Molecular Studies of Human Genetic Disease 
Arthur L. Beaudet, M.D. — Investigator 
Dr. Beaudet is also Professor in the Institute for Molecular Genetics and the Departments of Pediatrics and 
Cell Biology at Baylor College of Medicine. He received his B.S. degree in biology from Holy Cross College 
and his M.D. degree from Yale University. After completing his pediatric residency at the Johns Hopkins 
Hospital, he performed postdoctoral research at NIH. 
EXTRAORDINARY progress in the understand- 
ing and diagnosis of human genetic diseases 
has occurred over the past decade. Much of this 
progress was made possible by the application of 
recombinant DNA techniques to the analysis of 
those diseases caused by an alteration in a single 
gene. There are thousands of such disorders, in- 
cluding well-known conditions such as cystic fi- 
brosis, Duchenne muscular dystrophy, hemo- 
philia A and B, sickle cell anemia, and Tay Sachs 
disease. Although this progress in the diagnosis of 
single-gene disorders continues unabated, the 
ability to treat genetic disease virtually stands 
still by comparison. There is hope that at least 
some of these diseases will yield to somatic gene 
therapy. 
The extraordinary diagnostic ability that allows 
anticipation of genetic symptoms in individuals 
and their offspring raises important societal op- 
portunities and concerns. These include preven- 
tion of genetic disease through reproductive 
planning, treatment prior to development of 
symptoms, and possible discrimination (as for in- 
surance or employment) on the basis of one's ge- 
netic predispositions. 
Abnormalities of a single gene, however, are 
not responsible for most of the common medical 
problems of adult life. Rather, these are caused 
by differences in a number of genes in combina- 
tion with environment and life-style. Problems of 
this type include atherosclerosis, hypertension, 
diabetes mellitus, and autoimmune disease. 
Work in our laboratory involves various aspects 
of precise genetic diagnosis, efforts to develop 
somatic gene therapy, and attempts to understand 
the complex genetic basis of some of these multi- 
factorial disorders. 
Cystic Fibrosis 
Cystic fibrosis (CF) is a common genetic dis- 
ease alfecting approximately 1 in 2,500 Cauca- 
sians. Most CF patients die of progressive lung 
disease during childhood or young adult life. 
About 1 in 25 Caucasians carry an abnormal CF 
gene, and about 1 in 625 couples are at high risk 
of having an affected child. Our laboratory has 
been actively involved in developing and imple- 
menting DNA testing for purposes of prenatal 
diagnosis and carrier detection of CF. Prenatal 
diagnosis for high-risk couples who have a l-in-4 
chance that a pregnancy will be affected with CF 
is now a routine matter, and such diagnosis is per- 
formed at many laboratories throughout the 
world. Similarly, carrier detection for close rela- 
tives of CF patients is routine. 
Much more controversial is whether carrier 
testing for CF should be offered to most or all 
couples prior to reproduction. Although a single 
common defect is present in the majority of CF 
chromosomes, the remaining fraction of abnor- 
mal chromosomes contains dozens of different 
mutations. One goal of efforts in our laboratory is 
to develop efficient methods for detection of 
such multiple abnormalities. Currently carrier 
testing identifies 80-90 percent of carriers and 
would detect up to 80 percent of couples at risk 
for having a CF child. Although it is unclear 
whether CF carrier testing should be offered to all 
couples immediately or in the very near future, it 
is our view that carrier testing will be the starting 
point for multiphasic DNA testing to provide in- 
formation regarding reproductive and health 
risks. 
Precise genetic diagnosis for CF, and for other 
genetic disorders, does not guarantee an effective 
treatment. It would be desirable to have an ani- 
mal model for easier analysis and therapeutic 
trials. As one step in the process of developing an 
animal model in mice, we have characterized the 
sequence of the mouse CF gene. We have pre- 
pared DNA clones that are suitable for disrupting 
the normal mouse gene (which is similar to the 
human gene) in cultured embryonic stem (ES) 
cells. These altered ES cells can be used to gener- 
ate mice affected with CF. The work to obtain a 
CF mutant mouse is supported in part by a grant 
from the Cystic Fibrosis Foundation. 
Somatic gene therapy for CF focuses on the 
lung, since it is involvement of the lung that 
proves fatal for the vast majority of CF patients. 
Treatment of the lung presents a unique circum- 
stance, for therapeutic agents can be delivered by 
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