A comparative study of Greek nondeletional hereditary persistence of fetal hemoglobin and β-thalassemia compound heterozygotes

The coexistence of beta- and gamma-globin gene mutations in the compound heterozygous state presents a rare in vivo model that provides important data on gene regulation of clinical interest. In this unique comparative study we present the hematological, biosynthetic, and molecular data from six adult compound heterozygotes for the Greek nondeletional hereditary persistence of fetal hemoglobin (nd-HPFH, Agamma-117 G-->A) and four frequent beta-thalassemia mutations (IVS I- 110 G-->A, Cd 39 C--> T, IVS I-1 G-->A, and IVS I-6 T-->C) found in the Hellenic population. Fetal hemoglobin (HbF) levels were found to be considerably higher (25-50%) than in 19 Greek nd-HPFH heterozygotes (HbF=9.7+/-1.7%) and, interestingly, to depend on the type of the respective beta-thalassemia mutation, in trans to the nd-HPFH allele. All cases presented a typical beta-thalassemia heterozygote's phenotype despite the increased HbF and the normal HbA(2) levels, as indicated by both the hematological indices and the biosynthetic ratios. These data were compared with those from two unique cases of Greek origin: a homozygous case of the Greek nd-HPFH and a compound heterozygote with HbS. Our data suggest that in these compound heterozygous cases the beta-thalassemic chromosome indirectly determines the final outcome of the gamma- and of the in cis beta-globin gene expression, most likely at the post-transcriptional level.