In hereditary persistence of fetal haemoglobin (HPFH), inappropriately high gamma-globin expression in adult life is associated with deletions in the beta-globin cluster or with single-base changes upstream of the gamma-globin genes.
Genetic evidence indicates that single point mutations in the gamma-globin promoter may be the cause of high expression of the mutated gene in the adult period (Hereditary Persistence of Fetal Hemoglobin, HPFH).
The -175 T greater than C mutation in the promoter of the A gamma- or G gamma-globin gene causes a 50-100 fold increase of the expression of the respective gene in adult erythroid cells (Hereditary Persistence of Fetal Hemoglobin).
Three gamma-globin promoters containing mutations associated with hereditary persistence of fetal hemoglobin (-202 C----G, -196 C----T, and -117 G----A) were not overexpressed in the K562 cell environment, consistent with the hypothesis that these promoters are not overexpressed in fetal erythroblasts, only adult erythroid cells.
In a group of disorders called hereditary persistence of fetal hemoglobin (HPFH), expression of the gamma-globin gene of HbF persists at high levels in adult erythroid cells.
Persistent expression of the gamma-globin gene in adult life has been supposed to be caused by loss of a region located about 3-4 kb 5' to the delta-globin gene from comparison of the extents of deletions in several different forms of delta beta-thalassemia and HPFH (hereditary persistence of fetal hemoglobin).
In addition, our findings provide a mechanism for understanding the high levels of gamma-globin transcription seen in patients with Hereditary Persistence of Fetal Hemoglobin, and help explain why 5azaC and butyrate compounds stimulate gamma-globin expression in patients with beta-hemoglobinopathies.
Mutations within the β-globin CCAAT box result in β-thalassaemia, while mutations within the distal γ-globin CCAAT box cause the Hereditary Persistence of Foetal Haemoglobin, a benign condition which results in continued γ-globin expression during adult life.
Three gamma-globin promoters containing mutations associated with hereditary persistence of fetal hemoglobin (HPFH), -202 C----G, -196 C----T and -117 G----A, were not overexpressed in K562 cells, consistent with the hypothesis that these promoters are not overexpressed in fetal erythroblasts, only in adult red cells.
G gamma-196 C-->T, A gamma-201 C-->T: two novel mutations in the promoter region of the gamma-globin genes associated with nondeletional hereditary persistence of fetal hemoglobin in Greece.
The British form of hereditary persistence of fetal hemoglobin results from a single base mutation adjacent to an S1 hypersensitive site 5' to the A gamma globin gene.
The region within the hypersensitive site includes all the consensus promoter elements of the gamma-globin genes as well as an octamer sequence located between -182 and -175, and a region associated with a variety of mutations that may cause hereditary persistence of fetal hemoglobin (HPFH).
An intramolecular triplex in the human gamma-globin 5'-flanking region is altered by point mutations associated with hereditary persistence of fetal hemoglobin.
Single-base substitutions in the immediate 5'-flanking region of the fetal G gamma and A gamma globin genes have been associated with non-deletional forms of hereditary persistence of fetal haemoglobin (HPFH).
For example, in hereditary persistence of fetal hemoglobin (HPFH), a benign genetic condition, mutations attenuate γ-globin-to-β-globin switching, causing high-level HbF expression throughout life.
In this system expression of the G gamma-globin gene bearing the point mutation found in a Japanese patient of hereditary persistence of fetal hemoglobin (HPFH) (1) persisted at a equivalent level to beta-globin expression in fetal and adult mice.
An A gamma type of nondeletional hereditary persistence of fetal hemoglobin with a T----C mutation at position -175 to the cap site of the A gamma globin gene.