A fetal globin gene mutation in /sup A/. gamma. nondeletion hereditary persistence of fetal hemoglobin increases promoter strength in a nonerythroid cell
Single base substitutions have been identified in the promoter regions of /sup A/..gamma..-globin genes from individuals with certain types of nondeletion /sup A/..gamma.. hereditary persistence of fetal hemoglobin (HPFH). The presence of these mutations is closely associated with the /sup A/..gamma.. HPFH phenotype, but proof that they are the nondeletion HPFH determinants is lacking. To test directly whether these base substitutions can result in an increase in /sup A/..gamma..-globin gene transcription, we studied cosmid clones containing the /sup G/..gamma..-through ..beta..-globin gene regions from individuals with Greek-type (G-to-A base substitution at -117) and Chinese-type (C-to-T base substitution at -196) /sup A/..gamma.. HPFH in a transient expression assay. When tested as part of a cosmid clone, the Greek HPFH /sup A/..gamma..-globin gene consistently produced about 1.4 times as much RNA as the wild-type /sup A/..gamma..-globin gene when standardized against RNA transcribed from the /sup G/..gamma.. genes in cis. The relative strengths of the normal and HPFH /sup A/..gamma..-globin gene promoters were also compared in transient expression assays with plasmids containing the /sup A/..gamma..-globin genes. Pseudo-wild-type /sup A/..gamma..-globin genes containing a short, transcriptionally neutral deletion were used so that two /sup A/..gamma..-globin genes that differed in their promoter sequences could be compared in the same transfection. The plasmid transient expression results indicated a 1.3- to 1.4-fold increase in steady-state RNA levels from the Greek-type /sup A/..gamma.. HPFH promoter compared with the wild-type /sup A/..gamma.. promoter, while no difference was documented between the Chinese-type /sup A/..gamma.. HPFH promoter and the wild-type /sup A/..gamma.. promoter.
- Research Organization:
- Dow Chemical, U.S.A., Midland, MI 48674 (US)
- OSTI ID:
- 5115108
- Journal Information:
- Mol. Cell. Biol.; (United States), Journal Name: Mol. Cell. Biol.; (United States) Vol. 8:2; ISSN MCEBD
- Country of Publication:
- United States
- Language:
- English
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Related Subjects
550400 -- Genetics
59 BASIC BIOLOGICAL SCIENCES
CARBOXYLIC ACIDS
CHROMOSOMAL ABERRATIONS
DISEASES
DNA BASE TRANSITIONS
FETUSES
GENES
GLOBIN
HEMOGLOBIN
HEREDITARY DISEASES
HETEROCYCLIC ACIDS
HETEROCYCLIC COMPOUNDS
MUTATIONS
ORGANIC ACIDS
ORGANIC COMPOUNDS
ORGANIC NITROGEN COMPOUNDS
PHENOTYPE
PIGMENTS
PORPHYRINS
PROTEINS
TRANSCRIPTION