Alpha-globin locus (HBA locus)

The alpha-globin locus is a critical genomic region located on chromosome 16 (16p13.3) that contains the HBA1 and HBA2 genes, which are responsible for encoding the alpha-globin subunits of human hemoglobin. In healthy hematopoietic stem and progenitor cells (HSPCs), the expression of this locus is tightly regulated to maintain a 1:1 stoichiometric ratio with beta-globin chains, ensuring the formation of stable hemoglobin tetramers. In the context of beta-thalassemia, a deficiency in beta-globin leads to a relative excess of alpha-globin chains, which precipitate and cause oxidative damage to erythroid precursors, resulting in ineffective erythropoiesis. Consequently, the alpha-globin locus has become a primary target for therapeutic gene editing; by downregulating alpha-globin production through the disruption of the genes or their distal enhancers (such as MCS-R2), researchers aim to restore the globin balance and alleviate disease symptoms. Current experimental approaches utilize advanced genetic tools like CRISPR-Cas9 and base editors to modify patient-derived HSPCs ex vivo before re-infusion. This strategy represents a promising curative pathway for patients with severe hemoglobinopathies by improving the survival and functionality of mature red blood cells.

Other names

HBA1/HBA2 gene clusterHemoglobin subunit alpha locus16p13.3 locusAlpha-globin gene clusterHBZ-HBM-HBA2-HBA1-HBQ1 cluster

Reduction of alpha-globin chain synthesis via gene disruption or enhancer deletion to mitigate alpha/beta-globin chain imbalance in beta-thalassemia, or restoration of alpha-globin expression via gene addition/correction in alpha-thalassemia.