Genetic Analysis Of β-thalassemia Major And β-thalassemia Intermedia In Brazil

The development of methodologies to identify the molecular lesions responsible for different types of β-thalassemia has made it possible to correlate these data with clinical and hematological severity. We examined DNA from 35 patients with β-thalassemia, residents of the State of Sao Paulo, Brazil, for some types of genetic modifying factors: β-thalassemia mutations, the upstream XmnI (G)γ-globin gene polymorphisms, and α-globin gene deletions. Additionally, the β-like gene cluster haplotypes and the presence of the (A)γ(T) variant were studied. The following mutations were present in the 70 chromosomes studied: 54.3% codon 39 (C→T) (β+); 18.6% IVS-I-6 (T→C) (β+); 18.6% IVS-I-110 (G→A) (β+), and 4.3% IVS-I-1 (G→T) (β°). Haplotype II was associated with the nonsense mutation at codon 39, haplotype I with the IVS-I-110 and codon 39 mutations, and haplotypes VI and VII with the IVS-I-6 mutation. The XmnI polymorphism was detected in three out of 31 patients studied. No α-thalassemia was detected among the thalassemia intermedia patients. The (A)γ(T) variant was present in 87.1% of 31 thalassemia patients and was associated with the codon 39/haplotype II and IVS-I-6/haplotype VI mutations. This is the first study of the Brazilian population that has analyzed the β-thalassemia mutations and other molecular variants, and has correlated them with the clinical manifestations.223197207The β- and δ-Thalassemia Repository (1995) Hemoglobin, 19, p. 213. , eighth editionWainscoat, J.S., Old, J.M., Weatherall, D.J., Orkin, S.H., (1983) Lancet, 1, p. 1235Cappellini, M.D., Fiorelli, G., Bernini, L.F., (1981) Br. J. Haematol., 48, p. 561Weatherall, D.J., Pressley, L., Wood, W.G., Higgs, D.R., Clegg, J.B., (1981) Lancet, 1, p. 527Thein, S.L., Wainscoat, J.S., Sampietro, M., Old, J.M., Cappellini, M.D., Fiorelli, G., Modell, B., Weatherall, D.J., (1987) Br. J. Haematol., 65, p. 367Winichagoon, P., Thonglairoam, V., Fucharoen, S., Wilairat, P., Fukumaki, Y., Wasi, P., (1993) Br. J. Haematol., 86, p. 633Gringras, P., Wonke, B., Old, J., Fitches, A., Valler, D., Kuan, A.M., Hoffbrand, V., (1994) Arch. Dis. Child., 70, p. 30Ratip, S., Petrou, M., Old, J.M., Wonke, B., Porter, J.B., Modell, B., (1997) Eur. J. Haematol., 58, p. 14Costa, F.F., Tavella, M.A., Zago, M.A., (1990) Blood, 76, p. 58Martins, C.S.B., Ramalho, A.S., Sonati, M.F., Goncalves, M.S., Costa, F.F., (1993) J. Med. Genet., 30, p. 797Sambrook, J., Fritsch, E.F., Maniatis, T., (1989) Molecular Cloning: A Laboratory Manual, 2nd Edition, , Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New YorkSouthern, E.M., (1975) J. Mol. Biol., 98, p. 503Sonati, M.F., Farah, S.B., Ramalho, A.S., Costa, F.F., (1991) Hemoglobin, 15, p. 309Sutton, M., Bouhassira, E.E., Nagel, R.L., (1989) Am. J. Hematol., 32, p. 66Kulozik, A.E., Wainscoat, J.S., Serjeant, G.R., Kar, B.C., Al-Awamy, B., Essan, G.J.F., Falusi, A.G., Weatherall, D.J., (1986) Am. J. Hum. Genet., 39, p. 239Gilman, J.G., Josifovska, O., Erlingsson, S., Milner, P.F., Nagel, R.L., (1993) Am. J. Hematol., 43, p. 312Orkin, S.H., Kazazian Jr., H.H., Antonarakis, S.E., Goff, S.C., Boehm, C.D., Sexton, J.P., Waber, P.G., Giardina, P.J.V., (1982) Nature, 296, p. 627Kutlar, A., (1992) Hematol. Revs., 6, p. 17. , The β-Thalassemias: An Overview, Current Views of Thalassemia, edited by S. Roath and T.H.J. HuismanWeatherall, D.J., Clegg, J.B., (1981) The Thalassaemia Syndromes, 3rd Edition, , Blackwell Scientific Publications, OxfordFreitas, E.N., Rocha, F.J., (1983) Rev. Brasil. Genet, 4, p. 185Zago, M.A., Costa, F.F., Tone, L.G., Bottura, C., (1983) Hum. Hered., 33, p. 25Ramalho, A.S., (1976) Rev. Paul. Med., 88, p. 68Zago, M.A., Costa, F.F., Bottura, C., (1981) Braz. J. Med. Biol. Res., 14, p. 383Rosatelli, M.C., Tuveri, T., Scalas, M.T., Mosca, A., Galanello, R., Gasperini, D., Cao, A., (1991) Nouv. Rev. Fr. d'Haematol., 33, p. 441Saldanha, P.H., (1968) Boletim da Universidade de São Paulo, 248, p. 226Waye, J., Eng, B., Patterson, M., Wasi, P., Chui, D., Francombe, W., Sher, G., Olivieri, N., (1995) Am. J. Hematol., 50, p. 15Rund, D., Oron-Karni, V., Filon, D., Goldfarb, A., Rachmilewitz, E., Oppenheim, A., (1997) Am. J. Hematol., 54, p. 16Huisman, T.H.J., Reese, A.L., Gardiner, M.B., Wilson, J.B., Lam, H., Reynolds, A., Nagle, S., Sansone, G., (1983) Am. J. Hematol., 14, p. 133Huisman, T.H.J., Kutlar, F., Nakatsuji, T., Bruce-Tagoe, A., Kilinç, Y., Cauchi, M.N., Romero Garcia, C., (1985) Hum. Genet, 71, p. 127Masala, B., Formato, M., Manca, L., Demuro, P., Gallisai, D., Done, F., Longinotti, M., (1986) Acta Haematol., 76, p. 20