Molecular basis of β-thalassemia

Abstract

The β-thalassemias are a group of autosomal recessive disorders resulting from defective or absent production of β-globin chains from the β-globin locus. This disorder is very heterogeneous at the molecular level. At least 150 different mutations have been defined to date. Homozygosity or compound heterozygosity for β-thalassemia usually results in the clinical picture of a severe transfusion-dependent anemia, referred to as thalassemia major. However, in a consistent proportion of the cases, approx. 10% of the total, homozygous β-thalassemia produces a milder clinical condition not requiring continuous transfusion, which is referred to as thalassemia intermedia. Studies carried out in the last few years have, at least partially, elucidated the molecular bases of these attenuated forms of the disorder. Inherited modifying factors so far recognized are: a) the presence of a mild β-thalassemia mutation, namely a mutation associated with a consistent residual output of β-globin chains from the affected locus in homozygosity or compound heterozygosity with a severe mutation; b) the coinheritance of α-thalassemia or some genetic determinants able to sustain a continuous production of γ-chains in adult life. More rarely thalassemia intermedia results from double heterozygosity for β-thalassemia and the triple α-globin gene of from the presence of a hyperunstable hemoglobin. Likewise, homozygous β-thalassemia, even the hematological phenotype of heterozygous β-thalassemia may be modified consistently by inherited modifying factors, in such a way as to confuse the hematological diagnosis. The best characterized modifying factors defined to date are coinherited δ and α-thalassemia. These findings indicate that even a single gene disorder like β-thalassemia may be in a certain sense considered a polygenic condition.