Maximal gamma-globin expression in the compound heterozygous state for -175(G)gamma HPFH and beta degrees 39 nonsense thalassaemia: A case study

The -175 (T-->C) (G) gamma 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 (G) gamma type. We describe here a healthy Sardinian man who coinherited -175 (T-->C) (G) gamma HPFH with the beta-thalassaemia codon 39 nonsense mutation in trans: he showed 64% HbF, 100% of (G) gamma type. Although the beta-globin haplotype pattern (II/II) was indicative of the presence of the (A) gamma(T) allele on both chromosomes, the (A) gamma(T) 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 (A) gamma promoter which has recently been associated with decreased (A) gamma(T) globin expression. These findings suggest that this maximal overexpression of (G) gamma-globin probably reflects intensified stimulation of the mutated (G) gamma promoter in this hitherto undescribed genetic condition.