Compensatory increase in α1-globin gene expression in individuals heterozygous for the α-thalassemia-2 deletion

Abstract

α-Globin is encoded by the two adjacent genes, α1 and α2. Although it is clearly established that both α-globin genes are expressed, their relative contributions to α-globin messenger RNA (mRNA) and protein synthesis are not fully defined. Furthermore, changes that may occur in α-globin gene activity secondarily to the loss of function of one or more of these genes (α-thalassemia [Thal]) have not been directly investigated. This study further defines the expression of the two human α-globin genes by determining the relative levels of α1 and α2 mRNA in the reticulocytes of normal individuals and in individuals heterozygous for the common j3.7-kilobase deletion within the α-globin gene cluster that removes the α2-globin gene (the rightward type α-Thal-2 deletion). To quantitate accurately the ratio of the two α-globin mRNAs, we have modified a previously reported S1 nuclease assay to include the use of 32P end-labeled probes isolated from α1 - and α2-globin complementary DNA recombinant plasmids. In individuals with a normal α-globin genotype (as determined by Southern blot analysis [αα/αα]), α2-globin mRNA is present at an average 2.8-fold excess to α1. In individuals heterozygous for the rightward type α-Thal-2 deletion (-α/αα) the α2/α1 mRNA ratio is 1:1. These results suggest that the loss of the α2-globin gene in the α-Thal-2 deletion is associated with a 1.8-fold compensatory increase α1-globin gene expression.