Possible factors influencing the haemoglobin and fetal haemoglobin levels in patients with β‐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.

Spectrum of β‐thalassemia in Jordan: Identification of two novel mutations

“…These alleles were IVS1-110 (G>A), codon 39(C>T), codon 6 (-A) IVS2-1 (G>A), codon 5 (-CT), IVS2-745, and IVS1-1 (G>A). The small number of detected IVS1-6 (T>C) homozygotes in this study seemed to be partly due to the mild clinical course of the disease produced in homozygotes of this allele [41] that often leads to transfusion-independent phenotypes [42][43][44] and consequently, to under representation of this and other mild mutations such as the substitutions at positions −87 and −29.…”

Spectrum of β thalassemia mutations and HbF levels in the heterozygous Moroccan population

“…The latter opposes the rarity of ␤ + IVS1,nt110 (2%), in association with haplotype I, as in Algeria [30], Tunisia [31], and Portugal [18,32], supporting the idea of a recent introduction in the Moroccan genetic background. The third most frequent mutation is ␤ + IVS1,nt6 (T→C) (14%) in haplotypes VI and VII as described in Portugal [18,32,33], whereas in Algeria, Tunisia, and Egypt it is associated with haplotype VI [34,35]. ␤ 0 IVS1,nt1 (G→A), found mostly in Berbers in Algeria associated with haplotypes I, III, V, IX, and A [36,37], is found in Morocco in haplotypes IV and V with a frequency of 13%.…”

Fetal hemoglobin chemical inducers for treatment of hemoglobinopathies

“…This polymorphism, which is common in all population groups with a frequency of about 0.35 [25], has been shown to increase the G γ/( G γ+ A γ) ratio and to be associated with increased HbF levels under conditions of erythroid expansion, as observed in β-thalassemia and sickle cell anemia [28]. As the result of two genetic conversion events, the −158 C a T change was observed in the promoter of both G γ and A γ genes in healthy subjects with slightly elevated HbF levels [29].…”