Nucleotide changes in the gamma-globin promoter and the (AT)xNy(AT)z polymorphic sequence of beta LCRHS-2 region associated with altered levels of HbF.

We have studied 31 beta-thalassaemia intermedia, 30 beta-thalassaemia major patients and 50 normal individuals from Turkey, determining the relationship between the nucleotide variations in beta-globin gene cluster, the altered levels of foetal haemoglobin and the relative ratios of beta- and gamma mRNAs. We have found in beta-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 G gamma - 1396, the T-->C at A gamma - 228, and the GA-->AG at A gamma - 603/4, are linked to haplotype II in haplotypic homozygotes and the (AT)8N14(AT)7 motif in beta LCR. Conversely, the three single nucleotide substitutions in the 5' sequences of gamma globin genes, the G-->A at G gamma - 1225, the A-->G at A gamma + 25 and the C-->G at A gamma - 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 beta LCR are all associated with low foetal haemoglobin levels. The number of nucleotide changes in beta-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 beta thalassaemia intermedia and major patients with other yet unknown gene conversions.