β-thalassaemia-87 C → G: Relationship of the Hb F modulation and polymorphisms in compound heterozygous patients

Abstract

A clinical, haematological, biochemical and molecular study was carried out in 17 patients affected with thalassaemia intermedia, who were compound heterozygotes for the β-thalassaemia mutation β-87 C → G to determine the genetic basis of their clinical heterogeneity. The β-87 was found associated with haplotype VIII (β-87/VIII) or V (β-87/V). The 10 patients with the β-87/VIII showed milder clinical conditions, with significantly higher levels of haemoglobin (Hb) (9.8 ± 1.1 g/dl vs. 8.5 ± 1.3 g/dl) and fetal haemoglobin (Hb F) (6.2 ± 1.5 g/dl vs. 2.6 ± 1.5 g/dl; P = 0.034) and higher synthesis of Gγ ( Gγ/Totalγ 69.4 ± 2.6% vs. 42.8 ± 16.2%; P = 0.0042) than the seven patients with the β-87/V. The β-87/VIII showed a configuration of rare polymorphisms in the 5′ sub-haplotype, which have been reported to exert an increasing effect on Hb F. They were 'T' -158 Gγ-globin gene, T-A-G in pre- Gγ framework, (TG)11(CG)3 in the Gγ-IVS2, (AT)9N12(AT)10 in LCR-HS2; in contrast, the haplotype V had, respectively, 'C', T-G-A (TG)19(CG) 2CACG in the Gγ-IVS2, and (AT)10N 12(AT)11. In all patients the β-87 was associated with the (AT)9T5 motif 5′ β-globin gene with increased affinity for the BP-1 protein, and with the (TG)13 in the Aγ-IVS2. The high increase of the Hb F, mostly of the Gγ-type, strongly suggests the hypothesis that the 'T' -158 Gγ plays a principal role and that the other polymorphisms could exert a cooperative role in the modulation of Hb F in patients with erythropoietic stress.