Globin structural mutant α125Leu→Pro is a novel cause of α-thalassaemia

The duplicated human α-globin structural loci lie on chromosome 16 and are arranged in the order 5′ α2−αl 3′. Although the most common molecular mechanism for α-thalassaemia is deletion of segments of DNA that contain one or both of these α-globin structural loci1, two molecular lesions that are not due to gross gene deletion have been defined. In one, a point mutation in the termination codon of the α2 gene results in the production of an elongated α-globin chain2,3. As only a small amount of the mutant globin chain is produced, α-thalassaemia results. The second lesion, which is caused by a 5-base pair (bp) deletion in the first intervening sequence of the α2 gene, results in abnormal mRNA processing and α-globin chain deficiency4. We now describe a novel mechanism for α-thalassaemia not involving deletion. A single nucleotide mutation in the coding region of the α2 gene results in the substitution of proline (Pro) for leucine (Leu) in a region of the H helix of the α-globin chain, which is critical for αl−βl contact. This probably impedes α1−β1 dimer formation, the initial step of haemoglobin tetramer assembly, and produces an α-thalassaemia phenotype.