Molecular Basis of Hereditary Persistence of Fetal Hemoglobin

A bstract : Increased levels of fetal hemoglobin (HbF) can ameliorate the clinical course of inherited disorders of β‐globin gene expression, such as β thalassemia and sickle cell anemia. In a group of disorders called hereditary persistence of fetal hemoglobin (HPFH), expression of the γ‐globin gene of HbF persists at high levels in adult erythroid cells. Molecular studies of the HPFH syndromes have identified several important regulatory elements for the normal pattern of γ‐globin gene expression. Deletion as well as nondeletion types of HPFH have been identified. The nondeletion types of HPFH are characterized by the presence of point mutations, in the promoter region of one or another γ‐globin gene, that are thought to alter interactions between various transcription factors and the promoter. The deletion types of HPFH are thought to deregulate the normal developmental pattern of γ‐globin gene expression due to the juxtaposition of normally distant cis‐acting factors into the vicinity of the γ genes. These findings have provided us with a more sophisticated understanding of the molecular basis for the persistent γ‐gene expression in these syndromes and point to certain strategies for potential future attempts at gene therapy for β‐globin gene disorders.