Background

Types of Color Vision Defects

Normal color vision is the term used for the form of color vision shared by most humans. People with normal color vision can perceive four distinct (or unique) hues: red, yellow, green, and blue. Color information is extracted by neural circuits that compare the outputs of the cones. Red-green color vision is mediated by circuits that compare the outputs of the L and M cones. Blue-yellow color vision is mediated by circuits that compare the output of S cones to the summed outputs of the L and M cones. Together, these two neural systems provide the capacity to distinguish more than 100 different gradations of hue, which can be thought of as the sensations of the four unique hues individually or in combinations, such as shades of yellow-green, blue-green, purple (a red-blue color), and orange (a red-yellow color). People with congenital color vision defects see fewer hues than do people with normal color vision.

The term protan refers to color vision defects caused by the absence of functional L-cone pigment, and the term deutan refers to the absence of functional M-cone pigment. Together, protan and deutan defects are the most common inherited forms of color blindness, and they preferentially affect males. Their incidence varies with ethnicity (for a recent review see Sharpe et al., 1999). About 2% of Caucasian men suffer from a protan defect and 6% from a deutan defect. Only about 1 in 230 females is affected by protan or deutan defects. Within the protan and deutan categories of color vision deficiency, there is variation in the degree to which color vision is impaired. The most severe forms are the dichromatic types, protanopia and deuteranopia, in which color vision is based on just two pigments in two types of cones, either S and M (protanopes) or S and L (deuteranopes). The milder forms are the anomalous trichromacies, protanomaly and deuteranomaly, in which the L or M pigment, respectively, is missing but is replaced by a pigment that allows a reduced form of trichromatic color vision. Understanding the nature of the pigments underlying anomalous trichromacy compared to normal color vision is complicated by the fact that there are normal variations in the L and M pigments. The L and M pigments can be thought of as forming two variable but mutually exclusive classes, illustrated in the lower part of Figure 63.1. Individuals with deuteranomaly, a form of anomalous trichromacy, lack an M pigment, but they have two different pigments from the L class. Individuals with protanomaly lack an L pigment, but they have two slightly different pigments from the M class. Within the anomalous trichromacies there is a wide range of phenotypic variation, with some affected individuals having hue perception approaching normal, while others have color vision almost as poor as a dichromat's.

Figure 63.1..  

Spectral tuning in L and M photopigments. Shaded and unshaded arrows represent L- and M-photopigment genes, respectively. Thin black rectangles within the arrows represent the six exons, which are separated by five much larger introns. The relative sizes of introns and exons are drawn to scale. The seven spectral tuning sites encoded by exons 2 to 5 of the genes are indicated in the upper-left diagram along with the codon/amino acid number. The single-letter amino acid code is used to indicate the amino acid identities. When all seven amino acid residues are the ones shown for the schematic L gene (upper left), the pigment has the longest possible spectral peak (approximately 560 nm). When all the amino acids are those shown for the schematic M gene (upper left), the spectral peak is approximately 530 nm. Transposing the spectral tuning amino acids from L into M and vice versa produces pigments with intermediate spectral sensitivities. Amino acids 277 and 285, encoded by exon 5, produce the largest spectral shifts and define two major classes of pigments, M and L (bottom). Substitutions of amino acids encoded by exons 2, 3, and 4 are responsible for smaller spectral shifts that produce spectral subtypes within the L and M classes. The upper-right column shows the spectral variants of the L-class and M-class pigments encoded by genes that have been identified in humans. The shading surrounding individual exons indicates whether the spectral tuning site(s) specified by that exon encode the amino acids that shift the spectrum long (shaded) or short (unshaded). The wavelength of maximal sensitivity for each of variant pigments shown is an estimate derived by extrapolation from numerous studies (Asenjo et al., 1994; Merbs and Nathans, 1992; Neitz et al., 1995). The single-letter amino acid code is as follows: S, serine; Y, tyrosine; A, alanine; T, threonine; F, phenylalanine; I, isoleucine.

A third class of congenital color vision deficiency, referred to as tritan, is associated with defects in the S-cone pigment. These defects occur in males and females with equal frequency and are extremely rare, affecting fewer than 1 in 10,000 people. Also extremely rare are the monochromatic color vision defects, the achromatopsias. These disorders are associated with normal rod photoreceptor function but reduced (incomplete achromatopsia) or absent (complete achromatopsia) cone function. One form of incomplete achromatopsia is blue cone monochromacy, which is generally characterized by the absence of both normal L- and M-cone function (Nathans et al., 1989). In the human retina, about 7% of the cones are S, and the remainder are L and M. Blue cone monochromats base their vision on S cones and rods and thus have diminished capacity for all aspects of vision mediated by cones, including color vision and acuity. Rod monochromacy is a form of complete achromatopsia. Affected individuals are completely color-blind and have very poor acuity. This disorder affects up to 1 in 30,000 people (Sharpe et al., 1999).

Inheritance Patterns of Color Vision Defects

Protan and deutan defects are inherited as X-linked traits and are caused by mutation, rearrangement, or deletion of the genes encoding the L- and M-cone photopigments (Nathans et al., 1986a; Nathans et al., 1986b). These genes lie on the X chromosome, accounting for the pronounced gender differences in the frequency of red-green color vision defects. Females have two X chromosomes; males have only one. There is a dosage compensation mechanism, termed X inactivation, to ensure that each cell in the female expresses only the required amount of each X-chromosome gene product. Female somatic cells retain one X chromosome as active; the other one is inactivated. In any given L- or M-cone photoreceptor cell, only one pigment gene from the array on the active X chromosome is expressed. The choice of which X chromosome will be active and which will be inactive is random, so on average, 50% of cells retain the paternal X-chromosome pigment genes as active and 50% retain the maternal pigment genes as active. X inactivation also ensures that the visual pigment genes from the maternal and paternal arrays are expressed in separate populations of cones. If a female carries the genes for color-blindness on one X chromosome and the genes for normal color vision on the other, she will have normal color vision. If she carries genes for color-blindness on both X chromosomes, but together her two X's specify at least one functional L and one functional M pigment, she will also have normal color vision. A female will be color-blind only if her two X chromosomes together do not specify both a functional L and a functional M pigment. In rare instances, females can exhibit skewed X inactivation, whereby the cells of a given tissue all have the same active X chromosome. This is usually seen only when expression of genes from one of the X chromosomes severely diminishes the survival of cells in which it is active. Thus, in rare circumstances, a female with the genes for color blindness on only one X chromosome could be color-blind if she had a severely skewed X inactivation such that all of her L and M cones expressed genes from the “color-blind” X chromosome.

Blue cone monochromacy is also inherited as an X-linked trait, and is caused by a variety of mechanisms including a combination of deletion and mutation of the X-linked visual pigment genes or deletion of cis-acting regulatory elements necessary for the expression of the L- and M-pigment genes (Nathans et al., 1989, 1993). In blue cone monochromats, neither L nor M genes are functionally expressed.

Tritan defects are caused by mutations in the S-pigment gene on chromosome 7 and display a dominant inheritance pattern, with incomplete penetrance (Weitz et al., 1992a; Weitz et al., 1992b). Dominance refers to the fact that only one mutant copy of the S-pigment gene is required to cause the color vision defect. Incomplete penetrance means that not everyone who carries the mutant S-pigment gene will exhibit a color vision deficiency.

Complete achromatopsia and forms of incomplete achromatopsia besides blue cone monochromacy are inherited as autosomal recessive traits. Defects in two different genes have been implicated in these vision disorders. Each gene encodes a subunit of the cone photoreceptor-specific cyclic-GMP gated ion channel, the function of which is critical to the ability of cone photoreceptors to signal that light has been absorbed (Sundin et al., 2000; Wissinger et al., 2001).