Tracking Genes That Cause Human Disease 
Francis S. Collins, M.D., Ph.D. — Investigator 
Dr. Collins is also Professor of Internal Medicine and Human Genetics at the University of Michigan 
Medical School. He received his Ph.D. degree in physical chemistry from Yale University and his M.D. 
degree from the University of North Carolina. After completing his internship and residency in internal 
medicine at the North Carolina Memorial Hospital, he went on to a fellowship in human genetics at Yale. 
He recently received the Young Investigator Award of the American Federation of Clinical Research 
and the National Medical Research Award of the National Health Council and was elected to the Institute 
of Medicine and the American Association of Physicians. 
THE theme of our laboratory is the study of 
human genetic disease at the molecular 
level. Our goal is to identify genes involved in 
specific genetic disorders, to define their struc- 
ture and function, to understand the control of 
their expression, and to use this information to 
develop potential new therapies. 
Over 4,000 genetic disorders are listed in the 
most recent edition of Mendelian Inheritance in 
Man. For the majority of these, the normal func- 
tion of the gene involved is not known. The iden- 
tification of disease-causing genes without knowl- 
edge of their protein product or its normal role, 
now referred to as positional cloning, is a major 
endeavor in our research. 
Only recently has it become possible to iden- 
tify such genes, and the process is still laborious. 
First the gene must be mapped to a specific hu- 
man chromosome, using a process known as link- 
age analysis. This involves identification of fami- 
lies with the disorder and analysis of DNA from 
these families with a panel of probes from all 
parts of the human genome. The probes are used 
to establish the chromosomal location of a DNA 
sequence that may have been inherited in associa- 
tion with a disease gene that will probably lie 
close to it. Such sequences, or "markers," can 
pinpoint the chromosome on which the disease 
gene resides. Additional probes from that chro- 
mosome can then be tested to identify markers 
that are even closer. It is often possible to narrow 
the responsible region to about 1 percent of a 
particular chromosome. Although this is a major 
achievement, such a region may yet contain 30 to 
50 genes, only one of which is responsible for the 
disease. Thus additional refinements must be 
made before candidates for the responsible gene 
can be identified. 
In 1989, as part of a collaborative effort with 
investigators at the Hospital for Sick Children in 
Toronto, we were successful in identifying the 
gene for cystic fibrosis (CF), a common severe 
genetic disease characterized by lung infections, 
pancreatic insufficiency, and elevations in sweat 
chloride concentration. 
Although one mutation (AF508) is responsible 
for about 75 percent of CF chromosomes in the 
United States, numerous other mutations have 
now been found in other individuals with the dis- 
ease. This year we identified one mutation that 
gives rise to such a mild form of the disorder that 
it was not recognized as being caused by this 
same gene, because the affected individuals had 
normal sweat chloride. This observation indi- 
cates that mutations in the CF gene may have a 
broader clinical spectrum than previously 
suspected. 
Another important observation in CF this year 
has been the demonstration by our group that the 
AF508 mutation does not completely inactivate 
the gene. In fact, using a frog oocyte system, we 
were able to show that the AF508 protein can be 
activated to almost normal levels by using drugs 
that raise levels of cAMP, an intracellular second 
messenger. This suggests that drug therapy aimed 
at this second messenger might benefit patients 
with the disease by activating their defective CF 
protein. 
Another major project in our laboratory is an 
investigation of von Recklinghausen neurofibro- 
matosis (NFl), a common genetic disorder some- 
times incorrectly referred to as the Elephant Man 
disease. Having identified this gene in 1990, we 
are now intensively attempting to identify muta- 
tions that cause the disease and to determine the 
normal function of the protein product of this 
gene. Previous studies have demonstrated that 
this protein interacts with another class of pro- 
teins (encoded by the ras genes) involved in the 
regulation of cell growth. Recent data from our 
group have shown that the NFl protein also inter- 
acts with the cytoskeleton and can be seen to co- 
localize with microtubules using immunofluores- 
cence techniques. This unexpected observation 
suggests that the protein product of the NFl gene 
may play a crucial role in the regulation of cell 
division. In the longer term, it is hoped that this 
improved understanding of the biology of the dis- 
ease will lead to improved therapies. 
The Huntington disease (HD) gene has been 
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