several unrelated individuals with the kidney defect 
of nephrogenic diabetes insipidus. A mouse model 
of hemophilia also is being pursued for future gene 
therapy experimentation. 
The laboratory of Investigator Yuet Wai Kan, M.D. 
(University of California, San Francisco) has been 
investigating the molecular basis of a group of hered- 
itary disorders affecting the red cells. They have 
studied the mutations that give rise to hemoglobin- 
opathies and thalassemia and devised simple, rapid, 
and nonradioactive tests for these mutations, which 
will facilitate DNA diagnosis in regions of the world 
where these diseases are common. The group has 
initiated cooperative studies in the Mediterranean 
area and in China. They also are investigating the 
control of globin gene expression and are exploring 
the protein-DNA interactions in the globin gene re- 
gions that are important for the high-level expres- 
sion of globin in the erythroid cell, and the develop- 
mental switch from embryonic to fetal to adult 
hemoglobin. Sequences critical for the high level of 
globin gene expression have been identified and 
utilized to enhance globin gene expression in retro- 
virus-mediated gene transfer experiments. Such 
work may lead to the correction of the |8-globin de- 
fects in sickle cell anemia and thalassemia. In addi- 
tion, examination of the mechanism by which buty- 
rates increase fetal hemoglobin gene expression 
may also prove useful for treatment of the ^S-globin 
defect. 
The laboratory of Assistant Investigator David A. 
Williams, M.D. (Indiana University) studies factors 
that control the behavior of cells in the bone 
marrow, leading to the formation of all blood cells. 
Such cells, termed hematopoietic stem cells, repre- 
sent an important component of the blood system 
for normal blood cell production and are important 
in some forms of leukemia. These cells are also the 
target cell population for gene modification in so- 
called somatic gene therapy. Using molecular and 
cell biologic methods, Dr. Williams's laboratory has 
identified and studied several new proteins impor- 
tant in the production of blood cells in the bone 
marrow cavity. The group has now demonstrated an 
ability to produce mice that express human proteins 
through the use of genetically modified bone 
marrow cells. 
The laboratory of Assistant Investigator John W. 
Belmont, M.D., Ph.D. (Baylor College of Medicine) 
is studying how blood cell formation is controlled 
by the activity of the most primitive of blood cell 
precursors, the hematopoietic stem cells. Multiple 
approaches, including new tissue culture methods, 
introduction of marker genes, and gene cloning are 
being employed to analyze how these cells are 
committed either to undergo massive proliferation 
or to self-renew (make more stem cells). The long- 
term objective is to use this information in the 
treatment of human diseases by selective genetic 
alteration of these cells. In a second project. Dr. 
Belmont's group wishes to identify the gene respon- 
sible for Bruton's X-linked agammaglobulinemia, an 
inherited disease in which young males are unable 
to form antibodies because of a failure to develop B 
lymphocytes. The search for the gene has been 
narrowed to ~ 1/1, 000th of the human genome. 
The laboratory has also developed a new carrier test 
for this disorder. 
The research program of Associate Investigator 
David Ginsburg, M.D. (University of Michigan) and 
his colleagues focuses on the biology of the human 
blood-clotting system. The group has identified the 
molecular defects responsible for many forms of von 
Willebrand disease, the most common inherited 
bleeding disorder. The laboratory has continued to 
study plasminogen activator inhibitor- 1 (PAI-1 ) and 
has characterized the genetic defect in a new human 
bleeding disorder due to a defect in the PAI-1 gene. 
Analysis of genetically engineered variant PAI- 1 mol- 
ecules has shed new light on the function of this 
important blood-clotting protein. These studies may 
eventually lead to new strategies for the treatment of 
blood-clotting disorders, including heart attack and 
stroke. Finally, in a new program attempts are under 
way to identify the genes responsible for graft- 
versus-host disease, the major complication of bone 
marrow transplantation. 
Familial hypertrophic cardiomyopathy (FHC) is a 
primary heart muscle disorder, inherited as an auto- 
somal dominant trait characterized by inappropriate 
myocardial hypertrophy and early mortality. During 
the past year, Investigator Jonathan G. Seidman, 
Ph.D. (Harvard Medical School) and his colleagues 
used a rapid screening method involving ribonucle- 
ase protection assays to identify cardiac myosin 
heavy-chain missense mutations in the genomes of 
FHC probands. They have now identified 1 1 differ- 
ent missense mutations, all in the head or head/rod 
junction portions of the cardiac myosin heavy chain. 
Most of these mutations involve a charge change in 
the encoded amino acid. They have also demon- 
strated that de novo arising missense mutations in 
/3-cardiac myosin heavy chains can cause sporadic 
hypertrophic cardiomyopathy in patients whose par- 
ents are not affected. Surprisingly, individuals with 
certain mutations have a significantly shorter life 
expectancy than others, despite the fact that their 
clinical symptoms are otherwise indistinguishable. 
In many instances FHC cannot be diagnosed until 
patients have passed the growth spurt associated 
GENETICS 139 
