chromosome. There are over 400 inherited diseases 
whose genes are known to be located on the X 
chromosome. Investigator C. Thomas Caskey, M.D. 
(Baylor College of Medicine) and his colleagues 
have developed a simple means of scanning these 
disease-producing genes for the mutation that is 
specific for a given family. These developments have 
made possible the accurate diagnosis of affected 
children as well as the identification of female carri- 
ers at risk of bearing affected males. Given this suc- 
cess, the laboratory is now embarking on a strategy 
for cloning the X chromosome and identifying more 
readily all disease-producing genes on the chromo- 
some. 
The laboratory of Associate Investigator Francis S. 
Collins, M.D., Ph.D. (University of Michigan) is also 
engaged in the search for genes responsible for 
human genetic diseases. Working with collabora- 
tors in Toronto, they have identified the cystic fibro- 
sis gene and characterized the mutation that causes 
this disease, the most common genetic disorder of 
the Caucasian population. A similar set of strategies 
is being applied to identify the neurofibromatosis 
and Huntington disease genes. Efforts to under- 
stand gene regulation are also under way, both for 
the cystic fibrosis gene and for the human fetal he- 
moglobin genes. 
Associate Investigator Louis M. Kunkel, Ph.D. 
(Children's Hospital, Boston) and his colleagues 
have increased their understanding of dystrophin, 
the protein product of the Duchenne/Becker mus- 
cular dystrophy locus. By injecting normal muscle 
cells into mutant mouse muscle, they have success- 
fully replaced dystrophin in a mouse model of the 
disease. Dr. Kunkel's group is currently looking for 
patients with unexpected clinical symptoms for ab- 
normalities of dystrophin. The work has now ex- 
panded into identification and isolation of proteins 
related to dystrophin in the anticipation that these 
proteins may be disrupted in other neuromuscular 
disorders. 
The laboratory of Investigator Uta Francke, M.D. 
(Stanford University) has been engaged in assigning 
cloned genes of known functions for a variety of 
cell surface receptors, hormones, or regulatory pro- 
teins, as well as muscle-specific enzymes, to sites on 
human and mouse chromosomes. Panels of well- 
characterized somatic cell hybrids and in situ chro- 
mosomal hybridization techniques are being used. 
Recently, genetic mapping in the mouse has also 
been carried out with recombinant inbred strains 
for more precise localization on the genetic map. 
The comparative human and mouse maps are con- 
verging as more conserved syntenic regions are rec- 
ognized. Based on gene localization, hypotheses 
have been formulated and are being tested regard- 
ing candidate genes involved in specific mutations 
or human inherited disorders. In addition. Dr. 
Francke's laboratory is attempting to determine the 
molecular basis for autosomal forms of muscular 
dystrophy that clinically resemble the X-linked clas- 
sical Duchenne muscular dystrophy in families in 
which it has been shown that the dystrophin gene 
is not involved. 
Phenylketonuria (PKU) is a genetic disorder of 
amino acid metabolism that causes severe and 
permanent mental retardation in untreated chil- 
dren. A number of PKU mutations associated 
with prevalent mutant phenylalanine hydroxylase 
alleles have been characterized in both Caucasians 
and Orientals by the laboratory of Investigator 
Savio L. C. Woo, Ph.D. (Baylor College of Medi- 
cine). At present, about 50% and 30% of PKU car- 
riers, respectively, can be readily detected in the 
two populations. Once the 75% level has been 
reached by characterizing additional mutant alleles, 
screening can be implemented to reduce the carri- 
er frequency by a factor of four. This reduction 
can theoretically lead to the reduction of PKU 
incidence from 400/year to only 25/year in this 
country. 
Recombinant DNA techniques are being used by 
Investigator Arthur L. Beaudet, M.D. (Baylor Col- 
lege of Medicine) and his colleagues to study 
human genetic diseases. The exact mutations have 
been identified in numerous patients with 
citruUinemia, a fatal disorder of children caused by 
accumulation of ammonia in the body. Somatic 
gene therapy for citruUinemia also is being ex- 
plored. The gene for spinocerebellar ataxia, a fatal 
human disease manifested by neurological deterio- 
ration and loss of muscle control in middle age, has 
been mapped by Dr. Beaudet's group to a small 
portion of human chromosome 6. The laboratory 
has also worked extensively to develop DNA tests 
for prenatal diagnosis, carrier detection, and popu- 
lation screening for cystic fibrosis. 
Investigator David Valle, M.D. (The Johns Hop- 
kins University) and his colleagues also focus on 
molecular studies of genes responsible for inborn 
errors of metabolism. In particular, his laboratory 
has examined the regulation, expression, and ge- 
netic defects of the gene encoding ornithine-8-ami- 
notransferase. Deficiency of this enzyme disrupts 
ornithine metabolism and causes an inherited form 
of blindness due to progressive chorioretinal de- 
Continued 
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