A novel C-T transition within the distal CCAAT motif of the Gγ-globin gene in the Japanese HPFH: implication of factor binding in elevated fetal globin expression

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Abstract
Hereditary persistence of fetal hemoglobin (HPFH) is a condition characterized by the continued expression of the fetal globin gene in adulthood. Both deletional and nondeletional forms have been described. We studied one Japanese family with two different nondeletional forms of HPFH. Analysis of polymorphic restriction sites in the β-globin gene cluster suggested that one affecting both Gγ and Aγ globin expression in two members of the family could be associated with unknown conditions not linked to the β-globin gene loci. Characterization by the polymerase chain reaction (PCR) of another form producing a Gγ-HPFH phenotype in two other members demonstrated a novel C-T transition at the nucleotide −114 within the distal CCAAT motif of the Gγ-globin gene. Using gel retardation assays on various nuclear extracts, we also demonstrated that this novel mutation abolishes the binding of the ubiquitous CCAAT binding factor, CP1 to the distal CCAAT motif of the γ-globin gene but does not affect the binding of any erythroid specific factor, thereby suggesting a possible role for CP1 in the developmental regulation of fetal globin expression.