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Other entities represented in this entry:
SNOMEDCT: 51445007; ICD10CM: H53.54; DO: 13910;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| Xq28 | Colorblindness, protan | 303900 | X-linked | 3 | OPN1LW | 300822 |
A number sign (#) is used with this entry because protan colorblindness is caused by mutation in the OPN1LW gene (300822), which encodes red cone pigment.
Normal color vision in humans is trichromatic, being based on 3 classes of cone that are maximally sensitive to light at approximately 420 nm (blue cones; 613522), 530 nm (green cones; 300821), and 560 nm (red cones; 300822). Comparison by neural circuits of light absorption by the 3 classes of cone photoreceptors allows perception of red, yellow, green, and blue colors individually or in various combinations. Dichromatic color vision is severely defective color vision based on the use of only 2 types of photoreceptors, blue plus green (protanopia) or blue plus red (deuteranopia; see 303800). Anomalous trichromacy is trichromatic color vision based on a blue, green, and an anomalous red-like photoreceptor (protanomaly), or a blue, red, and an anomalous green-like photoreceptor (deuteranomaly). The color vision defect is generally mild but may in certain cases be severe. Common variation in red-green color vision exists among both normal and color-deficient individuals (review by Deeb, 2005).
Studies using reflection densitometry and retinal microbeam experiments showed that 2 different pigments mediate red and green sensitivity. These are located in the cones, each cone containing only 1 type of pigment (Waaler, 1968).
Simunovic et al. (2001) examined red-green color-deficient subjects, a small sample of monochromats, and age-matched color-normal control subjects to determine whether color vision deficiency confers a selective advantage under scotopic conditions. They found no evidence that red-green color deficiency or monochromatism confers a selective advantage under scotopic conditions, including dark adaptation, scotopic visual field sensitivity, or performance on a scotopic perceptual task.
The Nagel anomaloscope, used in determination of the type of colorblindness, consists of a viewing tube with a circular bipartite field, one half illuminated with yellow and the other half with a mixture of green and red. The yellow half is not variable except in brightness. The other half can be varied continuously from red to green. The subject's color sense is tested by having him mix colors in the variable half-field until he achieves a subjective match to the yellow field. Certain color combinations are considered normal whereas specific differences from the normal indicate the type and degree of anomalous color vision.
Ishihara plates alone are unreliable in distinguishing deutan and protan types. Although the Nagel anomaloscope is the 'last court of appeal' in making the differentiation, it is expensive, time-consuming, difficult for unsophisticated subjects, and, of course, not usable 'in the field.' Two 'book' tests, the Tokyo Medical College Test and the AO-HRR (Hardy-Rand-Rittler) pseudoisochromatic plates, especially when used together, probably represent the methods that are both the easiest and the most reliable available (Sloan, 1961). Identification of a small proportion of deutero-heterozygotes is possible by means of the luminosity quotient, determined by a modification of the Nagel anomaloscope designed by Crone. Most cases of proto-heterozygotes can be identified as such with a high degree of certainty using this method.
Several early observations supported a 2-locus model for the common type of red-green colorblindness. First, the data on relative frequency of colorblindness in males and females collected in Norway by Waaler (1927) and in Switzerland by von Planta (1928) agreed with the values predicted by a 2-locus theory. Second, females, who by the nature of the color vision defect in their sons are known to carry genes for both types of colorblindness, usually do not show a defect in color vision (Brunner, 1932; Kondo, 1941; Franceschetti and Klein, 1957). Third, the pedigrees of Vanderdonck and Verriest (1960) and Siniscalco et al. (1964) indicated independent assortment of deutan and protan genes among the offspring of a doubly heterozygous female. And fourth, Filippi et al. (1977) observed linkage disequilibrium for G6PD/protan but not for G6PD/deutan.
Nathans et al. (1986, 1986) determined that whereas there is a single red pigment gene, green pigment genes vary in number among persons with normal color vision. The multiple green pigment genes are arranged in a head-to-tail tandem array. The existence of multiple green pigment genes in tandem array may explain why deutan colorblindness is more frequent than protan colorblindness. Furthermore, nonhomologous pairing and unequal crossing-over can explain the development of colorblindness. Gene conversion may also be involved. The green pigment genes vary in restriction pattern.
Drummond-Borg et al. (1988) demonstrated the use of molecular methods for defining the defects in red-green color vision in a family carrying 3 types of defects: protanomaly, deuteranomaly, and protanopia. In the protanomalous and protanopic males, the normal red pigment gene was replaced by a 5-prime red--3-prime green fusion gene. The protanomalous male had more red pigment DNA in his fusion gene than did the more severely affected protanopic individual. The deuteranomalous individual had 4 green pigment genes and one 5-prime green--3-prime red fusion gene. The findings support the proposal that most red-green color-vision defects arise as a result of unequal crossing-over between the red and green pigment genes. Differences in severity of color-vision defects associated with fusion genes appear to be the result of differences in crossover sites between the red and green pigment genes. In this family, 2 compound heterozygotes for color-vision defects who tested as normal by anomaloscopy were found to carry abnormal fusion genes. The explanation for normal color vision appears to have been the presence, in addition, of a normal red pigment gene on one chromosome and at least 1 normal green pigment gene on the other.
In a study of genotype-phenotype relationships in 64 color-defective males, Deeb et al. (1992) found that in most there was either a deletion of the green-pigment gene or the formation of 5-prime red-green hybrid genes or 5-prime green-red hybrid genes. Protan color-vision defects appeared always associated with 5-prime red-green hybrid genes. Carriers of single red-green hybrid genes with fusion in introns 1-4 were protanopes. However, carriers of hybrid genes with red-green fusions in introns 2, 3, or 4 in the presence of additional normal green genes manifested as either protanopes or protanomalous trichromats, with the majority being protanomalous. Deutan defects were associated with green-pigment gene deletions, with 5-prime green-red hybrid genes, or, rarely, with 5-prime green-red-green hybrid genes. Complete green-pigment gene deletions or green-red fusions in intron 1 were usually associated with deuteranopia, although Deeb et al. (1992) unexpectedly found 3 subjects with a single red-pigment gene and no green-pigment genes to be deuteranomalous trichromats. All but one of the other deuteranomalous subjects had green-red hybrid genes with intron 1, 2, 3, or 4 fusions, as well as several normal green-pigment genes. Amino acid differences in exon 5 largely determine whether a hybrid gene will be more redlike or more greenlike in phenotype. When phenotypic color-vision defects exist, the kind of defect, protan or deutan, can be predicted by molecular analysis. Red-green hybrid genes are probably always associated with protan color-vision defects, while the presence of green-red hybrid genes may not always manifest phenotypically with color-vision defects. Among a group of 129 Caucasian males who had been recruited as volunteers for a vision study, Deeb et al. (1992) found 4 subjects who had 5-prime green-red hybrid genes in addition to normal red- and green-pigment genes and demonstrated normal color vision as determined by anomaloscopy. It may be that green-red hybrid genes in a more distal, 3-prime position of a gene array that includes one or more normal green genes may not be expressed sufficiently to affect color vision measurably.
Although there are 15 amino acid differences between the MW (green) and LW (red) opsins, the greater part of the spectral shift in sensitivity is the result of substitutions at sites 180, 277, and 285, with 5 other sites having smaller effects. Site 180 (see 300822.0002) is polymorphic in both MW and LW opsin genes. The middlewave opsin is missing or defective in deuteranopia and the longwave opsin in protanopia. Using refined methods, Neitz and Neitz (1995) reexamined the numbers and ratios of genes in the Xq28 cluster in men with normal color vision. Results indicated that many men have more pigment genes on the X chromosome than had previously been suggested and that many have more than 1 longwave pigment gene.
Jagla et al. (2002) investigated the genotypic variation in 50 red-green color vision-deficient males (27 deuteranopes and 23 protanopes) of middle European ancestry who possessed multiple genes in the X-linked photopigment gene array. Spectral sensitivities of the encoded pigments were inferred from published in vitro and in vivo data, and color vision phenotype was assessed by standard anomaloscopy. Most genotypes included hybrid genes whose sequence and position and whose encoded pigment correlated exactly with the phenotype. However, a few of the protanopes had gene arrays consistent with protanomaly rather than protanopia, since 2 spectrally different pigments may be encoded by their arrays. Two of the deuteranopes had only R- and G-photopigment genes, without any detectable G/R-hybrid genes or identified mutations. About half of the protanopes possessed an upstream R/G-hybrid gene with different exon 2 coding sequences than their downstream G-pigment gene(s), which is inconsistent with published data implying that a single amino acid substitution in exon 2 can confer red-green color discrimination capacity on multigene protans by altering the optical density of the cones.
Ueyama et al. (2002) analyzed DNA in 217 Japanese males with congenital red/green color vision deficiencies. The normal genotype of a single red gene, followed by a green gene, was found in 23 subjects. Four of the 23 were from the 69 protan subject groups and 19 of the 23 were from the 148 deutan subject group. Three of the 23 subjects had missense mutations: asn94 to lys (300821.0003) in the single green gene of a deutan subject; arg330 to gln (300821.0004) in both green genes of another deutan subject; and gly338 to glu (300822.0004) in the single red gene of a protan subject. Both normal and mutant opsins were expressed in cultured COS-7 cells and visual pigments were regenerated with 11-cis-retinal. The mutations resulted in no absorbance or a low absorbance spectrum. Therefore, these 3 mutant opsins probably affected the folding process, resulting in a loss of function as a visual pigment.
The terms protan, deutan, and tritan are derived from the Greek words for 'first,' 'second,' and 'third,' respectively. The terms protanopia, deuteranopia, and tritanopia were introduced in 1896 by von Kries and Nagel to represent the absence of the first, second, and third primary colors, respectively. Farnsworth (1943) found an intimate relationship between protanomaly and protanopia, and between deuteranomaly and deuteranopia. He invented the idea of joining the classes together under the generic names of protan, deutan, and tritan. This idea was a major contribution to clarifying the classification of color vision defects.
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