title: Possible factors influencing the haemoglobin and fetal haemoglobin levels in patients with beta-thalassaemia due to a homozygosity for the IVS-I-6 (T-->C) mutation.
abstract: We have collected haematological, haemoglobin (Hb) and DNA sequence data for 29 patients with a homozygosity for the IVS-I-6 (T-->C) mutation with the intention of identifying factors contributing to the observed variability in the severity of the disease. None of the patients had received blood transfusion therapy for at least 6 months prior to the study. Hb levels varied from 5.0 to 9.9 g/dl. Patients with high Hb F (more than 1.5 g/dl or > 20%) had high total Hb levels (7.5-9.7 g/dl) but some with low Hb F also had high total Hb levels; two had a concomitant alpha-thalassaemia-2 (alpha-thal-2) heterozygosity. An inverse correlation between the Hb F and Hb A2 levels was observed. The majority of the patients were homozygous for haplotype VI (49/58 chromosomes) but haplotypes IV (2/58) and VII (7/58) were also present. The only haplotype IV homozygote had high Hb F levels with high G gamma values and the C-->T mutation at position -158 in the G gamma promoter, while both high and low Hb F levels were observed among patients with haplotypes VI and VII. Analysis of sequence variations in regulatory regions included the 5' hypersensitive sites (HS) 4. 3 and 2 of the locus control region (LCR), the G gamma and A gamma 5' flanking regions, the second intervening sequence (IVS-II), and the 5' beta-globin gene region in two patients with high Hb F (one homozygote each for haplotypes VI and IV), and in two patients with low Hb F levels (one homozygote each for haplotypes VI and VII). Haplotype specific differences were observed in the LCR 5' HS-2 and in the G gamma and A gamma flanking and IVS-II regions; however, no differences were present between the low and high Hb F-producing haplotype VI chromosomes, suggesting a major role for factors which are not linked to the beta-globin gene cluster in mediating gamma-globin gene expression in patients with this type of beta-thal.
authors.affiliation: Department of Biochemistry and Molecular Biology, Medical College of Georgia, Augusta 30912-2100.
authors.forename: D G
authors.initials: DG
authors.lastname: Efremov
authors.forename: A J
authors.initials: AJ
authors.lastname: Dimovski
authors.forename: E
authors.initials: E
authors.lastname: Baysal
authors.forename: Z
authors.initials: Z
authors.lastname: Ye
authors.forename: A D
authors.initials: AD
authors.lastname: Adekile
authors.forename: M L
authors.initials: ML
authors.lastname: Ribeiro
authors.forename: G
authors.initials: G
authors.lastname: Schiliro
authors.forename: C
authors.initials: C
authors.lastname: Altay
authors.forename: A
authors.initials: A
authors.lastname: Gürgey
authors.forename: G D
authors.initials: GD
authors.lastname: Efremov
mesh_terms: D000293:Adolescent; D000328:Adult; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D005260:Female; D005319:Fetal Hemoglobin / Q000032:analysis; D005914:Globins / Q000235:genetics*; D006443:Hemoglobin A2 / Q000032:analysis; D006454:Hemoglobins / Q000032:analysis*; D006720:Homozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D017086:beta-Thalassemia / Q000097:blood* / Q000235:genetics*
chemical_list: D006454:Hemoglobins; D005914:Globins; D006443:Hemoglobin A2; D005319:Fetal Hemoglobin