Hemoglobin subunit alpha 2 (HBA2) (HBA2)

Hemoglobin subunit alpha 2 (HBA2) is a critical protein-coding gene that, together with HBA1, produces the alpha-globin chains required for functional adult hemoglobin (HbA) [1]. The specific c.427T>C mutation, known as Hemoglobin Constant Spring (HbCS), is a non-stop mutation that converts the terminal stop codon (TAA) into a glutamine codon (CAA), resulting in an elongated and highly unstable alpha-globin mRNA and protein [2]. This instability leads to a severe deficiency of alpha-globin chains, causing alpha-thalassemia or Hemoglobin H disease, characterized by chronic hemolytic anemia and ineffective erythropoiesis [3]. In the context of patient-derived CD34+ hematopoietic stem and progenitor cells (HSPCs), this mutation is a primary target for ex vivo gene therapy and precision gene editing [4]. Therapeutic approaches utilize CRISPR/Cas9 or adenine base editors to precisely revert the C to T at position 427, restoring the natural stop codon and normal hemoglobin synthesis [5]. Successful modification of these stem cells allows for the long-term production of healthy red blood cells, offering a potential permanent cure for patients with this specific genetic variant [6]. [1] UniProt P69905; [2] NCBI ClinVar VCV000015457; [3] Weatherall DJ, et al. (2001) The Thalassemias; [4] Smith et al. (2023) Nature Communications; [5] Gaudelli NM, et al. (2017) Science; [6] Higgs DR, et al. (2010) Lancet.

Other names

Alpha-2 globinHBA-T2Hemoglobin alpha-2 chainHb Constant Spring mutationHBA2 c.427T>C

Correction of the c.427T>C point mutation using gene editing tools to restore the natural TAA stop codon, thereby stabilizing alpha-globin mRNA and protein expression.