Among 7,153 samples studied for beta-thalassemia, 205 samples with lower than expected HbA2 levels were selected for our analysis and 183 samples (2.5%) were positive for delta-globin gene mutations.
We report the clinical and hematological data and the molecular analysis and discuss the occurrence of alpha-globin genes duplication defects in cases of beta-thalassemia heterozygotes with thalassemia intermedia phenotypes.
Several members had additional beta-chain abnormalities (Hb S, Hb D-Los Angeles, beta-thalassaemia); the 11 persons with a Hb S heterozygosity and various alpha-globin gene defects (-alpha/alpha alpha; alpha T alpha/alpha alpha, - -/alpha alpha, -alpha/-alpha and - -/alpha T alpha) showed a decrease in the level of Hb S that was directly related to the severity of the alpha-chain deficiency.
Characterization of the beta-thalassemia mutation in combination with alpha-globin mapping and haplotype analysis may allow a better estimate of the probability of a given clinical phenotype, thus permitting more accurate counseling.
In alpha-thalassemia, alpha/beta-globin mRNA ratio correlated with the number of functional alpha-globin genes present, whereas in beta-thalassemia, the ratio provided a good indicator of disease severity.
Comparison of the beta-globin gene cluster haplotypes, alpha globin genotypes and beta gene mutations of the thalassaemia major group with the thalassaemia intermedia group suggests that the co-inheritance of a high Hb F determinant associated with the - + - + + 5' beta haplotype and the inheritance of a mild beta-thalassaemia mutation are the major ameliorating factors of disease severity in Asian Indians.
We report the clinical, haematological, biosynthetic and molecular data in three beta-thalassaemia heterozygotes with the rare interaction of homozygosity for alpha-globin gene triplication, and in 17 heterozygotes with a single additional alpha-globin gene.
During a screening program to identify at risk couples for beta-thalassemia first-trimester prenatal diagnosis, we were able to detect, by polymerase chain reaction (PCR) and direct genomic sequencing of the PCR product, a homozygosis for the G-T substitution at the first nucleotide of codon 27 of the delta-globin gene in a pregnant Sicilian woman.
It has been estimated that 13% to 33% of Sardinians carry a mutant allele of the alpha-globin gene (alpha-thalassemia trait) and that 6% to 17% are beta-thalassemia carriers.
Therefore, it can be concluded that the high HbF concentration in the present study is predominantly associated with other mutations associated with β‑thalassemia rather than α‑globin deletions.
In particular, HbA(2) determination plays a key role in screening programs for beta-thalassemia because a small increase in this fraction is one of the most important markers of beta-thalassemia heterozygous carriers.
The transgenic mouse model described in this report should be very useful for the study of human alpha-globin gene regulation and for the development of strategies to down regulate alpha-globin production as a means of ameliorating the severity of beta-thalassaemia.
A large body of clinical, genetic, and experimental evidence suggests that altering globin chain imbalance by reducing the production of α-globin synthesis ameliorates the disease severity in patients with β-thalassemia.
The severe clinical phenotype seemed to be related to the considerable excess of the α-globin and the β-globin deficit caused by the presence of the β-thalassemia.
The presence of triplicated alpha-globin genes should always be considered in apparent beta-thalassemia carriers who were more symptomatic than expected, so that unnecessary investigations for the cause of anemia could be avoided.
It has been suggested that variations in the structure or amounts of a highly expressed red cell protein (alpha hemoglobin stabilizing protein [AHSP]), which can stabilize free alpha globin chains in vitro, could influence disease severity in patients with beta thalassemia.
Alpha thalassemia is caused by reduced or absent synthesis of alpha globin chains, and beta thalassemia is caused by reduced or absent synthesis of beta globin chains.
Suggestions proposing that the protein AHSP, a alpha-globin specific chaperone could influence disease severity in patients with beta-thalassemia, an inherited disorder characterized by a quantitative deficiency of beta-globin genes.