Summary
By using oligonucleotide hybridization, restriction endonuclease analysis and direct sequencing of amplified genomic DNA, we have been able to characterize 18 different mutations in the β-globin genes of 161 β thalassemia homozygotes and 107 β-thalassemia heterozygotes from Turkey (429 β-thalassemia chromosomes). Previous studies dealing with β-thalassemia in Mediterranean countries have shown that, in most Mediterranean populations, only a few mutations are prevalent. In contrast, β-thalassemia in Turkey does not seem to be associated with a few predominant mutations. The six most frequent alleles, IVS-I-110 (G→A), IVS-I-6(T→C), FSC-8 (-AA), IVS-I-1(G→A), -30(T→A) and FSC-5 (CT), account for only 69.3% of the disease genes; indeed, all 26 mutations assayed represent 85.8% of the disease genes, confirming the considerable molecular heterogeneity of β-thalassemia among Turks, and indicating the possible presence of rare, previously undefined, mutations in the population. Two mutations observed in this study, IVS-I-116 (T→G) and Cd44(-C), have not been reported in the Turkish population to date. Since preventive medical services, such as genetic counseling and prenatal diagnosis, are greatly improved by detailed knowledge of the molecular pathology of β thalassemia, we strongly believe that the presented data will facilitate the intended establishment of a prenatal diagnosis center, based on DNA analysis, in Turkey.
Similar content being viewed by others
References
Akar N, Çavdar AO, Dessi E, Loi A, Pirastu M, Cao A (1987) β Thalassemia mutations in the Turkish population. J Med Genet 24:378–381
Aksoy M, Dinçol G, Erdem Ş (1978) Different types of β-thalassemia intermedia. Genetic study in twenty patients. Acta Hematol 59:178–189
Aksoy M, Kutlar A, Kutlar F, Dinçol G, Erdem Ş, Baştesbihçi Ş (1985) Survey on hemologlobin variants, β+-thalassemia, glucose-6-phosphate-dehydrogenase deficiency and haptoglobin types in Turks from Western Thrace. J Med Genet 22:288–290
Amselem S, Nunes V, Vidaud M, Estivill X, Wong C, D'Auriol L, Vidaud D, Galibert F, Baiget M, Goosens M (1988) Determination of the spectrum of β-thalassemia genes in Spain by use of dot-blot analysis of amplified β-globin DNA. Am J Hum Genet 43:95–100
Angastiniotis MA, Hadjimanis MG (1981) Prevention of thalassemia in Cyprus. Lancet I:369–371
Arcasoy A, Çavdar AO, Cin Ş, Gözdaşoğlu S, Babacan E, Erten J, Ertem U, Göğüs S (1978) Türkiye'de thalassemi ve anormal hemoglobin insidansi. (Incidence of thalassemia and abnormal hemoglobins in Turkey) Tübitak, Ankara, Nuray Matbaasi
Aulehla-Scholz C, Başaran S, Ağaoğlu L, Arcasoy A, Holzgreve W, Miny P, Ridolfi F, Horst J (1990) Molecular basis of β thalassemia in Turkey: detection of rare mutations by direct sequencing. Hum Genet 84:195–197
Başaran N, Şayli BS, Başaran A, Artan S, Stevenson JD (1988) Consanguineous marriages in the Turkish population. Clin Genet 34:339–341
Cao A, Pintus L, Lecca U, Olla G, Cossu P, Rosatelli C, Galanello R (1984) Control of homozygous β-thalassemia by carrier-screening and antenatal diagnosis in Sardinians. Clin Genet 26:12–22
Cao A, Goossens M, Pirastu M (1989) β-Thalassemia mutations in Mediterranean populations. Br J Haematol 71:309–312
Çavdar AO, Arcasoy A (1971) The incidence of β-thalassemia and abnormal hemoglobins in Turkey. Acta Haematol 45:312
Chehab FF, Der Kaloustian V, Khouri FP, Deeb SS, Kan YW (1987) The molecular basis of β-thalassemia in Lebanon. Application to prenatal diagnosis. Blood 69:1141–1145
Coutinho-Gomes MP, Gomes da Costa MG, Braga LB, Cordeiro Ferreira NT, Loi A, Pirastu M, Cao A (1988) β-Thalassemia mutations in the Portuguese population. Hum Genet 78:13–15
Diaz-Chico JC, Yang KG, Stoming T, Efremov GD, Kutlar A, Aksoy M, Altay C, Gürgey A, Kilinc Y, Huisman THJ (1988a) Mild and severe β-thalassemia among homozygotes from Turkey: identification of the types of hybridization of amplified DNA with synthetic probes. Blood 71:248–251
Diaz-Chico JC, Yang KG, Yang KY, Efremov GD, Stoming TA, Huisman THJ (1988b) The detection of β-globin gene mutations in β-thalassemia using oligonucleotide probes and amplified DNA. Biochim Biophys Acta 949:43–48
Dimovski A, Efremov DG, Jankovic L, Juricic D, Zisovski N, Stojanovski N, Nikolov N, Petkov GT, Reese AL, Stoming AA, Efremov GD, Huisman THJ (1990) β-Thalassemia in Yugoslavia. Hemoglobin 14:15–24
Erlich HA, Gelfand DH, Saiki RK (1988) Specific DNA amplification. Nature 331:641
Gonzalez-Redonod JM, Stoming TA, Kutlar A, Kutlar F, Lanclos LKD, Howard EF, Fei YJ, Aksoy M, Altay Ç, Gürgey A, Başak AN, Efremov GD, Petkov G, Huisman THJ (1989) A C-T substitution at nt -101 in a conserved DNA sequence of the promoter region of the β-globin gene is associated with “silent” β-thalassemia. Blood 73:1705–1711
Gürgey A (1986) Thalassemi ve hemoglobinopatilerde yeni göruşler. (New perspectives on thalassemias and hemoglobinopathies) Tübitak Yayinlari, Tip Araştirma Grubu, Ankara
Gürgey A, Altay Ç, Diaz-Chico JC, Kutlar F, Kutlar A, Huisman THJ (1989) Molecular heterogeneity of β-thalassemia intermedia in Turkey. Acta Hematol 81:22–27
Gyllensten VB, Erlich HA (1988) Generation of single-stranded DNA by the polymerase chain reaction and its application to direct sequencing of the HLA-DQA locus. Proc Natl Acad Sci USA 85:7652–7656
Hadji A, Papadakis M, Antsaklis A, Mesoghitis S, Loukopoulos D, Fessas P (1987) Prevention of thalassemias in Greece. Prenatal Diagnosis, Second International Conference on thalassemia and the hemoglobinopathies, Island of Crete, Greece 1987, abstract RT7–56, II
Huisman THJ (1989) β-Thalassemia repository. Hemoglobin 13:775–787
Huisman THJ (1990) β-Thalassemia in four Mediterranean countries: an editorial commentary. Hemoglobin 14:35–39
Kattamis C, Hu H, Cheng G, Reese AL, Gonzalez-Redondo JM, Kutlar A, Kutlar F, Huisman THJ (1990) Molecular characterization of β-thalassemia in 174 Greek patients with thalassemia major. Br J Haematol 74:342–346
Kazazian HH Jr (1990) The thalassemia syndromes: molecular basis and prenatal diagnosis in 1990. Semin Hematol 27:209–228
Kazazian HH Jr, Boehm CD (1988) Molecular basis and prenatal diagnosis of β-thalassemia. Blood 72:1107–1116
Kogan SC, Doherty M, Gitschier J (1988) An improved method for prenatal diagnosis of genetic diseases by analysis of specifically amplified polymorphic sequences: application to hemophilia A. N Engl J Med 317:985–990
Kulozik AE, Lyons J, Kohne E, Bartram CR, Kleinhauer E (1988) Rapid and non-radioactive prenatal diagnosis of β-thalassemia and sickle cell disease: application of the polymerase chain reaction (PCR). Br J Haematol 70:455–458
Milland M, Berge-Lefranc JL, Lena D, Cartouzou G (1987) Oligonucleotide screening of β-thalassemia mutations in the south east of France. Hemoglobin 11:317–327
Miller SA, Dykes DD, Polesky HF (1988) A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res 16:1215
Öner R, Altay Ç, Gürgey A, Aksoy M, Kilinç Y, Stoming TA, Reese AL, Kutlar A, Kutlar F, Huisman THJ (1990) β-Thalassemia in Turkey. Hemoglobin 14:1–13
Orkin SH, Markham AF, Kazazian HH Jr (1983) Direct detection of the common Mediterranean β-thalassemia genes with synthetic DNA probes: an alternate approach for prenatal diagnosis. J Clin Invest 71:775–780
Petkov GH, Efremov GD, Efremov DG, Dimovski A, Tchaicarova P, Tchaicarov R, Rogina BG, Agarwal S, Kutlar A, Kutlar F, Reese AL, Stoming TA, Huisman THJ (1990) β-Thalassemia in Bulgaria. Hemoglobin 14:25–33
Pirastu M, Kan YW, Cao A, Conner BJ, Teplitz RL, Wallace RB (1983) Prenatal diagnosis of β-thalassemia: detection of a single nucleotide mutation in DNA. N Engl J Med 309:284–290
Poncz M, Solowiejczky D, Harpel B, Mory Y, Schwartz E, Surrey S (1982) Construction of human gene libraries from small amounts of peripheral blood. Hemoglobin 6:27–36
Rosatelli C, Tuveri T, Di Tucci A, Falchi AM, Scalas MI, Monni G, Cao A (1985) Prenatal diagnosis of β-thalassemia with the synthetic oligomer technique. Lancet I:241–243
Rosatelli C, Leoni GB, Tuveri T, Scalas MT, Di Tucci A, Cao A (1987) β-Thalassemia mutations in Sardinians: implications for prenatal diagnosis. J. Med Genet 24:97–100
Rund D, Cohen T, Filon D, Dowling CE, Warren TC, Barak I, Rachmilewitz E, Kazazian HH Jr, Oppenheim A (1991) Evolution of a genetic disease in an ethnic isolate: β-thalassemia in the Jews of Kurdistan. Proc Natl Acad Sci USA 88:310–314
Saiki RK, Gelfand DH, Stoffel S, Scharf SJ, Higuchi R, Horn GT, Mullis KB, Erlich HA (1988) Primer-directed enzymatic amplification of DNA with a thermostable DNA polymerase. Science 239:487–491
Sözüöz A, Berkalp A, Figus A, Loi A, Pirastu M, Cao A (1988) β Thalassemia mutations in Turkish Cypriots. J Med Genet 25:766–768
Spiegelberg R, Aulehla-Scholz C, Erlich H, Horst J (1989) A β thalassemia gene caused by a 290-bp deletion. Analysis by direct sequencing of amplified DNA. Blood 73:1695–1698
Stoming TA, Diaz-Chico JS, Yang KG, Efremov GD, Huisman THJ (1988) Newer developments in the identification of β thalassemia mutations. Hemoglobin 12:565–576
Wainscoat JS, Old JM, Weatherall DJ, Orkin SH (1983) The molecular basis for the clinical diversity of β-thalassemia in Cypriots. Lancet I:1235–1237
Wong C, Dowling CD, Saiki RD, Higuchi RG, Erlich HA, Kazazian HH Jr (1987) Characterization of β-thalassemia mutations using direct genomic sequencing of amplified single copy DNA. Nature 330:384–386
Wrischnik LA, Higuchi RG, Stoneking M, Erlich HA, Arnheim N, Wilson AC (1987) Direct sequencing of enzymatically amplified DNA. Nucleic Acids Res 15:529
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Başak, A.N., Özçelik, H., Özer, A. et al. The molecular basis of β-thalassemia in Turkey. Hum Genet 89, 315–318 (1992). https://doi.org/10.1007/BF00220549
Received:
Revised:
Issue Date:
DOI: https://doi.org/10.1007/BF00220549