Abstract
Hereditary persistence of fetal hemoglobin (HPFH) is associated with a high level of hemoglobin F (HbF) synthesis in adult heterozygotes. In this study, 2 of 6 unrelated HPFH Thai families were found to be Southeast Asian-type HPFH (SEA-HPFH) by analyses of the hematologic data and Southern blot hybridization with polymerase chain reaction-amplified DNA probes. DNA mapping with a probe for a δ-globin fragment showed a 27-kb deletion of DNA that included the β-globin gene and the 3′ deoxyribonuclease I hypersensitive site 1 (3′HS1) sequence downstream. Deletion of the insulator, 3′HS1, and the juxtaposition of the HPFH-3 core enhancer downstream to the 3′ breakpoint have been postulated to be the cause of high HbF production in these individuals. To test this hypothesis, we transfected K562 cells with 4 different bacterial artificial chromosome constructs containing the enhanced green fluorescent protein (EGFP) gene at the position of the Aγ-globin gene (pEBAC/148β:EGFP). Flow cytometry was used to compare EGFP expression from the pEBAC/148β:EGFP construct with the HPFH-3 core enhancer immediately 5′ to the SEA-HPFH breakpoint (pEnH), from the pEBAC/148β:EGFP construct with 8 kb of the breakpoint sequence and the HPFH-3 core enhancer (pSEA-HPFH), and from the construct with 3′HS1 followed by the pSEA-HPFH sequence (pSEA-HPFH_3pHS1). The results show that high HbF production in SEA-HPFH occurs from a deletion of the 3′HS1 sequence and the juxtaposition of the HPFH-3 enhancer downstream to the γ-globin gene.
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Changsri, K., Akkarapathumwong, V., Jamsai, D. et al. Molecular Mechanism of High Hemoglobin F Production in Southeast Asian-Type Hereditary Persistence of Fetal Hemoglobin. Int J Hematol 83, 229–237 (2006). https://doi.org/10.1532/IJH97.E0509
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DOI: https://doi.org/10.1532/IJH97.E0509