Molecular Genetics ofX-linked Disease 
Robert L. Nussbaum, M.D. — Associate Investigator 
Dr. Nussbaum is also Associate Professor of Human Genetics, Pediatrics, and Medicine at the University of 
Pennsylvania School of Medicine and Consultant in Clinical Genetics at the Children's Hospital of 
Philadelphia. He received his undergraduate training in applied mathematics at Harvard College and his 
M.D. degree at Harvard Medical School in the Harvard-MIT Joint Program in Health Sciences and 
Technology. After his residency in internal medicine at Barnes Hospital, Washington University School of 
Medicine, he moved to Baylor College of Medicine, first for a genetics fellowship with Thomas Caskey and 
Arthur Beaudet and later as a faculty member. He then moved to the University of Pennsylvania, where 
he developed his research program in molecular genetics and its application to the diagnosis and 
elucidation of human genetic disease. 
THE research in my laboratory is directed to- 
ward elucidating the molecular bases for a 
number of human genetic diseases. Each disease 
under investigation is known to be caused by a 
gene on the X chromosome, but the molecular 
mechanism, the gene involved, and the nature of 
the underlying mutations have been hitherto un- 
known. Recombinant DNA techniques have been 
employed to isolate the responsible genes, with 
the aim of furthering our understanding of the 
normal processes that when disrupted result in 
each of these diseases. 
Choroideremia 
Choroideremia is a rare X-linked disease of the 
retina that produces blindness in affected males. 
The gene responsible and the mechanism of reti- 
nal damage have until recently been unknown. 
Our laboratory is using information about where 
the choroideremia gene is to identify it and ex- 
plain why mutations in this gene cause the 
disease. 
We have isolated a gene from the region around 
a chromosomal translocation in a female patient 
with choroideremia. Her disease resulted from 
disruption of the choroideremia gene by the chro- 
mosomal break in the X chromosome in this re- 
gion. A transcribed gene that is disrupted by this 
chromosomal translocation has been identified 
and found to be very similar, although not identi- 
cal, to one isolated in the laboratory of Frans 
Cremers by his study of males with choroi- 
deremia and submicroscopic deletions. The ex- 
pression of this gene, at the level of mRNA, 
is abnormal in 75 percent of patients with 
choroideremia. 
The predicted protein sequence of the gene 
identified in both laboratories has a subtle similar- 
ity with a protein isolated from platelets that may 
be involved in regulation of the G proteins, a very 
large and heterogeneous group involved in carry- 
ing certain intracellular signals. The cellular 
mechanism by which vision occurs, known as vi- 
sual transduction, is the entire pathway by which 
light, the initial signal, is translated first into bio- 
chemical reactions and then nervous impulses in 
the retina. A growing body of evidence suggests 
that abnormalities in the proteins that carry out 
visual transduction contribute to a variety of de- 
generative retinal diseases that lead to blindness. 
The plan is to investigate the exact role of the 
choroideremia gene product in visual transduc- 
tion, in an attempt to understand how abnormali- 
ties in that gene lead to retinal degeneration. This 
work is supported by a grant from the National 
Institutes of Health. 
Lowe's Syndrome 
Lowe's syndrome is an uncommon X-linked 
disease that causes mental retardation, cataracts, 
and kidney dysfunction. The cause is unknown. 
As with choroideremia, our strategy is to identify 
the Lowe's syndrome gene through information 
about its location. 
We have isolated two cDNA sequences from the 
region around a translocation breakpoint in a fe- 
male with Lowe's syndrome. The transcript de- 
tected by one of these cDNAs is disrupted by the 
translocation and is absent or abnormal in nine 
unrelated males with the disease. This gene en- 
codes a protein involved in the metabolism of 
inositol phosphates, a very heterogeneous but 
important class of compounds with a complex 
biochemistry. These structural components of 
normal cell membranes also play an important 
role in anchoring proteins to cell membranes and 
in intracellular signaling pathways. 
Our goal is to understand the biochemical pro- 
cesses that, when defective, lead to brain, lens, 
and kidney dysfunction and damage. Insights into 
normal lens formation and normal brain and kid- 
ney function could result, and methods for im- 
proved diagnosis and therapy for the disease may 
be found. This work is supported by a grant from 
the National Institutes of Health. 
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