Human Genetic Diseases 
gene expression. These regions have been joined 
to the |8-globin gene and are capable of augment- 
ing globin gene expression in tissue culture cells 
and in transgenic mice. In addition, nuclear ex- 
tracts from cell lines with erythroid characteris- 
tics are being examined for factors that bind to 
putative control regions of the globin genes. A 
nuclear factor from erythroid cells appears to 
bind to a tandem repeat of a consensus recogni- 
tion sequence for a class of transacting factors 
called API . We are attempting to isolate this ery- 
throid-specific API -like protein. Our long-term 
goal is to understand the cellular processes con- 
trolling the tissue-specific expression of the dif- 
ferent globin genes and the signals that control 
the switch from fetal to adult globin. This knowl- 
edge may lead to better approaches for correcting 
the genetic defects in hereditary hemoglobin 
disorders. 
Red Cell Membrane Disorders 
Many hereditary hemolytic anemias are accom- 
panied by spherocytosis or elliptocytosis. The de- 
fects in these disorders are known to lie in the 
membrane proteins, though the mutations were 
not defined until recently. To facilitate the study 
of these groups of hemolytic anemias, we have 
isolated the gene encoding for protein 4.1. We 
have studied families with hereditary elliptocyto- 
sis due to protein 4.1 deficiency and have de- 
fined three different defects due to gene rear- 
rangements: one results in the absence of the 
mature form of protein 4.1 in the red cell, an- 
other produces an elongated 4.1 protein mole- 
cule due to duplication of three exons, and the 
third causes a shortened protein 4 . 1 due to a two- 
exon deletion. 
We continue to define the alternate splicing 
mechanism by which multiple isoforms of pro- 
tein 4.1 are generated. We have found at least five 
different regions that undergo alternate splicing. 
Antibodies prepared against these isoforms are 
being used to study their distribution and func- 
tion. Some isoforms are more abundant in nu- 
cleated cells, and others, in mature red cells. 
Also, protein 4.1 is found in many cell types out- 
side of the red blood cell. Thus it seems that, in 
addition to its role as a red cell cytoskeletal pro- 
tein, protein 4.1 serves other cellular functions 
that need to be defined. 
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