Nucleotide changes in the γ-globin promoter and the (AT)(x)N(y)(AT)(z) polymorphic sequence of βLCRHS-2 region associated with altered levels of HbF

Abstract

We have studied 31 β-thalassaemia intermedia, 30 β-thalassaemia major patients and 50 normal individuals from Turkey, determining the relationship between the nucleotide variations in β-globin gene cluster, the altered levels of foetal haemoglobin and the relative ratios of β- and γ mRNAs. We have found in β-thalassaemia intermedia patients with high foetal haemoglobin expression that the three nucleotide variations in the 5' sequences of the gamma globin genes, A→G at Gγ-1396, the T→C at Aγ-228, and the GA→AG at Aγ-603/4, are linked to haplotype II in haplotypic homozygotes and the (AT)8N14(AT)7 motif in βLCR. Conversely, the three single nucleotide substitutions in the 5' sequences of gamma globin genes, the G→A at Gγ - 1225, the A→G at Aγ + 25 and the C→G at Aγ - 369, which have a strong linkage with haplotype I, V or VI in haplotypic homozygotes and the (AT)10N12(AT)12 and the (AT)9N12(AT)12 motifs in HS-2 of βLCR are all associated with low foetal haemoglobin levels. The number of nucleotide changes in β-globin gene cluster implied in our study are not the primary cause of the differences in haemoglobin F levels. They perhaps may contribute to the variations in the clinical severity observed among β thalassaemia intermedia and major patients with other yet unknown gene conversions.