Diminished ^Aγ^T fetal globin levels in Sardinian haplotype II β°‐thalassaemia patients are associated with a four base pair deletion in the ^Aγ^T promoter

Abstract

In Sardinia, the beta-39 nonsense mutation is the primary cause of beta 0-thalassaemia. This mutation is found mainly on beta-globin gene cluster haplotypes I and II, which differ in their A gamma globin types (A gamma I and A gamma T, respectively). This report presents data on G gamma, A gamma I and A gamma T levels, and the presence or absence of a 4 base pair (bp) deletion at -225 to -222 of the A gamma globin promoter, in 55 poly-transfused beta 0-thalassaemia major patients. Six patients were homozygotes for the normal (N) A gamma promoter lacking the 4 bp deletion, had no A gamma T globin, and their mean G gamma:A gamma I: A gamma T ratio was 52.9:47.1:0. Twenty-five patients were homozygotes for the mutant (M) A gamma promoter with the 4 bp deletion, had no A gamma I globin, and the mean G gamma:A gamma I: A gamma T ratio was 62.1:0:37.9. For M/M compared to N/N, the lower A gamma T than A gamma I was significant by the t-test (P less than 0.001). Twenty-four N/M cases had mean G gamma:A gamma I:A gamma T of 56:24.4:19.6, and the lower A gamma T than A gamma I was also significant (P less than 0.001). Partial haplotype analysis on these and 17 other beta 0-thalassaemia patients suggested that the 4 bp deletion was strongly associated with haplotype II. Of 33 M/M, 32 were haplotype II/II and one was II/5a; of 31 N/M, 29 were I/II and two were II/IX; of eight N/N, seven were haplotype I/I and one was I/IX. These data show a strong association of the 4 bp promoter deletion with decreased expression of the A gamma T globin gene on haplotype II.

Native highland and lowland populations differ in .GAMMA.-globin gene promoter polymorphisms related to altered fetal hemoglobin levels and delayed fetal to adult globin switch after birth

“…One or more of the deleted AGCA nucleotides seem to contribute to the binding of the trans-acting factor (Beldjord et al, 1992). Therefore, the 4-bp deletion is associated with a reduced expression of HBG1 (Harvey et al, 1992), and newborns with this deletion showed a decreased level of total HbF (Manca et al, 1991;Beldjord et al, 1992). The 4-bp deletion not only affects the expression of the A γ globin gene HBG1, but also that of the G γ globin gene HBG2 (Coleman et al, 1994).…”

“…Diminished expression of A γ globin has been observed in subjects with a 4-basepair (bp) deletion of AGCA from nucleotide positions −222 to −225 in the promoter of the HBG1 gene (Gilman et al, 1988;Manca et al, 1991). This gene deletion affects the G γ: A γ ratio of both newborns and adults.…”

Fetal hemoglobin expression in the compound heterozygous state for ?117 (G?A)A? HPFH and IVSII-745 (C?G) ?+ thalassemia: A case study

“…The sister (II-2) was a simple IVSII-745 heterozygote with a T at −158 of the G ␥ promoter in one of the two alleles and 3.7% HbF. Genetic and molecular studies (Table II) T expression [19] and, as was expected, they were found negative since it has been reported that the 4-bp deletion is associated with haplotype II.…”

A novel four base-pair deletion within the A?-GLOBin gene promoter associated with slight increase of A? expression in adult

“…The higher G␥/A␥ ratio was hypothesized to be due to a decreased A␥ expression resulted from the 4 bp deletion, but it may also be explained by that an increasing anemic stress preferentially stimulates the G␥-globin gene [12]. By analyzing quantitatively the globin chains in the ␤ 0 -thalassemia individuals who had higher HbF levels (HbF > 3%), Nanca and Gelman et al further proved that the expression level of the A␥-globin gene with the 4 bp deletion (A␥ T ) was lower than that of the normal A␥ gene lacking the 4 bp deletion [13]. In the normal adults, HbF is usually lower than 1% of the total Hb and the A␥/G␥+A␥ is about 60%.…”

“…In the normal adults, HbF is usually lower than 1% of the total Hb and the A␥/G␥+A␥ is about 60%. In the ␤-thalassemia [11,13] cases, the A␥/G␥+A␥ was 33% [11] and 38% [13] that were indeed lower than the normal, but the HbF with A␥ type was still slightly higher than the normal adult (<0.6%) because the ␤-thalassemia patients had higher HbF levels. The exact mechanisms responsible for the high level of the G␥ and A␥ product in some ␤-thalassemia cases are not clear yet, nor have any cases been provided to show how the -225 to -222 deletion influences the the A␥-globin gene expression in the non-␤-thalssemia adult.…”