to isolate it and identify its function. In addition to 
genetic studies directed toward identifying markers 
for diabetogenic genes. Dr. Bell's laboratory em- 
ploys molecular biology to study insulin secretion. 
These two complementary approaches are leading 
to a better understanding of the cause of diabetes 
mellitus that will ultimately result in new ap- 
proaches for treating this disorder and for identify- 
ing individuals at increased risk. 
Associate Investigator Stephen T. Reeders, M.D. 
(Yale University) and his colleagues have used the 
techniques of molecular genetics to gain insight 
into the underlying mechanisms of human heredi- 
tary renal disease. They have identified a number of 
genes that are candidates for sites for mutations in 
autosomal dominant polycystic kidney disease. In 
addition, two novel basement membrane collagen 
genes of potential importance in hereditary human 
nephritis have been isolated. One is the site for au- 
toantibody binding in Goodpasture syndrome, a rare 
autoimmune disorder. These collagen genes also 
appear to be mutated in some cases of Alport 
syndrome. 
Phenylketonuria (PKU), an inherited disease that 
causes severe mental retardation in children who 
lack a metabolic enzyme (phenylalanine hydroxy- 
lase, or PAH) in the liver, has been studied exten- 
sively by Investigator Savio L. C. Woo, Ph.D. (Baylor 
College of Medicine ) and his colleagues. The proce- 
dure for genetic analysis in prenatal diagnosis of 
PKU was improved by the identification of addi- 
tional polymorphic markers in the human PAH 
gene. Mutations in the PAH gene that are responsible 
for the disease were determined. The defective 
genes were found to have originated in different re- 
gions in Europe and Asia and then spread indepen- 
dently through prehistoric population migration. In 
addition, methods for directly introducing func- 
tional genes into the liver of animals were devel- 
oped, and the simple procedure is expected to be 
useful for future correction of PKU and other liver 
deficiencies in humans. 
Investigator David M. Kurnit, M.D., Ph.D. (Univer- 
sity of Michigan) and his colleagues have found that 
the vast majority of nondisjunction errors are mater- 
nal and that deficient crossing over occurs in a plu- 
rality of Down syndrome offspring. By correlating 
maternal age with the type of nondisjunction, the 
group expects to determine the basis for the ad- 
vanced maternal age effect on nondisjunction. A flu- 
orescent detection system to monitor molecular 
polymorphisms will be employed to accomplish 
this analysis on a collection of four pericentromeric 
polymorphisms. A recombination-based assay to ac- 
complish the isolation of genes on chromosome 21 
has been developed that will assist in an efficient 
transcriptional analysis of chromosome 2 1 . This 
protocol was used to demonstrate that the gene re- 
sponsible for the fragile X syndrome is widely tran- 
scribed during fetal life. 
The laboratory of Assistant Investigator Fred D. 
Ledley, M.D. (Baylor College of Medicine) is ex- 
ploring the potential of somatic gene therapy by de- 
veloping methods of potential application to meth- 
ylmalonic acidemia (a model inborn error of 
metabolism) , congenital hypothyroidism , and arthri- 
tis. The group has described two novel targets for 
gene therapy involving direct introduction of DNA 
into tissues. 
The research activities of the laboratory of Inves- 
tigator Stuart H. Orkin, M.D. (Children's Hospital, 
Boston) center on the molecular biology and genet- 
ics of blood cells. Mechanisms controlling gene ex- 
pression and development of both red and white 
blood cells are under study. Genetic experiments 
have demonstrated that erythroid cell development 
is dependent on a single major transcription regula- 
tory protein. A gene transfer rescue assay has been 
established that permits more refined study of the 
role of this protein in red cell development. 
Through study of a white blood cell-expressed cy- 
tochrome subunit, a repressor of gene expression 
has been identified. This protein (CDP) resembles a 
Drosophila protein (encoded by the cut gene) and, 
as such, highlights the extensive parallels of gene 
regulation across species boundaries. 
The laboratory of Investigator Stephen A. Lieb- 
haber, M.D. (University of Pennsylvania) studies the 
human hemoglobin and growth hormone genes, 
with the goal of understanding how specific 
members of these two gene families are expressed at 
particular times during fetal development and how 
their expression is limited to particular tissues (the 
red cells in the case of the globin genes and the 
pituitary and placenta with growth hormone genes) . 
Answers to these questions will contribute to a more 
detailed understanding of gene function in normal 
individuals, as well as clarify defects underlying a 
broad range of genetic diseases. 
The laboratory of Assistant Investigator Jane M. 
Gitschier, Ph.D. (University of California, San Fran- 
cisco) studies the molecular basis of a variety of sex- 
linked disorders, including hemophilia A. A number 
of genes have been isolated and are being examined 
for their role in several of the inherited disorders. 
One appears to code for a copper transport protein 
and is defective in patients with the sex-linked dis- 
order, Menkes syndrome. In a separate line of exper- 
imentation, the gene coding for an antidiuretic hor- 
mone in the kidney was found to be mutated in 
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