The molecular basis of β-thalassemia

Abstract

The β-thalassemias are characterized by a quantitative deficiency of β-globin chains underlaid by a striking heterogeneity of molecular defects. Although most of the molecular lesions involve the structural β gene directly, some down-regulate the gene through distal cis effects, and rare trans-acting mutations have also been identified. Most β-thalassemias are inherited in a Mendelian recessive fashion but there is a subgroup of β-thalassemia alleles that behave as dominant negatives. Unraveling the molecular basis of β-thalassemia has provided a paradigm for understanding of much of human genetics.

Figure 1.

Mutations causing β-thalassemia. The upper panel depicts the β-globin gene cluster with the upstream locus control region (βLCR). The mutations can be cis-acting and include point mutations affecting the structural β gene, deletions restricted to the β gene, and large deletions involving the βLCR with or without the β gene. The dashed lines represent variations in the amount of flanking DNA removed by the deletions—detailed in Figures 3 and 4, respectively.

Figure 2.

Point mutations causing β-thalassemia. The β-globin gene is depicted in the upper panel with conserved sequences in the 5′ and 3′ UTRs, and the invariant dinucleotides in exon–intron junctions of the gene, important in the control of gene expression. The boxes represent the different categories of mutants. The vertical lines within the boxes represent the sites of the different mutations. Dominantly inherited mutants are found within shaded boxes.

Figure 3.

β-thalassemia deletions that are restricted to the gene. The vertical bar indicates the promoter region that is removed in common by these deletions except for the 619 bp Asian Indian and the 7.7 kb Cape Verde deletions.

Figure 4.

Deletions causing β-thalassemia as part of (εγδβ)⁰-thalassemia. The deletions can be classified into two groups: group I deletions (in black) remove all or most of the cluster including the βLCR and the β-globin gene, whereas group II deletions remove all or part of βLCR leaving the β gene intact. Only about one-third of the breakpoints of these deletions have been defined; the white boxes and jagged ends indicate undefined breakpoints.