Sardinian dß°-thalassemia: A further example of a C to T substitution at position -196 of the (A)? globin gene promoter

Abstract

Selective overexpression (50- to 100-fold) in adult erythroid cells of either (G)? or (A)? fetal globin gene is observed in hereditary conditions known as dß°-thalassemia and hereditary persistence of fetal hemoglobin (HPFH). Recently, a C ? T change at position -196 of an overexpressed (A)? globin gene from an Italian HPFH was hypothesized, on the basis of indirect evidence to represent the cause of the functional defect. We now show that the same mutation is present in a different overexpressed (A)?-globin gene from a Sardinian patient with a different syndrome (dß°-thalassemia). The Sardinian (A)? globin gene differs from both the HPFH and the normal (A)? globin gene at nucleotide 1,560 in the noncoding portion of the third exon, where an A is deleted. In addition, the mutant -196 (A)?-globin gene is linked to a normal ß globin gene in HPFH, and to a ß-thalassemic gene (ß39CAG ? TAG) in dß°-thalassemia. These data strengthen the suggestion that -196 mutation is causally linked to the abnormal phenotype and raise the question of whether the same or multiple mutational events are responsible for the appearance of the -196 mutation in different syndromes.