007; 127: 221–6.
Davies, PS, Zhang, AS, Anderson, EL, et al. Evidence for the interaction of the hereditary haemochromatosis protein, HFE, with the transferrin receptor in endocytic compartments. Biochem J 2003; 373: 1453.
Mackenzie, B, Ujwal, ML, Chang, MH, Romero, MF, Hediger, MA. Divalent metal-ion transporter DMT1 mediates both H+ coupled Fe2+ transport and uncoupled fluxes. Pflugers Arch 2006; 451: 5448.
Rahier, J, Loozen, S, Goebbels, RM, Abrahem, M. The haemochromatotic human pancreas: a quantitative immunohistochemical and ultrastructural study. Diabetologia 1987; 30: 5–12.
Lu, JP, Hayashi, K. Selective iron deposition in pancreatic islet B cells of transfusional iron overloaded autopsy cases. Pathol Int 1994; 44: 194–9.
Sheldon, JH. Haemochromatosis. London, Oxford University Press, 1935.
Peillon, F, Racadot, J.[Histopathological modification in the hypophysis in 6 cases of hemochromatosis.]Ann Endocrinol (Paris) 1969; 30: 800.
Bergeron, C, Kovacs, K.Pituitary siderosis. A histologic, immunocytologic, and ultrastructural study. Am J Pathol 1978; 93: 295–309.
Atkin, SL, Burnett, HE, Green, VL, White, MC, Lombard, M. Expression of the transferrin receptor in human anterior pituitary adenomas is confined to gonadotrophinomas. Clin Endocrinol (Oxf) 1996; 44: 4671.
Tampanaru-Sarmesiu, A, Stefaneanu, L, Thapar, K, Kontogeorgos, G, Sumi, T, Kovacs, K. Transferrin and transferrin receptor in human hypophysis and pituitary adenomas. Am J Pathol 1998; 152: 413–22.
McDermott, JH, Walsh, CH. Hypogonadism in hereditary hemochromatosis. J Clin Endocrinol Metab 2005; 90: 2451.
Barton, JC, Bertoli, LF, Rothenberg, BE. Peripheral blood erythrocyte parameters in hemochromatosis: evidence for increased erythrocyte hemoglobin content. J Lab Clin Med 2000; 135: 96–104.
Beutler, E, Felitti, V, Gelbart, T, Ho, N. The effect of HFE genotypes on measurements of iron overload in patients attending a health appraisal clinic. Ann Intern Med 2000; 133: 329–37.
McLaren, CE, Barton, JC, Gordeuk, VR, et al. Determinants and characteristics of mean corpuscular volume and hemoglobin concentration in white HFE C282Y homozygotes in the hemochromatosis and iron overload screening study. Am J Hematol 2007; 82: 898–905.
Feeney, GP, Carter, K, Masters, GS, Jackson, HA, Cavil, I, Worwood, M. Changes in erythropoiesis in hereditary hemochromatosis are not mediated by HFE expression in nucleated red cells. Haematologica 2005; 90: 180.
Lin, JP, O'Donnell, CJ, Jin, L, Fox, C, Yang, Q, Cupples, . Evidence for linkage of red blood cell size and count: genome-wide scans in the Framingham Heart Study. Am J Hematol 2007; 82: 605–10.
Kozewski, BJ. The occurrence of megaloblastic erythropoiesis in patients with hemochromatosis. Blood 1952; 7: 1182–95.
Quigley, JG, Yang, Z, Worthington, MT, et al. Identification of a human heme exporter that is essential for erythropoiesis. Cell 2004; 118: 757–66.
Keel, SB, Doty, RT, Yang, Z, et al. A heme export protein is required for red blood cell differentiation and iron homeostasis. Science 2008; 319: 825–8.
Gehrke, SG, Kulaksiz, H, Herrmann, T, et al. Expression of hepcidin in hereditary hemochromatosis: evidence for a regulation in response to the serum transferrin saturation and to non-transferrin-bound iron. Blood 2003; 102: 371–6.
Piperno, A, Girelli, D, Nemeth, E, et al. Blunted hepcidin response to oral iron challenge in HFE-related hemochromatosis. Blood 2007; 110: 4096–100.
Ganz, T. Iron homeostasis: fitting the puzzle pieces together. Cell Metab 2008; 7: 288–90.
Tanno, T, Bhanu, NV, Oneal, PA, et al. High levels of GDF15 in thalassemia suppress expression of the iron regulatory protein hepcidin. Nat Med 2007; 13: 1096–101.
Mast, AE, Foster, TM, Pinder, HL, et al. Behavioral, biochemical, and genetic analysis of iron metabolism in high-intensity blood donors. Transfusion 2008; 48: 2197–204.
Lee, PL, Gelbart, T, West, C, Halloran, C, Felitti, V, Beutler, E. A study of genes that may modulate the expression of hereditary hemochromatosis: transferrin receptor-1, ferroportin, ceruloplasmin, ferritin light and heavy chains, iron regulatory proteins (IRP)-1 and -2, and hepcidin. Blood Cells Mol Dis 2001; 27: 783–802.
Hofmann, WK, Tong, XJ, Ajioka, RS, Kushner, JP, Koeffler, HP. Mutation analysis of transferrin-receptor 2 in patients with atypical hemochromatosis. Blood 2002; 100: 1099–100.
Lee, P, Gelbart, T, West, C, Halloran, C, Beutler, E. Seeking candidate mutations that affect iron homeostasis. Blood Cells Mol Dis 2002; 29: 471–87.
Kelleher, T, Ryan, E, Barrett, S, O'Keane, C, Crowe, J. DMT1 genetic variability is not responsible for phenotype variability in hereditary hemochromatosis. Blood Cells Mol Dis 2004; 33: 35–9.
Lee, PL, Barton, JC, Brandhagen, D, Beutler, E. Hemojuvelin (HJV) mutations in persons of European, African-American and Asian ancestry with adult onset haemochromatosis. Br J Haematol 2004; 127: 224–9.
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: 1913–18.
Mura, C, Gac, G, Scotet, V, Raguenes, O, Mercier, AY, Ferec, C. Variation of iron loading expression in C282Y homozygous haemochromatosis probands and sib pairs. J Med Genet 2001; 38: 632–6.
Barton, JC, Wiener, HW, Acton, RT, Go, RC. HLA haplotype A*03-B*07 in hemochromatosis probands with HFE C282Y homozygosity: frequency disparity in men and women and lack of association with severity of iron overload. Blood Cells Mol Dis 2005; 34: 38–47.
Olatunbosun, D, Corbett, WE, Ludwig, J, Valberg, LS. Alteration of cobalt absorption in portal cirrhosis and idiopathic hemochromatosis. J Lab Clin Med 1970; 75: 754–62.
Akesson, A, Stal, P, Vahter, M. Phlebotomy increases cadmium uptake in hemochromatosis. Environ Health Perspect 2000; 108: 289–91.
Barton, JC, Patton, MA, Edwards, CQ, et al. Blood lead concentrations in hereditary hemochromatosis. J Lab Clin Med 1994; 124: 193–8.
Barton, JC. The absorption and metabolism of non-ferrous metals in hemochromatosis. In: Barton, JC, Edwards, CQ, eds. Hemochromatosis: Genetics, Pathophysiology, Diagnosis and Treatment. Cambridge, Cambridge University Press. 2000; 131–44.
Pietrangelo, A, Rocchi, E, Casalgrandi, G, et al. Regulation of transferrin, transferrin receptor, and ferritin genes in human duodenum. Gastroenterology 1992; 102: 802–9.
Feder, JN, Penny, DM, Irrinki, A, et al. The hemochromatosis gene product complexes with the transferrin receptor and lowers its affinity for ligand binding. Proc Natl Acad Sci USA 1998; 95: 1472.
Altstatt, LB, Pollack, S, Feldman, MH, Reba, RC, Crosby, WH. Liver manganese in hemochromatosis. Proc Soc Exp Biol Med 1967; 124: 353.
Adams, PC, Bradley, C, Frei, JV. Hepatic zinc in hemochromatosis. Clin Invest Med 1991; 14: 16–20.
Brissot, P, Treut, A, Dien, G, Cottencin, M, Simon, M, Bourel, M. Hypovitaminemia A in idiopathic hemochromatosis and hepatic cirrhosis. Role of retinol-binding protein and zinc. Digestion 1978; 17: 4698.
Sargent, T, Lim, TH, Jenson, RL. Reduced chromium retention in patients with hemochromatosis, a possible basis of hemochromatotic diabetes. Metabolism 1979; 28: 70–9.
Spencer, H, Sontag, SJ, Derler, J, Osis, D. Intestinal absorption of iron in patients with hemochromatosis. In: Weintraub, LR, Edwards, CQ, Krikker, M, eds. Hemochromatosis. Proceedings of the First International Conference. New York, The New York Academy of Sciences. 1988; 336–8.
Barton, JC, Bertoli, LF. Zinc gluconate lozenges for treating the common cold. Ann Intern Med 1997; 126: 738–9.
Walshe, JM, Cox, DW. Effect of treatment of Wilson's disease on natural history of haemochromatosis. Lancet 1998; 352: 112–13.
Dib, N, Valsesia, E, Malinge, MC, Mauras, Y, Misrahi, M, Cales, P. Late onset of Wilson's disease in a family with genetic haemochromatosis. Eur J Gastroenterol Hepatol 2006; 18: 43.
Onalaja, AO, Claudio, L. Genetic susceptibility to lead poisoning. Environ Health Perspect 2000; 108 Suppl 1: 23–8.
Mandelli, C, Cesarini, L, Piperno, A, et al. Saturability of hepatic iron deposits in genetic hemochromatosis. Hepatology 1992; 16: 956–9.
Niederau, C, Fischer, R, Sonnenberg, A, Stremmel, W, Trampisch, HJ, Strohmeyer, G. Survival and causes of death in cirrhotic and in non-cirrhotic patients with primary hemochromatosis. N Engl J Med 1985; 313: 1256–62.
Wood, MJ, Powell, LW, Ramm, GA. Environmental and genetic modifiers of the progression to fibrosis and cirrhosis in hemochromatosis. Blood 2008; 111: 4456–62.
Adams, PC, Reboussin, DM, Barton, JC, et al. Hemochromatosis and iron overload screening in a racially diverse population. N Engl J Med 2005; 352: 17698.
Edwards, CQ, Griffen, LM, Goldgar, D, Drummond, C, Skolnick, MH, Kushner, JP. Prevalence of hemochromatosis among 11,065 presumably healthy blood donors. N Engl J Med 1988; 318: 1355–62.
Bulaj, ZJ, Ajioka, RS, Phillips, JD, et al. Disease-related conditions in relatives of patients with hemochromatosis. N Engl J Med 2000; 343: 1529–35.
McLaren, GD, McLaren, CE, Adams, PC, et al. Clinical manifestations of hemochromatosis in HFE C282Y homozygotes identified by screening. Can J Gastroenterol 2008; 22: 923–30.
Adams, PC. Non-expressing homozygotes for C282Y hemochromatosis: minority or majority of cases?Mol Genet Metab 2000; 71: 81–6.
Barton, JC, Harmon, L, Rivers, C, Acton, RT. Hemochromatosis: association of severity of iron overload with genetic markers. Blood Cells Mol Dis 1996; 22: 195–204.
Pratiwi, R, Fletcher, LM, Pyper, WR, et al. Linkage disequilibrium analysis in Australian haemochromatosis patients indicates bipartite association with clinical expression. J Hepatol 1999; 31: 39–46.
Piperno, A, Arosio, C, Fargion, S, et al. The ancestral hemochromatosis haplotype is associated with a severe phenotype expression in Italian patients. Hepatology 1996; 24: 43–6.
Barton, JC, Wiener, HW, Acton, RT, Go, RC. HLA haplotype A*03-B*07 in hemochromatosis probands with HFE C282Y homozygosity: frequency disparity in men and women and lack of association with severity of iron overload. Blood Cells Mol Dis 2005; 34: 38–47.
Cartwright, GE, Edwards, CQ, Kravitz, K, et al. Hereditary hemochromatosis. Phenotypic expression of the disease. N Engl J Med 1979; 301: 175–9.
Pietrangelo, A. Hereditary hemochromatosis—a new look at an old disease. N Engl J Med 2004; 350: 2383–97.
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; 25: 1475.
Beutler, E, Gelbart, T, West, C, et al. Mutation analysis in hereditary hemochromatosis. Blood Cells Mol Dis 1996; 22: 187–94.
Marshall, DS, Linfert, DR, Tsongalis, GJ. Prevalence of the C282Y and H63D polymorphisms in a multi-ethnic control population. Int J Mol Med 1999; 4: 389–93.
Bradley, , Johnson, DD, Palomaki, GE, Haddow, JE, Robertson, NH, Ferrie, RM. Hereditary haemochromatosis mutation frequencies in the general population. J Med Screen 1998; 5: 34–6.
McDonnell, SM, Hover, A, Gloe, D, Ou, CY, Cogswell, ME, Grummer-Strawn, L. Population-based screening for hemochromatosis using phenotypic and DNA testing among employees of health maintenance organizations in Springfield, Missouri. Am J Med 1999; 107: 30.
Garry, PJ, Montoya, GD, Baumgartner, RN, Liang, HC, Williams, TM, Brodie, SG. Impact of HLA-H mutations on iron stores in healthy elderly men and women. Blood Cells Mol Dis 1997; 23: 277–87.
Monaghan, KG, Rybicki, BA, Shurafa, M, Feldman, GL. Mutation analysis of the HFE gene associated with hereditary hemochromatosis in African-American(s). Am J Hematol 1998; 58: 213–17.
A simple genetic test identifies 90% of UK patients with haemochromatosis. The UK Haemochromatosis Consortium. Gut 1997; 41: 841–4.
Willis, G, Jennings, BA, Goodman, E, Fellows, IW, Wimperis, JZ. A high prevalence of HLA-H 845A mutations in hemochromatosis patients and the normal population in eastern England. Blood Cells Mol Dis 1997; 23: 288–91.
Murphy, S, Curran, MD, McDougall, N, Callender, ME, O'Brien, CJ, Middleton, D. High incidence of the Cys282Tyr mutation in the HFE gene in the Irish population—implications for haemochromatosis. Tissue Antigens 1998; 52: 484–8.
Ryan, E, O'Keane, C, Crowe, J. Hemochromatosis in Ireland and HFE. Blood Cells Mol Dis 1998; 24: 428–32.
Miedzybrodzka, Z, Loughlin, S, Baty, D, et al. Haemochromatosis mutations in northeast Scotland. Br J Haematol 1999; 106: 385.
Jazwinska, EC, Cullen, LM, Busfield, F, et al. Haemochromatosis and HLA-H. Nat Genet 1996; 14: 2491.
Rossi, E, Henderson, S, Chin, CY, et al. Genotyping as a diagnostic aid in genetic haemochromatosis. J Gastroenterol Hepatol 1999; 14: 427–30.
Adams, PC, Chakrabarti, S. Genotypic/phenotypic correlations in genetic hemochromatosis: evolution of diagnostic criteria. Gastroenterology 1998; 114: 319–23.
Milman, N, Koefoed, P, Pedersen, P, Nielsen, FC, Eiberg, H. Frequency of the HFE C282Y and H63D mutations in Danish patients with clinical haemochromatosis initially diagnosed by phenotypic methods. Eur J Haematol 2003; 71: 403.
Erhardt, A, Niederau, C, Osman, Y, Hassan, M, Haussinger, D. [Demonstration of HFE polymorphism in German patients with hereditary hemochromatosis.]Dtsch Med Wochenschr 1999; 124: 14482.
Gottschalk, R, Seidl, C, Schilling, S, et al. Iron overload and genotypic expression of HFE mutations H63D/C282Y and transferrin receptor Hin6I and BanI polymorphism in German patients with hereditary haemochromatosis. Eur J Immunogenet 2000; 27: 129–34.
Hellerbrand, C, Bosserhoff, AK, Seegers, S, et al. Mutation analysis of the HFE gene in German hemochromatosis patients and controls using automated SSCP-based capillary electrophoresis and a new PCR-ELISA technique. Scand J Gastroenterol 2001; 36: 1211–16.
Nielsen, P, Carpinteiro, S, Fischer, R, Cabeda, JM, Porto, G, Gabbe, EE. Prevalence of the C282Y and H63D mutations in the HFE gene in patients with hereditary haemochromatosis and in control subjects from northern Germany. Br J Haematol 1998; 103: 842.
Vlierberghe, H, Messiaen, L, Hautekeete, M, Paepe, A, Elewaut, A. Prevalence of the Cys282Tyr and His63Asp mutation in Flemish patients with hereditary hemochromatosis. Acta Gastroenterol Belg 2000; 63: 250–3.
Juan, D, Reta, A, Castiella, A, Pozueta, J, Prada, A, Cuadrado, E. HFE gene mutations analysis in Basque hereditary haemochromatosis patients and controls. Eur J Hum Genet 2001; 9: 961–4.
Guix, P, Picornell, A, Parera, M, et al. Prevalence of the C282Y mutation for haemochromatosis on the Island of Majorca. Clin Genet 2000; 58: 123–8.
Sanchez, M, Bruguera, M, Quintero, E, et al. Hereditary hemochromatosis in Spain. Genet Test 2000; 4: 171–6.
Fabrega, E, Castro, B, Sanchez-Castro, L, Benito, A, Fernandez-Luna, JL, Pons-Romero, F.[The prevalence of the Cys282Tyr mutation in the hemochromatosis gene in Cantabria in patients diagnosed with hereditary hemochromatosis.]Med Clin (Barc) 1999; 112: 451–3.
Sanchez, M, Bruguera, M, Bosch, J, Rodes, J, Ballesta, F, Oliva, R. Prevalence of the Cys282Tyr and His63Asp HFE gene mutations in Spanish patients with hereditary hemochromatosis and in controls. J Hepatol 1998; 29: 725–8.
Moreno, L, Vallcorba, P, Boixeda, D, Cabello, P, Bermejo, F, San Roman, C.[The usefulness of the detection of Cys282Tyr and His63Asp mutations in the diagnosis of hereditary hemochromatosis.]Rev Clin Esp 1999; 199: 632–6.
Jorquera, F, Dominguez, A, Diaz-Golpe, V, et al. C282Y and H63D mutations of the haemochromatosis gene in patients with iron overload. Rev Esp Enferm Dig 2001; 93: 293–302.
Jouanolle, AM, Fergelot, P, Gandon, G, Yaouanq, J, Gall, JY, David, V. A candidate gene for hemochromatosis: frequency of the C282Y and H63D mutations. Hum Genet 1997; 100: 544.
Mura, C, Raguenes, O, Ferec, C. HFE mutations analysis in 711 hemochromatosis probands: evidence for S65C implication in mild form of hemochromatosis. Blood 1999; 93: 2502.
Aguilar-Martinez, P, Biron, C, Blanc, F, et al. Compound heterozygotes for hemochromatosis gene mutations: may they help to understand the pathophysiology of the disease?Blood Cells Mol Dis 1997; 23: 2696.
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: 320–4.
Mercier, G, Burckel, A, Bathelier, C, Boillat, E, Lucotte, G. Mutation analysis of the HLA-H gene in French hemochromatosis patients, and genetic counseling in families. Genet Couns 1998; 9: 181–6.
Cardoso, EM, Stal, P, Hagen, K, et al. HFE mutations in patients with hereditary haemochromatosis in Sweden. J Intern Med 1998; 243: 203–8.
Olsson, KS, Ritter, B, Sandberg, L, Raha-Chowdhury, R, Gruen, J, Worwood, M. The ancestral haplotype in patients with genetic hemochromatosis from central and western Sweden. 1997. St. Malo, International Symposium on Iron in Biology and Medicine.
Calandro, L, Thorsen, T, Barcellos, L, Griggs, J, Baer, D, Sensabaugh, GF. Mutation analysis in hereditary hemochromatosis. Blood Cells Mol Dis 1996; 22: 194A–4B.
Sham, RL, Ou, CY, Cappuccio, J, Braggins, C, Dunnigan, K, Phatak, PD. Correlation between genotype and phenotype in hereditary hemochromatosis: analysis of 61 cases. Blood Cells Mol Dis 1997; 23: 314–20.
Brandhagen, DJ, Fairbanks, VF, Baldus, WP, et al. Prevalence and clinical significance of HFE gene mutations in patients with iron overload. Am J Gastroenterol 2000; 95: 2910–14.
Asberg, A, Hveem, K, Thorstensen, K, et al. Screening for hemochromatosis: high prevalence and low morbidity in an unselected population of 65 238 persons. Scand J Gastroenterol 2001; 36: 1108–15.
Porto, G, Sousa, M. Variation of hemochromatosis prevalence and genotype in national groups. In: Barton, JC, Edwards, CQ, eds. Hewmochromatosis; Genetics, Pathophysiology, Diagnosis and Treatment. Cambridge, Cambridge University Press. 2000; 51–62.
Datz, C, Lalloz, MR, Vogel, W, et al. Predominance of the HLA-H Cys282Tyr mutation in Austrian patients with genetic haemochromatosis. J Hepatol 1997; 27: 773–9.
Carella, M, D'Ambrosio, L, Totaro, A, et al. Mutation analysis of the HLA-H gene in Italian hemochromatosis patients. Am J Hum Genet 1997; 60: 828–32.
Piperno, A, Sampietro, M, Pietrangelo, A, et al. Heterogeneity of hemochromatosis in Italy. Gastroenterology 1998; 114: 996–1002.
Papanikolaou, G, Politou, M, Roetto, A, et al. Linkage to chromosome 1q in Greek families with juvenile hemochromatosis. Blood Cells Mol Dis 2001; 27: 744–9.
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