Biopolym. Cell. 2003; 19(6):536-540.
Molecular Biomedicine
Analysis of C282Y and H63D mutations of the hereditary haemochromatosis gene HFE among the Ukrainian population and patients with brain glial tumor
1Pampukha V. M., 2Rozumenko V. D., 2Cherchenko A. P., 1Livshits L. A.
  1. Institute of Molecular Biology and Genetics, NAS of Ukraine
    150, Akademika Zabolotnoho Str., Kyiv, Ukraine, 03680
  2. Institute of Neurosurgery named after A. P. Romodanov, AMS of Ukraine
    32, Manuilskogo Str., Kyiv, Ukraine, 04050

Abstract

The research deals with the spreading of C282Y and H63D mutations of hereditary chromatosis gene HFE among the inhabitants of various regions of Ukraine as compared to the people with brain tumors. It was found that t he frequency of C282Y mutation is 2.5 % within the whole population of Ukraine whereas it is 2.9 % for the eastern regions, 2 % for the central regions, 2.5 % for the western regions, and 1 % as for the Crimean Tatar population. The frequency of H63D mutation within the whole population is 17 %. As for the people suffering from brain tumors (86 patients investigated) a tendency of decreasing H63D-mutated heterozygotes has been shown.

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;13(4):399-408.
[2] Fleming MD, Trenor CC 3rd, Su MA, Foernzler D, Beier DR, Dietrich WF, Andrews NC. Microcytic anaemia mice have a mutation in Nramp2, a candidate iron transporter gene. Nat Genet. 1997;16(4):383-6.
[3] Gunshin H, Mackenzie B, Berger UV, Gunshin Y, Romero MF, Boron WF, Nussberger S, Gollan JL, Hediger MA. Cloning and characterization of a mammalian proton-coupled metal-ion transporter. Nature. 1997;388(6641):482-8.
[4] Zoller H, Pietrangelo A, Vogel W, Weiss G. Duodenal metal-transporter (DMT-1, NRAMP-2) expression in patients with hereditary haemochromatosis. Lancet. 1999;353(9170):2120-3.
[5] Fleming RE, Migas MC, Zhou X, Jiang J, Britton RS, Brunt EM, Tomatsu S, Waheed A, Bacon BR, Sly WS. Mechanism of increased iron absorption in murine model of hereditary hemochromatosis: increased duodenal expression of the iron transporter DMT1. Proc Natl Acad Sci U S A. 1999;96(6):3143-8.
[6] Donovan A, Brownlie A, Zhou Y, Shepard J, Pratt SJ, Moynihan J, Paw BH, Drejer A, Barut B, Zapata A, Law TC, Brugnara C, Lux SE, Pinkus GS, Pinkus JL, Kingsley PD, Palis J, Fleming MD, Andrews NC, Zon LI. Positional cloning of zebrafish ferroportin1 identifies a conserved vertebrate iron exporter. Nature. 2000;403(6771):776-81.
[7] Kawabata H, Yang R, Hirama T, Vuong PT, Kawano S, Gombart AF, Koeffler HP. Molecular cloning of transferrin receptor 2. A new member of the transferrin receptor-like family. J Biol Chem. 1999;274(30):20826-32.
[8] Camaschella C, Roetto A, Cal? A, De Gobbi M, Garozzo G, Carella M, Majorano N, Totaro A, Gasparini P. The gene TFR2 is mutated in a new type of haemochromatosis mapping to 7q22. Nat Genet. 2000;25(1):14-5.
[9] Simon M, Bourel M, Fauchet R, Genetet B. Association of HLA-A3 and HLA-B14 antigens with idiopathic haemochromatosis. Gut. 1976;17(5):332-4.
[10] Waheed A, Parkkila S, Zhou XY, Tomatsu S, Tsuchihashi Z, Feder JN, Schatzman RC, Britton RS, Bacon BR, Sly WS. 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 U S A. 1997;94(23):12384-9.
[11] Beutler E, Gelbart T, West C, Lee P, Adams M, Blackstone R, Pockros P, Kosty M, Venditti CP, Phatak PD, Seese NK, Chorney KA, Ten Elshof AE, Gerhard GS, Chorney M. Mutation analysis in hereditary hemochromatosis. Blood Cells Mol Dis. 1996;22(2):187-94.
[12] Jazwinska EC, Cullen LM, Busfield F, Pyper WR, Webb SI, Powell LW, Morris CP, Walsh TP. Haemochromatosis and HLA-H. Nat Genet. 1996;14(3):249-51.
[13] Jouanolle AM, Gandon G, J?z?quel P, Blayau M, Campion ML, Yaouanq J, Mosser J, Fergelot P, Chauvel B, Bouric P, Carn G, Andrieux N, Gicquel I, Le Gall JY, David V. Haemochromatosis and HLA-H. Nat Genet. 1996;14(3):251-2.
[14] 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;60(4):828-32.
[15] Cardoso EM, St?l P, Hagen K, Cabeda JM, Esin S, de Sousa M, Hultcrantz R. HFE mutations in patients with hereditary haemochromatosis in Sweden. J Intern Med. 1998;243(3):203-8.
[16] Rossi E, Henderson S, Chin CY, Olynyk J, Beilby JP, Reed WD, Jeffrey GP. Genotyping as a diagnostic aid in genetic haemochromatosis. J Gastroenterol Hepatol. 1999;14(5):427-30.
[17] Brissot P, Moirand R, Jouanolle AM, Guyader D, Le Gall JY, Deugnier Y, David V. A genotypic study of 217 unrelated probands diagnosed as "genetic hemochromatosis" on "classical" phenotypic criteria. J Hepatol. 1999;30(4):588-93.
[18] Piperno A, Sampietro M, Pietrangelo A, Arosio C, Lupica L, Montosi G, Vergani A, Fraquelli M, Girelli D, Pasquero P, Roetto A, Gasparini P, Fargion S, Conte D, Camaschella C. Heterogeneity of hemochromatosis in Italy. Gastroenterology. 1998;114(5):996-1002.
[19] Feder JN, Tsuchihashi Z, Irrinki A, Lee VK, Mapa FA, Morikang E, Prass CE, Starnes SM, Wolff RK, Parkkila S, Sly WS, Schatzman RC. The hemochromatosis founder mutation in HLA-H disrupts beta2-microglobulin interaction and cell surface expression. J Biol Chem. 1997;272(22):14025-8.
[20] Barton JC, Shih WW, Sawada-Hirai R, Acton RT, Harmon L, Rivers C, Rothenberg BE. 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(1):135-45.
[21] Beutler E. The significance of the 187G (H63D) mutation in hemochromatosis. Am J Hum Genet. 1997;61(3):762-4.
[22] Rasmussen ML, Folsom AR, Catellier DJ, Tsai MY, Garg U, Eckfeldt JH. A prospective study of coronary heart disease and the hemochromatosis gene (HFE) C282Y mutation: the Atherosclerosis Risk in Communities (ARIC) study. Atherosclerosis. 2001;154(3):739-46.
[23] Kelly C. Can excess iron increase the risk for coronary heart disease and cancer? Nutrition Bulletin. 2002;27(3):165–79.
[24] Li J, Zhu Y, Singal DP. HFE gene mutations in patients with rheumatoid arthritis. J Rheumatol. 2000;27(9):2074-7.
[25] Sampietro M, Piperno A, Lupica L, Arosio C, Vergani A, Corbetta N, Malosio I, Mattioli M, Fracanzani AL, Cappellini MD, Fiorelli G, Fargion S. High prevalence of the His63Asp HFE mutation in Italian patients with porphyria cutanea tarda. Hepatology. 1998;27(1):181-4.
[26] Bulaj ZJ, Phillips JD, Ajioka RS, Franklin MR, Griffen LM, Guinee DJ, Edwards CQ, Kushner JP. Hemochromatosis genes and other factors contributing to the pathogenesis of porphyria cutanea tarda. Blood. 2000;95(5):1565-71.
[27] Macdonald GA, Tarish J, Whitehall VJ, McCann SJ, Mellick GD, Buttenshaw RL, Johnson AG, Young J, Leggett BA. No evidence of increased risk of colorectal cancer in individuals heterozygous for the Cys282Tyr haemochromatosis mutation. J Gastroenterol Hepatol. 1999;14(12):1188-91.
[28] Alt?s A, Gimferrer E, Capella G, Barcel? MJ, Baiget M. Colorectal cancer and HFE gene mutations. Haematologica. 1999;84(5):479-80.
[29] Gimferrer E, Nomdedeu J, Gich I, Barcel? MJ, Baiget M. Prevalence of hemochromatosis related HFE gene mutations in patients with acute myeloid leukemia. Leuk Res. 1999;23(6):597-8.
[30] Dorak MT, Burnett AK, Worwood M, Sproul AM, Gibson BE. The C282Y mutation of HFE is another male-specific risk factor for childhood acute lymphoblastic leukemia. Blood. 1999;94(11):3957.
[31] Kwan T, Leber B, Ahuja S, Carter R, Gerstein HC. Patients with type 2 diabetes have a high frequency of the C282Y mutation of the hemochromatosis gene. Clin Invest Med. 1998;21(6):251-7.
[32] Willis G, Wimperis JZ, Lonsdale R, Fellows IW, Watson MA, Skipper LM, Jennings BA. Incidence of liver disease in people with HFE mutations. Gut. 2000;46(3):401-4.
[33] Fargion S, Stazi MA, Fracanzani AL, Mattioli M, Sampietro M, Tavazzi D, Bertelli C, Patriarca V, Mariani C, Fiorelli G. Mutations in the HFE gene and their interaction with exogenous risk factors in hepatocellular carcinoma. Blood Cells Mol Dis. 2001;27(2):505-11.
[34] Beckman LE, Van Landeghem GF, Sikstr?m C, Wahlin A, Markev?rn B, Hallmans G, Lenner P, Athlin L, Stenling R, Beckman L. Interaction between haemochromatosis and transferrin receptor genes in different neoplastic disorders. Carcinogenesis. 1999;20(7):1231-3.
[35] Van Landeghem GF, Beckman LE, Wahlin A, Markev?rn B, Beckman L. Interaction between haemochromatosis and transferrin receptor genes in multiple myeloma. Lancet. 1998;352(9136):1285-6.
[36] Martinez di Montemuros F, Tavazzi D, Salsano E, Piepoli T, Pollo B, Fiorelli G, Finocchiaro G. High frequency of the H63D mutation of the hemochromatosis gene (HFE) in malignant gliomas. Neurology. 2001;57(7):1342.
[37] Wehnert M, Herrmann FH, Metzke H, Thiele H, Vogel G, Kuhnert W, Ebener U, Wulff K. [Initial results of genetic carrier diagnosis in risk pedigrees with hemophilia A and B in East Germany]. Z Gesamte Inn Med. 1988;43(16):441-4.
[38] Saiki RK, Gelfand DH, Stoffel S, Scharf SJ, Higuchi R, Horn GT, Mullis KB, Erlich HA. Primer-directed enzymatic amplification of DNA with a thermostable DNA polymerase. Science. 1988;239(4839):487-91.
[39] Lynas C. A cheaper and more rapid polymerase chain reaction-restriction fragment length polymorphism method for the detection of the HLA-H gene mutations occurring in hereditary hemochromatosis. Blood. 1997;90(10):4235-6.
[40] Merryweather-Clarke AT, Pointon JJ, Jouanolle AM, Rochette J, Robson KJ. Geography of HFE C282Y and H63D mutations. Genet Test. 2000;4(2):183-98.
[41] Merryweather-Clarke AT, Pointon JJ, Shearman JD, Robson KJ. Global prevalence of putative haemochromatosis mutations. J Med Genet. 1997;34(4):275-8.
[42] Ryan E, O'keane C, Crowe J. Hemochromatosis in Ireland and HFE. Blood Cells Mol Dis. 1998;24(4):428-32.
[43] Mortimore M, Merryweather-Clarke AT, Robson KJ, Powell LW. The haemochromatosis gene: a global perspective and implications for the Asia-Pacific region. J Gastroenterol Hepatol. 1999;14(9):838-43.
[44] Connor JR. Cellular and regional maintenance of iron homeostasis in brain tissue. Iron in central nervous disorders. New-York: Springer, 1993: 1-18.
[45] Mykhaylyk OM, Dudchenko NA, Razumenko VD, Cherchenko AP, Dudchenko NA. Glial brain tumor in patients is associated with hyperferremia in the blood, plasma, tumor and peritumoral brain tissue. Mengem- und Spuren-Elemente. Leipzig: Harald Schubert, 1999: 592-9.
[46] Zozulya YuP, Mykhaylyk OM, Rozumenko VD, Cherchenko AP, Dudchenko NO, Lebedev EO, Shurunov BS. Peculiarities of nonheme iron metabolism in patients bearing glial brain tumours. Ukr Neurokhirurg Zh. 2000; (2): 29-37.
[47] Zozulya YuP, Mykhaylyk OM, Cherchenko AP, Rozumenko VD, Dudchenko NO, Lebedev EO, Shurunov BS. Peculiarities of nonheme iron metabolism in rat experimental glial brain tumours. Zh Akad Med Nauk Ukrainy. 2001; 7(1):3-21.
[48] Mychaylic O, Dudchenko N, Cherchenko A, Razumenko VD, Zozulya YP. Peculiarities of nonheme iron metabolism upon glial brain tumors. 3rd Int. Symp. «On trace elements in human: new perspectives: Proc. book (4-6 Oct. 2001). New York, 2001: 1100-1110