The deletion of the distal CCAAT box region of the A gamma-globin gene in black HPFH abolishes the binding of the erythroid specific protein NFE3 and of the CCAAT displacement protein

Non-deletion Hereditary Persistence of Fetal Hemoglobin (HPFH) Is characterized by great elevation of the synthesis, In adult age, of fetal hemoglobin (HbF), of either the Aγ or Gγ type. Strong genetic evidence Indicates point mutations In the Gγ or Aγ -globln promoter as responsible for overexpresston of the mutated gene. Here we report that a 13 nucleotkles deletion In the CCAAT box region of the Aγ -globln promoter, associated with greater than 100 fold overexpresston of the gene, abolishes the In vitro binding of the ubiquitous factors CP1 and COP (CCAAT displacement protein) and of the erythroW specific protein NFE3. Loss of NFE3 binding Is consistent with a simlar effect of the -117 G - A HPFH mutation, suggesting a possible role of NFE3 as a negatively acting factor. In addition, Ices of CDP binding Indicates that this alteration might also contribute to the HPFH phenotype In this particular case, suggesting possible heterogeneity of the mechanisms causing HPFH.