An initiation codon mutation (AUG → GUG) of the human α1-globin gene: Structural characterization and evidence for a mild thalassemic phenotype

Abstract

α-globin is encoded by two adjacent genes, α1 and α2. Recent evidence suggests that these genes are not equally expressed and that the α2-globin gene encodes the majority of α-globin. This finding would predict that a thalassemic mutation of the α2-globin gene would result in a more severe loss of α-chain synthesis than a similar mutation in the α1-globin gene. In a previous study we described a nondeletion α-thalassemia defect in the α2-globin gene resulting from an AUG → ACG initiation codon mutation. In the present study we describe a different initiation codon mutation, AUG → GUG, present in the α1-globin gene. The α1- and α2-globin gene initiation codon mutations result in similarly lowered levels of encoded mRNA. Despite the similarity of these two mutations, the α2 mutant results in a more severe loss of α-globin synthesis and a more severe clinical α-thalassemia phenotype than the corresponding α1-globin gene mutation. This difference reflects the dominant role of α2-globin gene in overall α-globin synthesis.