Molecular Biology of Visual Pigments 
map coordinates for the wiring of the visual 
system. 
Inherited Variation 
The human visual system has several experi- 
mental attributes that facilitate a genetic analysis: 
first, humans can accurately report their visual 
experience in sensitive, noninvasive behavioral 
tests; second, inherited alterations in visual func- 
tion rarely affect longevity or fecundity — and 
thus usually persist in the gene pool; and third, 
persons with significant visual disorders usually 
present themselves to the medical community. 
We have taken advantage of these attributes to 
identify persons with mutations in each of the 
four genes for visual pigments. 
Several years ago we showed that the common 
forms of red-green colorblindness are due to mu- 
tations in the red and green cone pigments. More 
recently Charles Weitz has identified amino acid 
substitutions in the blue pigment gene in patients 
with defects in blue sensitivity. A rare form of 
severe color vision deficiency, blue cone mono- 
chromacy, occurs when both red and green cone 
systems are inactive. Our analysis of 30 blue cone 
monochromat families shows that deletion of a 
small DNA sequence adjacent to the red and 
green pigment genes suffices to cause the defect. 
Yanshu Wang, a graduate student, has recently 
shown that a large DNA fragment containing this 
region directs expression of a reporter gene to 
cone photoreceptor cells in transgenic mice. 
To identify rhodopsin gene mutations, we ex- 
amined patients with defects in night vision and 
peripheral vision. (Rhodopsin is the visual pig- 
ment in rods — the photoreceptors, enriched in 
the peripheral retina, that subserve dim-light vi- 
sion.) Night blindness and loss of peripheral vi- 
sion are the hallmarks of retinitis pigmentosa, a 
family of genetic disorders that affect 1 person in 
4,000. We recruited patients with retinitis pig- 
mentosa, and Ching-Hwa Sung, a postdoctoral 
fellow, screened their rhodopsin genes, using de- 
naturing gradient gel electrophoresis, a new and 
rapid method for detecting point mutations. 
Thus far we have discovered 1 3 different point 
mutations in the rhodopsin gene, together ac- 
counting for 24 percent of patients with autoso- 
mal dominant retinitis pigmentosa. All of the mu- 
tant proteins have been produced in the tissue 
culture expression system. The single most com- 
mon mutation, a proline-to-histidine substitution 
at amino acid 23, results in a protein that be- 
comes stuck in the endoplasmic reticulum. 
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