repeat expansion, which has been found to operate 
in the major mental retardation disease of fragile X 
syndrome and in myotonic dystrophy. This points 
the way technically toward the isolation of other 
disease genes by simple methods. Dr. Caskey's labo- 
ratory will now expand its search to cancer and the 
genes of aging. Mouse genetic technology now al- 
lows testing of human disease mechanisms and 
treatment with speed and precision. 
Investigator Louis M. Kunkel, Ph.D. (Children's 
Hospital, Boston) and his associates are continuing 
their study of dystrophin and dystrophin-related 
proteins. Dystrophin is the protein disrupted by mu- 
tation that gives rise to Duchenne/Becker muscular 
dystrophy. The related proteins are likely to be in- 
volved in the generation of other neuromuscular 
genetic diseases. They are also proteins with the 
potential of replacing dystrophin's function in dis- 
eased muscle and represent a potential avenue for 
therapeutic intervention. The overall aims of the 
laboratory are to identify new neuromuscular dis- 
ease genes and to design means of treating children 
affected with muscular dystrophy. 
The research in the laboratory of Associate Inves- 
tigator Robert L. Nussbaum, M.D. (University of 
Pennsylvania) has been directed in the past toward 
elucidating the molecular bases for three human ge- 
netic diseases that cause mental retardation and/or 
abnormalities in vision or hearing: fragile X syn- 
drome, choroideremia, and the Lowe oculocere- 
brorenal syndrome. Each disease under investiga- 
tion was known to be caused by a gene on the X 
chromosome, but the molecular mechanism, the 
gene involved, and the nature of the underlying mu- 
tations have been hitherto unknown. Work by this 
group and in other laboratories has allowed the 
identification and isolation of the genes responsible 
for all three of these diseases. The laboratory will 
now concentrate on studying the gene responsible 
for the Lowe oculocerebrorenal syndrome and the 
normal processes that are disrupted by defects in 
this gene. The group is also undertaking an analysis 
of a human gene that shows strong similarity to cer- 
tain genes in yeast and fruit flies that encode a class 
of transcription factors known as global activators of 
transcription. 
Investigator David L. Valle, M.D. (Johns Hopkins 
University) and his colleagues have continued their 
studies of genes involved in human genetic disease. 
In particular, they have examined the cell biology, 
expression, and genetic defects of the ornithine-6- 
aminotransferase gene. Deficiency of this enzyme 
disrupts ornithine metabolism and causes an in- 
herited, blinding, progressive chorioretinal degen- 
eration known as gyrate atrophy of the choroid and 
retina. Other genes important for retinal function, 
including the human homologue of recoverin, have 
been cloned, and their possible role in retinal de- 
generation is being explored. Finally, molecular 
studies of genes involved in peroxisomal biogenesis 
are ongoing. The genes for two peroxisomal integral 
membrane proteins have ben cloned. One, which 
encodes the 70-kDa peroxisomal membrane pro- 
tein, appears to be responsible for the inborn errors 
of peroxisomal biogenesis in a subset of patients. 
Associate Investigator Jeremy Nathans, M.D., 
Ph.D. (Johns Hopkins University) and his col- 
leagues are investigating the function and develop- 
ment of the human retina, the light-absorbing tissue 
in the eye that carries out the first steps in vision. 
This past year his laboratory succeeded in produc- 
ing the light-sensing compounds, called visual pig- 
ments, that mediate color vision. By producing and 
characterizing the visual pigments found in those 
6-8% of males with anomalous color vision. Dr. 
Nathans was able to define precisely the way in 
which their vision differs from that of the majority of 
the population. In other work, the laboratory has 
continued its analysis of the genetic defects respon- 
sible for retinitis pigmentosa, a progressive degen- 
eration of the retina that affects 1 person in 4,000. 
Thus far, 18 different mutations have been identi- 
fied in the gene encoding rhodopsin, the visual pig- 
ment mediating dim light vision. Biochemical stud- 
ies of these mutant proteins show that there are at 
least two different types of defect. 
Hearing loss is the most common form of sensory 
impairment. Profound childhood hearing loss in hu- 
man populations has an incidence of 4-8/1,000 
births in developed countries, with the likely etiol- 
ogy of a single gene mutation in at least half. An 
estimated 5% of school-age children have unilateral 
and/or mild-to-moderate hearing loss, representing 
a potentially reversible cause of learning difficulty. 
Progressive hearing loss, or presbycusis, occurs as 
pan of the normal aging process, with a one in six 
chance of functionally significant hearing loss by 
age 65. While environmental causes such as acous- 
tic trauma, infection, and ototoxic drugs play a sig- 
nificant causative role in auditory sensory impair- 
ment, underlying predisposing genetic factors are 
likely. Some types of genetic hearing loss can easily 
be distinguished, since they occur in association 
with other features as part of a syndrome and are a 
major component in more than 100 defined genetic 
disorders. Nonsyndromic or undifferentiated hear- 
ing loss represents the second major category of 
hearing loss in which auditory sensory impairment 
is an isolated finding. Analysis of such families is 
complicated by the difficulty in determining 
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