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The New -474(C→T) Substitution Discovered in the HBG2 Promoter of a Sardinian δβ-Thalassemia Carrier

During a screening for hemoglobinopathies, we found a carrier of the Sardinian δβ-thalassemia condition. The proband's hematology and hemoglobin (Hb) profile agreed with those of the other carriers previously identified during our diagnostic program except for the fetal Hb (HbF) composition, which consisted of both α<sub>2</sub><sup>A</sup>γ<sub>2</sub> and α<sub>2</sub><sup>G</sup>γ<sub>2</sub> instead of nearly 100% α<sub>2</sub><sup>A</sup>γ<sub>2</sub>. In order to explain the unusual γ-chain ratio, sequencing of the <sup>G</sup>γ promoter was carried out and revealed two nucleotide substitutions in cis: C→T at position -474 and A→G at position -309 from the Cap site. The latter had previously been observed in subjects with raised HbF levels, although it has not yet been evaluated at functional level. We used the luciferase assay to determine whether the two mutations modify the transcriptional activity of the <sup>G</sup>γ promoter. Results indicated that the observed in vivo <sup>G</sup>γ-globin production cannot be translated into increased in vitro promoter function, suggesting that the assessed mutations cannot be considered as functional single nucleotide polymorphisms per se; instead, a more complex regulatory mechanism might be involved.