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Color Vision Defects
Color Vision Defects
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Maureen Neitz, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
Jay Neitz, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
Article contents
Introduction
Inherited Color Blindness
Color blind individuals see many fewer colors than do people with normal color vision.
Among color blind people there is tremendous variation in the capacity for color vision,
ranging from no color vision to nearly normal color vision.
Introduction
The biological basis of color vision can be divided into
two stages: the first is the light-sensitive cone photoreceptor cells in the retina and the second is the neural
components that process information about wavelength gathered by the photoreceptors. Humans with
normal color vision have three populations of cone
photoreceptors that are classed according to their
relative spectral sensitivities as short-, medium- and
long-wavelength sensitive, and abbreviated S, M and L
respectively. Red–green color vision is mediated by
neural circuitry that compares the quantal catches of L
and M cones; blue–yellow color vision is mediated by
circuitry that compares the summed quantal catches of
L and M cones with the quantal catch of S cones.
People with normal color vision can distinguish more
than a million colors, but people who are color blind
see many fewer colors. Color blindness can be
inherited or acquired. Inherited color blindness affects
the first stage of color vision and is commonly
caused by rearrangements, deletions and mutations of
genes that encode the light-absorbing photopigment
molecules in cones. Acquired color blindness
arises through insult to the visual system, for
example through drug or chemical toxicity, disease
or trauma. (See Visual Pigment Genes: Evolution.)
Inherited Color Blindness
Inherited color blindness can be categorized according
to the number of functional cone types present in the
retina. Autosomal recessive achromatopsia is a rare
disorder associated with the absence of functional
cones (complete achromatopsia) or with residual cone
function (incomplete achromatopsia). Defects in the
alpha and beta subunits of the cone photoreceptorspecific cyclic guanosine monophosphate (GMP)
gated ion channel are known causes (Sundin et al.,
2000; Wissinger et al., 2001). All three cone classes
require the function of this ion channel to generate an
electrical signal in response to light. It has been
Acquired Color Blindness
doi: 10.1038/npg.els.0006000
suggested that mutations causing complete
achromatopsia abolish ion channel function, whereas
incomplete achromatopsia is associated with mutations that allow residual channel function.
Monochromacy, dichromacy and anomalous
trichromacy are forms of color blindness characterized
by the presence of one, two or three functional types of
cone, respectively. All are caused by mutations that
lead to an altered complement of functional cone
photopigments expressed in the retina. Photopigments
are light-absorbing molecules that determine the cone
spectral sensitivities, and like cones are classed as S,
M and L. Photopigments have two components: a
transmembrane protein, termed opsin; and the chromophore, 11-cis-retinal. The chromophore is covalently attached to the opsin and is nestled in a
hydrophobic pocket formed by opsin’s transmembrane domain. Human L and M opsins share over
98% amino acid sequence identity and each is about
43% identical to S opsin (Nathans et al., 1986b).
Photopigment absorption spectra are tuned by the
amino acid sequence differences in the opsins (Neitz
et al., 1991; Asenjo et al., 1994). Two amino acid
substitutions together produce a large spectral shift
that separates the pigments into L and M classes
(Figure 1). Small shifts in spectrum resulting from
normal amino acid polymorphisms create spectral
variants of L and M pigments (Figure 1). Normal
sequence variation in the S pigment has not been
observed.
Tritan color vision deficiency or blue–yellow color
blindness is caused by mutations in the S cone pigment
gene (opsin 1 (cone pigments), short-wave-sensitive
(color blindness, tritan) (OPN1SW)) on chromosome 7
at 7q31.3–q32, and it affects less than 1 in 10 000
people (Nathans et al., 1992). The dichromatic form,
tritanopia, is autosomal dominant with incomplete
penetrance. Three amino acid substitutions in the
transmembrane domain of S opsin are known causes.
The existence of an anomalous trichromatic form and
its possible cause is uncertain.
Red–green color blindness is extremely common
and is caused by the absence of normal M or L cone
ENCYCLOPEDIA OF LIFE SCIENCES & 2005, John Wiley & Sons, Ltd. www.els.net
1
Absorption
(per cent of maximum)
Color Vision Defects
100
80
60
40
20
0
350
400
450
500
550
600
650
700
Wavelength (nm)
(a)
C-terminus
Helix 5
Helix 1
Helix 6
Helix 3
Helix 2
Helix 7
Helix 4
277
285
N -terminus
(b)
Figure 1 Tuning of cone photopigment absorption spectra.
(a) Absorption curves for S (blue curve), M-class (family of green
curves) and L-class (family of red curves) pigments. Wavelength of
peak absorption is 415 nm for S pigment, near 530 nm for M-class
pigments and near 560 nm for L-class pigments. The rectangular bar
below the x axis indicates the color appearance of different
wavelengths to a person with normal color vision. (b) Twodimensional representation of L and M opsins. Balls represent
amino acids. Gray balls are invariant amino acid positions among
normal L and M opsins. The black ball is the residue to which the
chromophore is attached. Red balls are the two amino acid positions
that produce the spectral difference between M- and L-class
pigments. Yellow balls are positions that produce small spectral
shifts and produce subtypes of M and L pigment. Blue balls are
variant positions with no influence on the spectrum.
function. The incidence varies with ethnicity, affecting
8% of Caucasian men, 4% of Japanese men and 3% of
African men. Only about 1 in 230 Caucasian females is
affected, but 15% are heterozygous carriers. The genes
opsin 1 (cone pigments), long-wave-sensitive (color
blindness, protan) (OPN1LW ) and opsin 1 (cone
pigments), medium-wave-sensitive (color blindness,
deutan) (OPN1MW ), encoding respectively the L and
M opsins, lie in a head-to-tail tandem array on the
distal tip of the long arm of the X chromosome at
Xq28. Rearrangements, deletions and mutations within the array are the main causes of red–green color
blindness. The X-chromosome location of the L and
M genes accounts for the dramatic gender difference in
2
the incidence of color blindness. Females have two X
chromosomes, males have one. If a male inherits an X
chromosome that confers expression of only one
functional class of pigment, he will be color blind. A
female will be affected only if both of her
X chromosomes together confer expression of a single
functional type of pigment.
Protan color vision defects are characterized by the
absence of normal L cone function, and affect about
2% of Caucasian men: 1% are dichromats (protanopes)
and 1% are anomalous trichromats (protanomalous).
Deutan color vision defects are characterized by the
absence of normal M cone function, and affect about
6% of Caucasian men: 1% are dichromats (deuteranopes) and 5% are anomalous trichromats (deuteranomalous). Figure 2 illustrates the difference between
dichromatic and normal color vision. People with
normal color vision see black, white, gray and four
unique color categories, red, green, yellow and blue,
which occur in combinations to produce thousands of
intermediates, but for the dichromat, all colors appear
as mixtures of just two hues (in this illustration, blue
and yellow) with black, white and gray. The region of
the spectrum between blue and yellow appears white
or gray to the dichromat.
Normal color vision requires at least one L, one M
and one S pigment gene. The tandemly repeated L and
M genes are prone to unequal homologous recombination and this has produced the diversity seen in the
modern human population in the gene sequences, the
number and arrangement of genes in the array and in
color vision phenotype (Nathans et al., 1986a; Neitz
et al., 1996). Both intragenic and intergenic recombination will produce new arrays with a different
number of genes from the parental arrays (Figure 3).
The ancestor to modern humans is believed to have
had an array with one L and one M pigment gene.
Unequal recombination between two such arrays will
produce one array with three genes, and another with
one gene (Figures 3a, 3b). A male who inherits an
array with one gene is an obligate dichromat, and will
be a protanope if the gene encodes an M-class pigment
or a deuteranope if it encodes an L-class pigment.
Chimeric genes in which parental L and M pigment
gene sequences are intermixed arise from intragenic
recombination (Figures 3b, 3c). Whether the chimeric
gene will encode an M-class or an L-class pigment is
determined by which parental gene contributes the
sequences encoding amino acid positions 277 and 285.
The most common array structure in deuteranomalous
men is an L gene followed by a chimeric gene that
encodes an L-class pigment, followed by an M gene
(Figures 3b, 3c). The M genes in deutan arrays are not
functionally expressed. Whether the chimeric and
parental L genes encode spectrally identical L-class
pigments depends on whether the pigments differ at
Color Vision Defects
(a)
(b)
Figure 2 Comparison of dichromatic and normal color vision. (a) The colors of the visible spectrum as they appear to a person with normal
color vision (left) were digitally altered (right) to illustrate the appearance of the same spectrum to a red–green color blind dichromat.
(b) Photograph of red and green peppers (left) digitally altered to illustrate the appearance of the same peppers to a red–green color blind
dichromat. There are two properties of color: hue and brightness. A person with normal color vision can detect the difference in hue between
bell peppers that do not differ significantly in brightness. A dichromat cannot detect the difference in hue, and the peppers appear to be all the
same color.
Normal
Normal
Normal
Normal
Normal
(a)
Deuteranope
Deutan
(b)
Normal
Deutan
Normal
Normal
Deutan
Deutan
(c)
Protan
Protanope
Deuteranope
or
Deuteranomalous
(d)
Normal
Figure 3 Recombination between X-chromosome pigment gene arrays required to produce arrays observed in the present-day
population underlying normal, protan and deutan color vision. (a) Intergenic recombination between ancestral two-gene arrays that
confer normal color vision gives rise to one new array that confers normal color vision and another that confers dichromacy (deuteranopia).
(b) Intragenic recombination between two two-gene arrays that confer normal color vision produces two new arrays that both confer
color blindness. (c) Intragenic crossover needed to produce protanomalous arrays. The parental three-gene array must be produced by
crossover between two ancestral two-gene arrays, and this added step probably accounts for the lower frequency of protanomaly in the
population. (d) To delete the M gene from a deutan array requires a crossover between a deutan array with an M gene and another array.
spectral tuning sites. If the encoded L-class pigments
have identical spectral properties, then a male with this
array will be a deuteranope (dichromat), but if they
differ in spectral properties he will be deuteranomalous (trichromat). Among deuteranomalous men,
there is variation in the extent of loss of color vision.
Generally, the more similar the L-class pigments are in
spectral sensitivity, the poorer the person’s color
vision, and conversely the more dissimilar the L-class
pigments, the better the person’s color vision (Neitz
et al., 1996).
Crossovers that produce arrays containing one or
more genes encoding M-class pigments, but lacking
genes for L pigments, give rise to protan defects
3
Color Vision Defects
(Figures 3b, 3c). A male inheriting an array with more
than one gene encoding an M-class pigment will be
protanomalous if the encoded pigments have different
spectral properties, but he will be a protanope if they
have identical spectral properties.
Although the genotype of the L/M gene array is a
strong predictor of color vision phenotype, it is not
100% accurate. For example, some individuals would
be predicted to be anomalous trichromats from
genotype, but behave as dichromats. Rarely, males
with red–green color blindness have an X-chromosome
visual pigment gene array that is grossly indistinguishable from an array underlying normal color vision. In
some cases, missense mutations that render either the
L or M opsin nonfunctional have been identified; the
most common mutation is substitution of arginine for
cysteine at amino acid position 203 of the opsin.
Blue cone monochromacy is a rare inherited color
vision defect characterized by the lack of functional
L and M cones (Nathans et al., 1989). There are two
known causes. First, some affected individuals have a
single X-chromosome visual pigment gene that has a
deleterious mutation. Second, about 40% of genetically characterized blue cone monochromats have a
deletion of an enhancer that lies upstream of the
X-chromosome visual pigment gene array and that is
required for expression of the L and M genes (Nathans
et al., 1993).
Acquired Color Blindness
Acquired color blindness generally affects all three
cone classes, although not necessarily equally. It can
be caused by toxicity, for example by exposure to
ethambutol (used to treat tuberculosis), to drugs for
treating hypertension and to solvents used in the
plastics industry. Color vision loss is associated with
systemic diseases such as multiple sclerosis and
diabetes, and with ocular diseases such as glaucoma
and optic neuropathy.
See also
Chromosome X: General Features
Visual Pigment Genes: Evolution
References
Asenjo AB, Rim J and Oprian DD (1994) Molecular determinants of
human red/green colour discrimination. Neuron 12: 1131–1138.
Nathans J, Davenport CM, Maumenee IH, et al. (1989) Molecular
genetics of blue cone monochromacy. Science 245: 831–838.
Nathans J, Maumenee IA, Zrenner E, et al. (1993) Genetic
heterogeneity among blue-cone monochromats. American Journal of Human Genetics 53: 987–1000.
Nathans J, Merbs SL, Sung C, Weitz CJ and Wang Y (1992)
Molecular genetics of human visual pigments. Annual Review of
Genetics 26: 403–424.
4
Nathans J, Piantanida TP, Eddy RL, Shows TB and Hogness DS
(1986a) Molecular genetics of inherited variation in human
colour vision. Science 232: 203–210.
Nathans J, Thomas D and Hogness DS (1986b) Molecular genetics
of human colour vision: the genes encoding blue, green and red
pigments. Science 232: 193–202.
Neitz M, Neitz J and Jacobs GH (1991) Spectral tuning of pigments
underlying red–green colour vision. Science 252: 971–974.
Neitz J, Neitz M and Kainz PM (1996) Visual pigment gene structure
and the severity of color vision defects. Science 274: 801–804.
Sundin OH, Yang JM, Li Y, et al. (2000) Genetic basis of total
colourblindness among the Pingelapese islanders. Nature Genetics
25(3): 289–293.
Wissinger B, Gamer D, Jägle H, et al. (2001) CNGA3 mutations in
hereditary cone photoreceptor disorders. American Journal of
Human Genetics 69: 722–732.
Further Reading
Birch J (1993) Diagnosis of Defective Colour Vision. New York, NY:
Oxford University Press.
Nathans J (1989) The genes for colour vision. Scientific American
260: 24–49.
Nathans J, Merbs SL, Sung C, Weitz CJ and Wang Y (1992)
Molecular genetics of human visual pigments. Annual Review of
Genetics 26: 403–424.
Neitz M and Neitz J (1998) Molecular genetics and the biological
basis of colour vision. In: Backhaus WGK, Reinhold K and
Werner JS (eds.) Color Vision: Perspectives from Different
Disciplines, pp. 101–119. New York, NY: Walter de Gruyter.
Neitz M and Neitz J (2000) Molecular genetics of colour vision and
colour vision defects. Archives of Ophthalmology 118: 691–700.
Neitz J, Carroll J and Neitz M (2001) Colour vision: almost reason
enough for having eyes. Optics and Photonics News 12: 26–33.
Piantanida T (1988) The molecular genetics of colour vision and
colour blindness. Trends in Genetics 4: 319–323.
Sharpe LT, Stockman A, Jägle H and Nathans J (1999) Opsin genes,
cone photopigments, colour vision, and colour blindness. In:
Gegenfurtner KR and Sharpe LT (eds.) Colour Vision: From
Genes to Perception, pp. 3–52. New York, NY: Cambridge
University Press.
Web Links
Color Vision molecular Genetics. Neitz Lab Color Vision Web Page
http://www.mcw.edu/cellbio/colorvision/
Opsin 1 (cone pigments), short-wave-sensitive (color blindness,
tritan) (OPN1SW ); Locus ID: 611. LocusLink:
http://www.ncbi.nlm.nih.gov/LocusLink/LocRpt.cgi?l=611
Opsin 1 (cone pigments), medium-wave-sensitive (color blindness,
deutan) (OPN1MW ); Locus ID: 2652. LocusLink:
http://www.ncbi.nlm.nih.gov/LocusLink/LocRpt.cgi?l=2652
Opsin 1 (cone pigments), long-wave-sensitive (color blindness,
protan) (OPN1LW); Locus ID: 5956. LocusLink:
http://www.ncbi.nlm.nih.gov/LocusLink/LocRpt.cgi?l=5956
Opsin 1 (cone pigments), short-wave-sensitive (color blindness,
tritan) (OPN1SW); MIM number: 190900. OMIM:
http://www.ncbi.nlm.nih.gov/htbin-post/Omim/
dispmim?190900
Opsin 1 (cone pigments), medium-wave-sensitive (color blindness,
deutan) (OPN1MW); MIM number: 303800. OMIM:
http://www.ncbi.nlm.nih.gov/htbin-post/Omim/
dispmim?303800
Opsin 1 (cone pigments), long-wave-sensitive (color blindness,
protan) (OPN1LW); MIM number: 303900. OMIM:
http://www.ncbi.nlm.nih.gov/htbin-post/Omim/
dispmim?303900