Hemoglobin subunit beta (HBB) IVS2-654 mutation site (HBB IVS2-654)

The HBB IVS II-654 genomic locus is a specific site of mutation within the second intron of the hemoglobin subunit beta (HBB) gene, located on chromosome 11 (HbVar ID: 831). A C-to-T transition at this position (c.316-197C>T) creates a novel 5' splice site that activates a cryptic 3' splice site upstream, leading to the inclusion of a 73-nucleotide intronic fragment in the mature mRNA (Kole et al., 1993, Proc Natl Acad Sci U S A). This inclusion causes a frameshift and a premature stop codon, preventing the synthesis of functional beta-globin protein and resulting in beta-thalassemia, a severe blood disorder characterized by anemia (Suwanmanee et al., 2002, Mol Ther). This locus is a significant therapeutic target for precision medicine, particularly for patients of East Asian descent where the mutation is prevalent. Therapeutic strategies include the use of splice-switching antisense oligonucleotides (SSOs) to mask the cryptic splice sites and restore normal splicing, as well as advanced gene-editing tools like CRISPR/Cas9 and base editors to correct the mutation at the genomic level (Li et al., 2022, Nat Commun). By restoring the production of normal beta-globin, these treatments aim to increase functional adult hemoglobin (HbA) levels and alleviate the clinical symptoms of the disease.

Other names

HBB:c.316-197C>TIVS-II-654 (C>T)Beta-globin intron 2 mutationHBB IVS2-654 locus

Correction of aberrant RNA splicing or direct genomic correction of the C-to-T mutation to restore functional beta-globin synthesis.