GγAγ(β+) hereditary persistence of fetal hemoglobin: The Gγ – 158 C → T mutation in cis to the − 175 T → C mutation of the Aγ‐globin gene results in increased Gγ‐globin synthesis

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Hereditary persistence of fetal hemoglobin (HPFH) can be generally classified into deletional and nondeletional forms. The family described in the present study has characteristics of both types of HPFH. The proband is a healthy 30‐year‐old black woman. Analysis of her hemoglobin revealed 40.4% HbS, 40.9% HbF (Gγ/Aγ ratio 0.53), 16.8% HbA, and 1.9% HbA2. All of her hematologic indices were normal, and the distribution of HbF in her red cells was pancellular. Family studies demonstrated that the proband has one chromosome 11 bearing the βs‐globin gene and the other bearing a GγAγ(β+) HPFH determinant in cis to the βA‐globin gene. Gene mapping studies of the region between the Gγ‐ and β‐globin genes were normal. However, when the Aγ and Gγ promoters were amplified by polymerase chain reaction (PCR) and sequenced, the Aγ promoter was found to have the T→C mutation at −175, and the Gγ promoter region was found to have the C→T mutation at −158. The −158 C→T mutation has been associated with elevated Gγ levels and high HbF in hemolysis, although its role in causing these effects is unclear. The present study suggests that this mutation can also enhance Gγ‐globin expression in cis to the −175 T→C mutation in the absence of hemolysis. We suggest that the alteration of the Aγ gene octamer binding site by the −175 mutation, as well as the loss of a putative Gγ “silencer” caused by the −158 mutation may account for this phenotype. We propose calling these linked mutations the GγAγ(β+) HPFH. © 1993 Wiley‐Liss, Inc. Copyright © 1993 Wiley‐Liss, Inc., A Wiley Company

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