Disorders of the synthesis of human fetal hemoglobin

Fetal hemoglobin (HbF), the predominant hemoglobin in the fetus, is a mixture of two molecular species (α 2 G γ 2 and α 2 A γ 2 ) that differ only at position 136 reflecting the products of two nonallelic γ‐globin genes. At the time of birth, HbF accounts for ∼70% of the total Hb. The G γ: A γ globin ratio in the HbF of normal newborn is 70:30 whereas in the trace amounts of HbF that is found in the adult it reverses to 40:60 because of a γ‐ to β‐globin gene switch. Alterations of these ratios are indicative of a molecular defect at the level of the HbF synthesis. Qualitative hemoglobinopathies due to G γ and A γ chain structural variants, and quantitative hemoglobinopathies affecting the synthesis of HbF such as γ‐thalassemias, duplications, triplications, and even sextuplications of the γ‐globin genes, which may be detected in newborn blood lysates, have been described. Moreover, several pathological and nonpathological conditions affecting the β‐globin gene cluster, such as β‐thalassemia, sickle cell disease, δβ‐thalassemia, and hereditary persistence of HbF syndromes, are characterized by the continued synthesis of γ‐globin chains in the adult life. Studies of these natural mutants associated with increased synthesis of HbF in adult life have provided considerable insight into the understanding of the control of globin gene expression and Hb switching. © 2008 IUBMB IUBMB Life, 60(2): 94–111, 2008