De Angioletti, Maria and Lacerra, Giuseppina and Pagano, Leonilde and Alessi, Mario and D'Avino, Rossana and Manca, Laura and Carestia, Clementina (2004) Beta-thalassaemia-87 C→G: relationship of the Hb F modulation and polymorphisms in compound heterozygous patients. British Journal of Haematology, Vol. 126 (5), p. 743-749. eISSN 1365-2141. Article.
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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 = 0·0034) 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)10N12(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.
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