Identification and Characterization of the Gene 
Responsible for Neurofibromatosis Type 1 
Raymond L. White, Ph.D. — Investigator 
Dr. White is also Professor of Human Genetics at the University of Utah School of Medicine. He received a 
B.S. degree in microbiology from the University of Oregon, Eugene, and a Ph.D. degree in microbiology 
from the Massachusetts Institute of Technology. He did postdoctoral research with David Hogness at 
Stanford University. Dr. White has held various academic appointments at the University of Massachusetts, 
Worcester, and the University of Utah. He has received many honors for his cancer research and recently 
was co-recipient of both the Charles 5. Mott Prize and the National Neurofibromatosis Foundation 's 
Friedrich von Recklinghausen Award. 
THE search for the gene that is altered in a 
dominantly inherited disorder, neurofibro- 
matosis type 1 (NFl), was successful when 
workers in our laboratory found in patients an 
abnormal sequence of DNA in the relevant region 
of chromosome 17. Knowledge of the normal 
and abnormal functioning of this gene will eluci- 
date the biochemical processes that lead to dis- 
ease in patients with NFl, and will open new 
opportunities to develop therapies for this 
relatively common and sometimes devastating 
disorder. 
Furthermore, the product of this gene falls into 
the category of proteins that help to control 
growth and differentiation, and for that reason 
the discovery has broad implications for those 
seeking to learn more about the intracellular 
chemical signals that determine the basic activi- 
ties of life and that may lead, when defective, to 
the formation of tumors. 
The region of chromosome 1 7 known to harbor 
the NF 1 gene had been narrowed to a point where 
only a few genes were likely to exist. However, 
the first candidate to be examined, EVI2A, did 
not differ in DNA sequence between NFl and 
non-NFl individuals. 
Two other genes, OMGP and EVI2B, were sub- 
sequently identified. OMGP was especially inter- 
esting because it is the coding element for a pro- 
tein expressed in cells of the central nervous 
system — cells thought to be counterparts of the 
peripheral Schwann cells affected in NFl. More- 
over, OMGP lies very near to the site of a chromo- 
somal break in a patient with NFl, a mutation 
assumed to be the cause of her disease. Neverthe- 
less, OMGP and EVI2B were eventually elimi- 
nated as candidates on the same grounds as 
EVI2A. 
All three genes lie in the same orientation on 
the chromosome. That is, they are all transcribed, 
or "read," in the same direction when the ge- 
netic code is being translated to form a protein 
within the cell. 
Finally, examination of DNA from many individ- 
uals detected three deletion mutations specific to 
NFl, within the region defined by translocations 
in two unrelated patients. Two of these deletions 
of DNA material were large enough to disrupt one 
or another of the known genes. The third, how- 
ever, did not affect any of them. This observation 
suggested that the mutation in that patient was 
disrupting a fourth gene. Furthermore, the se- 
quence affected by this mutation was very similar 
to one present in mouse DNA. (Conservation of 
sequence in evolution between widely disparate 
species often signals the presence of an important 
coding element.) 
The conserved sequence was used to seek out 
complementary DNA (cDNA) — that is, recombi- 
nant DNA copies of an active gene — from a "li- 
brary" of clones reflecting gene expression in 
human fetal brain tissue. When the DNA se- 
quence of the cDNA corresponding to this new 
gene was compared among normal individuals 
and several NFl patients, a number of mutations 
involving single base pairs of DNA were detected, 
and at least some of these changes were of a kind 
expected to be damaging to the protein product. 
These results, combined with other information, 
indicated that the NFl gene had at last been 
found. 
The remarkable finding of three other genes 
within the NFl gene, all oriented in the opposite 
direction to it on the chromosome, appears 
unique so far in human molecular biology. The 
significance of this phenomenon, and the possi- 
ble effect (s) of mutations in the NFl gene upon 
expression of any of the embedded genes, are 
subjects for further investigation. 
The NFl gene is very large, with coding re- 
gions, or exons, scattered over a wide region of 
genomic DNA. To date, several thousand base 
pairs of its sequence have been determined. The 
first discovery to emerge from the sequence data 
was a similarity between the predicted protein 
product of the NFl gene and the catalytic region 
of certain proteins, called GTPase-activating pro- 
teins or GAPs, that are known to interact with 
growth regulators within the cell. Experiments 
showed that, in fact, the NFl protein could sub- 
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