Maximal γ-globin expression in the compound heterozygous state for –175 ^Gγ HPFH and β⁰39 nonsense thalassaemia: a case study

Abstract

The –175 (T→C) Gγ hereditary persistence of fetal haemoglobin is a very rare promoter mutation occurring in Caucasians as well as in African-Americans. Heterozygotes for this non-deletional HPFH show 20% HbF, mostly of Gγ type. We describe here a healthy Sardinian man who coinherited –175 (T→C) Gγ HPFH with the β-thalassaemia codon 39 nonsense mutation in trans; he showed 64% HbF, 100% of Gγ type. Although the β-globin haplotype pattern (II/II) was indicative of the presence of the AγT allele on both chromosomes, the AγT expression was undetectable by HPLC even in red cell populations separated by age. The proband was, moreover, homozygous for the –4 bp deletion at position -225 to -222 of Aγ promoter which has recently been associated with decreased AγT globin expression. These findings suggest that this maximal overexpression of Gγ-globin probably reflects intensified stimulation of the mutated Gγ promoter in this hitherto undescribed genetic condition