Structural Determinants of a-Globin Gene Expression 
mental expression, it should be possible to arrive 
at a definition of the signal (s) critical to globin 
gene switching. 
Selective stabilization of globin mRNA is essen- 
tial to its accumulation in terminally differentiat- 
ing red cells to levels of 95 percent of total cellu- 
4ar mRNA. We are attempting to define the 
structural basis for the stability of a-globin mRNA 
through investigation of an a-thalassemia muta- 
tion in which this stability is lost: a Constant 
Spring (aCS). This mutation, the most common 
cause of nondeletional a-thalassemia in Southeast 
Asia, is a codon substitution (CAA for UAA) at the 
termination of the normal a 2 -globin gene. As a 
result of this single-base substitution, the ribo- 
some translates into the normally untranslated 3' 
region and destabilizes the mRNA. 
To study the basis for this destabilization in de- 
tail, we have established an experimental system 
that reproduces the selective instability of aCS 
mRNA in tissue culture cells. Remarkably, we 
find that the mRNA is unstable when the gene is 
expressed in an erythroid cell line, but normally 
stable when expressed in nonerythroid cell lines. 
This suggests that the stability of globin mRNA 
may depend upon interaction with one or more 
erythroid-specific factors. 
By making specific alterations in the structure 
of the a-globin genes prior to expression, it has 
been possible to demonstrate that the region 
within the a-globin mRNA critical to its stability 
is located in a segment of the 3'-nontranslated re- 
gion just past the translation termination codon. 
In future experiments the critical cellular factors 
or structures mediating this response, and the 
mechanism involved, will be further defined. 
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