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β ‐thalassaemia‐87 C→G: relationship of the Hb F modulation and polymorphisms in compound heterozygous patients
Author(s) -
De Angioletti Maria,
Lacerra Giuseppina,
Pagano Leonilde,
Alessi Mario,
D'Avino Rossana,
Manca Laura,
Carestia Clementina
Publication year - 2004
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1111/j.1365-2141.2004.05089.x
Subject(s) - compound heterozygosity , haplotype , medicine , heterozygote advantage , fetal hemoglobin , hemoglobinopathy , endocrinology , biology , gene , mutation , microbiology and biotechnology , genotype , genetics , hemolytic anemia , fetus , pregnancy
Summary 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 G γ ( G γ / Total γ 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 G γ ‐globin gene, T‐A‐G in pre‐ G γ framework, (TG) 11 (CG) 3 in the G γ ‐IVS2, (AT) 9 N 12 (AT) 10 in LCR‐HS2; in contrast, the haplotype V had, respectively, ‘C’, T‐G‐A (TG) 19 (CG) 2 CACG in the G γ ‐IVS2, and (AT) 10 N 12 (AT) 11 . In all patients the β ‐87 was associated with the (AT) 9 T 5 motif 5′ β ‐globin gene with increased affinity for the BP‐1 protein, and with the (TG) 13 in the A γ ‐IVS2. The high increase of the Hb F, mostly of the G γ ‐type, strongly suggests the hypothesis that the ‘T’−158 G γ 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.