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Beta O-39 thalassemia gene: a premature termination codon causes beta- mRNA
deficiency without affecting cytoplasmic beta-mRNA stability
RK Humphries, TJ Ley, NP Anagnou, AW Baur and AW Nienhuis
The function of a beta O-thalassemia globin gene with a premature
termination codon at position 39 was studied in tissue culture cells using
plasmid expression vectors. The thalassemic globin gene was isolated by
molecular cloning from the bone marrow DNA of an Italian patient with
severe thalassemia. Sequences upstream of the normal beta- globin gene and
the beta O-39 globin gene were removed to 127 nucleotides (nt) 5' to the
start site of transcription, thereby eliminating uncharacterized DNA
sequences but preserving promoter function. To create a hybrid gene
differing from the normal by only the single nt change in codon 39, the
truncated 5' end of the beta O-39 gene was recombined with the 3' end of
the normal gene. The beta O-39 substitution resulted in a 6-14-fold
reduction in cytoplasmic RNA accumulation in transfected monkey kidney or
HeLa cells. This decrease in mRNA did not appear to be due to instability,
as the beta-mRNA present 24-36 hours after transfection was stable for up
to 24 hours in the presence of actinomycin D. In the presence of
actinomycin D, the globin mRNA precursor disappeared, suggesting that
globin gene transcription had been effectively blocked. We also examined a
second globin mRNA with a premature termination codon; this RNA that arises
from incorrect splicing of the transcript of a beta + -24 thalassemia gene
was as stable as the correctly spliced species. Thus, the presence of a
premature termination codon does not necessarily alter cytoplasmic mRNA
stability, nor does cytoplasmic instability account for the quantitative
deficiency of beta-globin mRNA. Our observations suggest that a premature
termination codon alters intranuclear stability and/or nuclear to
cytoplasmic transport of the beta-globin mRNA.
Volume 64,
Issue 1,
pp. 23-32,
07/01/1984
Copyright © 1984 by The American Society of Hematology
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