Genotype-phenotype association analysis identifies the role of α globin genes in modulating disease severity of β thalassaemia intermedia in Sri Lanka.
To evaluate the therapeutic potential we crossed the transgenic mice carrying a single copy activated δ-globin gene with a mouse model of β-thalassemia intermedia.
The combination of these alleles with severe beta-thalassemia genotypes leads to the phenotype of beta-thalassemia intermedia even though there are no any attenuating factors such as XmnI Gg polymorphism at position -158 of the HBG2 promotor or the alpha-globin defects.
Expression of gamma-globin RNA at a modest 7-14% of total alpha-globin RNA resulted in the selective survival of HbF(+) erythrocytes, a fivefold increase in total HbF, and a phenotypic improvement in the beta-thalassaemia intermedia model.
The clinical course of the 2 propositi underlines the importance of full genotyping and a long period of observation before treatment is instituted, particularly in patients with beta thalassemia intermedia associated with extended alpha globin gene arrangements.
Triplication of alpha-globin gene and heterozygosity for beta0-thalassemia accounted for 15% of beta-thalassemia intermedia patients at our locality and was associated with a mild clinical phenotype.
This compound heterozygous condition of a beta39 C-to-T mutation and triplicate alpha-globin gene increases alpha:beta-globin chain imbalance and accounts for the presence of beta-thalassemia intermedia.
Variations in the number of alpha-globin genes resulted in modifications of the phenotypical expression of the beta-thalassemia intermedia determinants.