The G→A Mutation at Position +22 31to the Cap Site of the β-Globin Gene as a Possible Cause for a β-Thalassemia

Abstract

We describe the occurrence of a chromosome with a G→A mutation at position +22 relative to the Cap site that was found in five patients with β-thalassemia. All patients had a common type of β-thalassemia mutation on the second chromosome, namely the frameshift at codon 8 (-AA), the IVS-I-110 (G→A) and the IVS-II-1 (G→A) mutations. The β genes of two patients, including the 5′ and 3′ untranslated regions, were completely sequenced and no other mutations, except a few polymorphic sites, were observed. Dot-blot analyses failed to demonstrate this G→A mutation at +22 in nearly 400 β-thalassemia chromosomes and 180 normal chromosomes. Hetero-zygotes have the features of a high Hb A₂-β-thalassemia hetero-zygosity, although the hematological parameters might be less abnormal than observed in heterozygotes for the more common β-thalassemia mutations. The possibility has been presented suggesting that this mutation might impair the binding of mRNA to ribosomes. Another mutation in this segment of DNA, i.e. a C→G mutation at position +20, is observed exclusively on a chromosome which also carries the C→G mutation at IVS-II-745. It is postulated that the +20 C→G mutation accentuates the β-thalassemia condition caused by the IVS-II-745 mutation; the mechanism might be similar to that suggested for the G→A at +22 mutation.