of sickle cell anemia are being developed so that 
the test can be performed in many countries where 
the disease is common. Mutations that cause 
thalassemia continue to be discovered, and the mo- 
lecular basis of the control of globin gene expres- 
sion is being investigated. The complex pattern of 
alternate splicing of the cytoskeleton protein 4.1 
and the function of its different isoforms are also 
being delineated. A new form of post-transcrip- 
tional processing was described in the red cell en- 
zyme glucose-6-phosphate dehydrogenase (G6PD). 
This protein is encoded by two genes on two differ- 
ent chromosomes. A single protein is made from 
these two genes post-transcriptionally either by 
cross translation of the two mRNAs or by joining of 
the two polypeptides by transpeptidation. 
Classic hemophilia is an inherited male-specific 
bleeding disorder resulting from a defect in a blood 
coagulation protein, factor VIII. The laboratory of 
Assistant Investigator Jane Gitschier, Ph.D. (Uni- 
versity of California at San Francisco) has used 
the sensitive technique of denaturing gradient gel 
electrophoresis to find mutations in the factor VIII 
genes of hemophilia patients. Knowledge of these 
mutations can be helpful for understanding factor 
VIII function and in genetic counseling. The fac- 
tor VIII gene is located at the tip of the long arm of 
the X chromosome and is closely linked to a num- 
ber of genes associated with other inherited dis- 
eases, including a site responsible for a major cause 
of mental retardation in males. This year a large- 
scale map of the DNA in this region was con- 
structed. The map should provide a basis for isolat- 
ing other disease genes. 
The research program of Assistant Investigator 
David Ginsburg, M.D. (University of Michigan) and 
his colleagues focuses on the biology of the human 
blood clotting system. Progress has been made in 
our understanding of the biology of von Willebrand 
factor (vWF) and the molecular basis of von 
Willebrand's disease (vWD), the most common in- 
herited bleeding disorder in humans. Specific ab- 
normalities were identified within the vWF gene 
that may cause one of the more common types of 
vWD and help to characterize how specific parts of 
the vWF molecule function in the blood clotting 
system. The group has continued also to study plas- 
minogen activator inhibitor- 1, a blood protein that 
plays a critical role in the body's system for break- 
ing down blood clots. Abnormalities in this protein 
may contribute to a number of human diseases, in- 
cluding heart attack and stroke. Progress has been 
made also in the laboratory's study of bone marrow 
transplantation, an important treatment for leuke- 
mia and a number of other cancers. 
Assistant Investigator Jeffrey M. Friedman, M.D., 
Ph.D. (The Rockefeller University) and his associ- 
ates are studying the regulation and function of 
hormones and other molecules that are involved in 
the control of feeding behavior. They have taken 
two approaches to this problem. The first approach 
is directed at understanding, at the molecular level, 
the control of the mouse cholecystokinin gene. 
Cholecystokinin is a hormone that suppresses feed- 
ing behavior when administered to rats. This hor- 
mone, normally synthesized in the brain and intes- 
tine, has been found by this laboratory to be 
overexpressed in certain pediatric tumors, includ- 
ing Ewing's sarcoma of bone, neuroepithelioma (a 
chest wall tumor), and rhabdomyosarcoma (a mus- 
cle tumor) . These observations may prove useful in 
the diagnosis and management of the tumors. The 
second approach of the laboratory is aimed at the 
molecular cloning of two mouse genes, obese and 
diabetes, which are defects in a single gene and re- 
sult in profound obesity and abnormalities in feed- 
ing behavior. The proteins that code for these obe- 
sity genes have not yet been identified. The cloning 
of these genes and the characterization of the en- 
coded proteins should provide insight into how 
food intake and body weight are regulated in mice 
and probably also in humans. 
The laboratory of Associate Investigator Graeme 
I. Bell, Ph.D. (The University of Chicago) is using 
the techniques of genetics and molecular biology to 
identify and study the genes that contribute to the 
development of diabetes mellitus. Progress has 
been made in identifying the gene responsible for 
diabetes in a large family with maturity-onset diabe- 
tes of young people, a form of non-insulin-depen- 
dent diabetes mellitus. It is now possible to ex- 
clude this diabetogenic gene from about 12% of the 
human genome. The human insulin receptor gene 
is a very large gene, spanning over 120,000 base 
pairs. Its protein product mediates the cellular re- 
sponses to insulin. The structural organization of 
the gene has been completed, and a general strat- 
egy has been developed that will facilitate the iden- 
tification of mutations in this gene. Studies of the 
proteins responsible for the transport of glucose 
across the plasma membrane have revealed that 
there is a family of structurally related proteins that 
are responsible for glucose transport. Insulin regu- 
lates the amount of the unique glucose transport 
protein that is present in muscle and adipose tis- 
sue. As diabetes is characterized by an absolute or 
Continued 
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