Genetic Control of Hemoglobin Synthesis 
elements called NFE2-AP1 -binding sites are es- 
sential for these enhancing activities. In addition, 
using in vivo footprint experiments, we have ex- 
amined the consensus sequences that are impor- 
tant for in vivo interaction. We have studied sev- 
eral cell lines that express different amounts of 6-, 
7-, and /3-globin genes and have found that the 
consensus sequences are bound differently in 
these cell lines, depending on the type of fi- 
globin gene expressed. We are now characteriz- 
ing the factors responsible for this binding in 
order to understand the molecular basis of hemo- 
globin switching. 
Red Cell Membrane Disorders 
Many hereditary hemolytic anemias are accom- 
panied by spherocytosis or elliptocytosis. The de- 
fects in these disorders lie in mutations of various 
cytoskeleton proteins, such as spectrin, ankyrin, 
and protein 4.1. We have studied families with 
hereditary elliptocytosis due to protein 4.1 defi- 
ciency and have defined three different defects 
due to gene rearrangements. 
Protein 4. 1 is found in all cell types and exists 
in multiple isoforms generated by alternate splic- 
ing in at least five different regions of the gene. 
Some isoforms are more abundant in nucleated 
cells, others in mature red cells. Although pro- 
tein 4.1 maintains the integrity of the cytoskele- 
ton in the red cell, its function in nucleated cells 
is not yet known. In a patient who has no protein 
4.1 in the red cell, severe hemolytic anemia en- 
sues, while other cellular functions are normal. 
Structural analysis showed that the protein 4.1 
gene is rearranged at the region corresponding to 
the amino terminal of the erythroid protein 4.1. 
Otherwise it continues to produce functional 
protein 4.1 by an alternate splicing mechanism, 
which skips the mutated region. This example 
may point out an advantage of alternate splicing. 
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