Molecular Biology of Visual Pigments 
Interestingly, the human gene pool contains 
two versions of the red pigment. One carries an 
alanine at position 180 and absorbs maximally at 
552 nm, whereas the second version carries a ser- 
ine at position 180 and absorbs maximally at 557 
nm. This spectral difference explains a number of 
long-standing observations regarding differences 
in color vision among otherwise color-normal in- 
dividuals. We are now using this system to study 
hybrid pigments encoded by hybrid genes that 
were generated by recombination between the 
red and green pigment genes. Hybrid genes of 
this type are carried by 7 percent of human X 
chromosomes and account for most of the com- 
mon forms of red-green color blindness. 
Control of Visual Pigment Gene Expression 
We have been interested for some time in the 
general question of how different cells in the ret- 
ina assume their correct identities. As an initial 
approach, we have examined the control of vi- 
sual pigment gene expression. Each photorecep- 
tor cell appears to produce only a single type of 
visual pigment: rhodopsin in the rods, and the 
red, green, and blue pigments in their respective 
cone types. As a working model, we assume that 
this specificity in protein production reflects a 
corresponding specificity at the level of gene 
transcription. 
One region of DNA that is important for activa- 
tion of the red and green pigment genes has re- 
cently been identified. Over the past several 
years, we have studied families with a rare X- 
linked disorder called blue cone monochromacy, 
in which both red and green cone sensitivities are 
absent. In many families a DNA deletion is ob- 
served in which sequences are removed adjacent 
to the cluster of red and green pigment genes on 
the X chromosome. This set of deletions defines a 
region of 0.6 kilobases that appears to be re- 
quired for normal red and green visual pigment 
gene function, even though the start sites of tran- 
scription of these genes are, respectively, 3 kilo- 
bases and 42 kilobases away. 
Yanshu Wang, a graduate student, has recently 
shown that a segment of human DNA encompass- 
ing this essential region and including the red 
pigment gene promoter directs expression of a 
linked reporter gene to cone cells in the mouse 
retina. An otherwise identical construct from 
which the 0.6-kilobase segment has been re- 
moved is inactive. We have observed that within 
this essential segment, there is a smaller region 
that has a high degree of DNA sequence homol- 
ogy across species. Most likely, this region repre- 
sents a binding site for one or more transcription 
factors present in the red and green cones. 
Retinitis Pigmentosa 
During the past several years, we have begun to 
work on a group of inherited retinal diseases 
called retinitis pigmentosa (RP). The hallmarks 
of RP are night blindness and a slow progressive 
loss of peripheral vision, leading in most cases to 
complete blindness by the fifth or sixth decades 
of life. RP affects one person in 4,000 in all popu- 
lations examined. Last year Ching-Hwa Sung, a 
postdoctoral fellow, reported finding rhodopsin 
mutations in one-quarter of patients with autoso- 
mal dominant RP, an inheritance pattern that is 
found in approximately one-fifth of the patient 
population. In a group of l6l unrelated patients, 
13 different mutations were identified, and in all 
cases the mutations co-inherited with the disease 
in affected families. 
Dr. Sung has produced each of the mutant op- 
sins, as well as normal human opsin, in tissue cul- 
ture cells and has analyzed their biochemical 
properties. The mutant proteins fall into two 
classes. Members of one class resemble wild-type 
opsin in yield, ability to bind 1 l-cis retinal, and 
efficient transport to the cell surface. By contrast, 
members of the second class are produced in low 
yield, bind 1 1 -cis retinal variably or not at all, and 
are transported inefficiently to the cell surface. 
These characteristics suggest that the second 
class of mutant proteins are either incorrectly 
folded or unstable. It seems reasonable to sup- 
pose that production of large quantities of an un- 
stable opsin may be deleterious to the photore- 
ceptor. The biochemical defect in the first class 
of mutant proteins is not apparent from the ex- 
periments performed thus far and is currently 
under investigation. 
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