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

Abstract

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 HbA2 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.

PGC-1 Coactivator Activity Is Required for Murine Erythropoiesis

“…The human ␤-globin locus has been extensively studied as a paradigm for genetic regulation of lineage-and stage-specific gene expression (42), as well as for its clinical relevance to ␤-globin disorders. Elucidation of the molecular basis for ␥-globin gene silencing during definitive erythropoiesis in particular has been the focus of intense investigation, since coinheritance of genetic conditions that confer elevated ␥-globin synthesis alleviates many symptoms and at least some of the pathology associated with inherited ␤-globin disorders (43,44).…”

The Corfu δβ thalassemia deletion disrupts γ-globin gene silencing and reveals post-transcriptional regulation of HbF expression

“…The possibility of post-transcriptional regulation of HbF expression has been suggested before. 25,26 However, it has not been supported by comprehensive experimental data and, as a consequence, has remained largely overlooked. The Corfu case is not the only example of a mutation displaying low HbF expression in the heterozygote state and very high HbF expression in a compound heterozygote background.…”

Nuclear Receptors TR2 and TR4 Recruit Multiple Epigenetic Transcriptional Corepressors That Associate Specifically with the Embryonic β-Type Globin Promoters in Differentiated Adult Erythroid Cells

“…The human ␤-globin locus is composed of ε-(embryonic), G␥-and A␥-(fetal), and ␦-and ␤-globin (adult) genes, which are spatially arranged from 5Ј to 3Ј and developmentally expressed in the same order (72). The elucidation of the molecular basis for ␥-globin silencing in the adult stage in particular has been the focus of intense investigation, since it has been observed that coinheritance of genetic conditions that confer elevated ␥-globin synthesis can significantly alleviate the symptoms of ␤-globin disorders (44,56). Previously, several adult-stage ␥-globin repressors have been identified, such as BCL11A and SOX6 that physically interact with each other to repress the ␥-globin genes (67,84,86), as well as Ikaros (42) and GATA1 (20).…”