A single point mutation is the cause of the Greek form of hereditary persistence of fetal haemoglobin

IN normal humans the fetal stage-specific γ-globin genes are silenced after birth and not expressed in the adult. Exceptions are seen in cases of hereditary persistence of fetal haemoglobin (HPFH). These are clinically important because the elevated levels of γ-globin can alleviate β-thalassaemia and sickle cell anaemia. One class of mutations is associated with point mutations in the promoter of the γ-globin genes (non-deletion HPFH), whereas others seem to be caused by large deletions 3′ to the γ-globin genes1. To test whether the point mutation found in the Greek non-deletion HPFH2,3 (guanine to adenine at nucleotide position –117) is the cause of the raised γ-globin levels in the adult stage and is not just a linked polymorphism, we engineered this mutation into a γ-globin gene. When this gene was introduced into mice, the presence of the –117 mutation results in persistence of γ-globin expression at a high level and a concomitant decrease in β-globin expression in fetal and adult mice. We show that these changes correlate with the loss of binding of the transcription factor GATA1 to the γ-globin promoter, suggesting that it may act as a negative regulator of the γ-globin gene in adults.