title: An A gamma globin promoter (four base-pair deletion) mutant shows linked polymorphic changes throughout the A gamma gene.
abstract: The A gamma fetal globin genes from a large Australian kindred with nondeletional A gamma hereditary persistence of fetal hemoglobin (HPFH) were cloned and sequenced. The -198 T----C mutation (British type HPFH) was demonstrated upstream of the A gamma gene on one allele. On the other allele, a 4-deletion was identified -222 to -225 bp upstream from the cap site. The 4-bp deletion allele was associated with a number of variations in the A gamma gene sequence: anA gamma T transition, in the second exon (T----C at +402 relative to the cap site); a HindIII polymorphism in the second intron; and a G gamma-like sequence in the 3' untranslated region (TCAC in place of CTCT, creating a SacI site). An association between the -222 to -225 deletion, the A gamma T polymorphism, and the second intron HindIII polymorphism has previously been reported. In addition, linkage of the HindIII polymorphism with the G gamma-like sequence in the 3' untranslated region of A gamma has also been described. The case described here is unique, with all four changes present in the one A gamma gene. It is also noteworthy because there is simultaneous occurrence of high (HPFH) and low (-222 to -225 deletion) expression mutants in the same patient. Despite the presence of the 4-bp deletion, the resulting hematological phenotype remained that of HPFH. When the 4-bp deletion promoter was studied in a K562-cell transient expression assay, there was found to be no statistically significant reduction in activity compared to the control A gamma promoter. The possible reasons for the observed differences between the in vivo and in vitro activity of this mutation are discussed.
authors.affiliation: Department of Medicine, University of Sydney, New South Wales, Australia.
authors.forename: M P
authors.initials: MP
authors.lastname: Harvey
authors.forename: P
authors.initials: P
authors.lastname: Motum
authors.forename: R
authors.initials: R
authors.lastname: Lindeman
authors.forename: R J
authors.initials: RJ
authors.lastname: Trent
mesh_terms: D000483:Alleles; D001483:Base Sequence; D002872:Chromosome Deletion; D004273:DNA, Neoplasm / Q000032:analysis / Q000235:genetics; D005091:Exons; D005319:Fetal Hemoglobin / Q000235:genetics; D005914:Globins / Q000235:genetics*; D006453:Hemoglobinopathies / Q000235:genetics; D006579:Heterozygote; D006801:Humans; D004915:Leukemia, Erythroblastic, Acute / Q000235:genetics / Q000473:pathology; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics*; D010641:Phenotype; D011110:Polymorphism, Genetic / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics*; D014407:Tumor Cells, Cultured / Q000378:metabolism / Q000473:pathology
chemical_list: D004273:DNA, Neoplasm; D005914:Globins; D005319:Fetal Hemoglobin