Alternative titles; symbols
Other entities represented in this entry:
SNOMEDCT: 246674000, 77479002; ICD10CM: H53.53; ICD9CM: 368.52; DO: 13909;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| Xq28 | Colorblindness, deutan | 303800 | X-linked | 3 | OPN1MW | 300821 |
A number sign (#) is used with this entry because deutan colorblindness is caused by mutation in the OPN1MW gene (300821), which encodes green 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; see 303900) or blue plus red (deuteranopia). 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.
Combining their own with published data, Arias and Rodriguez (1972) concluded that the recombination fraction for the deutan and protan loci may be higher than originally thought, perhaps 0.095.
Emmerson et al. (1974) excluded close linkage of the HGPRT and deutan loci.
Race and Sanger (1975) pointed out that when the 3-generation linkage data for deutan, protan, G6PD and classic hemophilia (on the one hand) versus Xg (on the other) are pooled, the score is 236 nonrecombinants and 193 recombinants: a recombination fraction of 45% (chi square 4.3, expecting 50% recombination).
In Sardinia, studying G6PD, protan, deutan and Xg, Filippi et al. (1977) found linkage disequilibrium between G6PD and protan colorblindness but not between other pairs of these X-linked loci. From this they concluded that G6PD and protan are nearer one another than are G6PD and deutan. Purrello et al. (1984) followed up on the Sardinian kindred reported by Siniscalco et al. (1964). The kindred had an instance of recombination between the protan and deutan loci and was segregating also for G6PD, leading to the conclusion that the G6PD locus is between the 2 colorblindness loci.
In a study of 4 common X-linked DNA polymorphisms, Brennand et al. (1982) found that only 1, a BamHI polymorphism identified with a cDNA probe of the HPRT gene, was segregating. Analysis of the chromosome haplotypes in the sons of the phase-known penta-heterozygous mother suggested the probable order HPRT--deutan--G6PD--protan--Xqter. The colorblindness genes lie proximal to the F8C and EMD loci.
The frequency of red-green color vision defects among populations of northern European origin is around 8% of males and 0.5% of females, as determined by anomaloscopy in many studies. The frequency is lower in non-European populations (review by Deeb, 2005).
Drummond-Borg et al. (1989) found abnormalities of color vision pigment genes in 15.7% of Caucasian men, a higher frequency than is shown by color vision testing. This may indicate that some color vision gene arrays associated with hybrid genes mediate normal color vision.
Colorblindness genes were the first to be mapped to a specific chromosome in any mammal. Wilson (1911), a noted cytologist, pointed out that the pedigree pattern described by Horner was explicable if the gene is X-linked recessive, if man has an XX-XY sex chromosome constitution, and if the colorblindness gene is on the X chromosome.
Jorgensen et al. (1992) studied 2 female monozygotic twins who were obligatory heterozygotes for X-linked deuteranomaly associated with a green-red fusion gene derived from their deuteranomalous father. On anomaloscopy, however, one of the twins was phenotypically deuteranomalous while the other had normal color vision. The color vision-defective twin had 2 sons with normal color vision and 1 deuteranomalous son. Using a methylation-sensitive probe, M27-beta, for differentiating the active and the inactive X chromosomes, Jorgensen et al. (1992) showed that the skin cells of the color vision-defective twin had almost all paternal X chromosomes with the abnormal color vision gene as the active one, thereby explaining her color-vision defect. In contrast, a different pattern was observed in the skin cells from the woman with normal color vision; her maternal X chromosome was for the most part the active one. However, in blood lymphocytes, both twins showed identical methylation patterns with mixtures of inactivated maternal and paternal X chromosomes. Deuteranomaly in one of the twins was explained by extremely skewed X inactivation, as shown in skin cells. Failure to find this skewed pattern in blood cells was explained by the sharing of fetal circulation and exchange of hematopoietic precursor cells between twins. They reviewed other cases of monozygotic twins in which only one was affected by this particular disorder and cited an example of female MZ triplets in which only one had deuteranomaly (Yokota et al., 1990).
Squirrel monkeys have a striking color-vision polymorphism; each animal has 1 of 6 different types of color vision. These arise from individual variation in the presence of 3 different middle- to long-wavelength cone pigments. Jacobs and Neitz (1987) presented evidence indicating that the 3 cone pigments are specified by 3 alleles on a single locus on the X chromosome of this species. Females, having 2 X chromosomes, have the possibility of inheriting alleles that code for 2 different pigments; this provides the basis for trichromatic color vision, by functioning in conjunction with the presence of a short-wavelength pigment coded by an autosome, as is the case in man (190900). That Old World monkeys appear to show no color-vision polymorphism, while humans do, may reflect differences in the selection pressures against color-vision variations in the 2 lines. Deeb et al. (1994) determined the coding sequences of the red and green visual pigment genes of the chimpanzee, gorilla, and orangutan. The deduced amino acid sequences were highly homologous to the equivalent human pigments. None of the amino acid differences occurred at sites previously shown to influence pigment absorption characteristics. Therefore, Deeb et al. (1994) predicted that the spectra of red and green pigments of the apes have wavelengths of maximum absorption differing very little from the equivalent human pigments and that color vision in these nonhuman primates is very similar, if not identical, to that in humans. Fourteen within-species polymorphisms (6 involving silent substitutions) were observed in the coding sequences of the red and green pigment genes of the great apes. Remarkably, the polymorphisms at 6 of these sites had been observed in human populations, suggesting that they predated the evolution of higher primates. Alleles at polymorphic sites were often shared between the red and green pigment genes. The average synonymous rate of divergence of red from green sequences was approximately one-tenth of that estimated for other proteins of higher primates, indicating the involvement of gene conversion in generating these polymorphisms. The high degree of homology and the juxtaposition of these 2 genes on the X chromosome has promoted unequal recombination and/or gene conversion, leading to sequence homogenization. However, natural selection operated to maintain the degree of separation in peak absorbance between the red and green pigments that resulted in optimal chromatic discrimination. Color vision represents, therefore, a unique case of molecular coevolution between 2 homologous genes that functionally interact at the behavioral level.
It has been suggested that the colorblindness polymorphism is a heritage from frugivorous arboreal ancestors (Crossman, 1974). New World monkeys have only a single pigment encoded on the X chromosome. Old World monkeys have the same green and red pigments as man. The split between these 2 monkey classes occurred some 30 to 40 million years ago. The duplication of the X-linked genes presumably occurred thereafter. From the sequence homology figures, it appears that the short wavelength (blue), long wavelength (red and green), and rod pigments all diverged from a common ancestor about the same time, perhaps 500 million years ago.
Nathans (1999) reviewed the evolution and physiology of human color vision. He quoted at the outset Theodosius Dobzhansky: 'Nothing in biology makes sense except in light of evolution.'
Nathans et al. (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.
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.
Deeb (2005) noted that the high homology between the red and green pigment genes has predisposed the locus to relatively common unequal recombination events that give rise to red/green hybrid genes and to deletion of the green pigment genes. Such events constitute the most common cause of red-green color vision defects. Only the first 2 pigment genes of the red/green array are expressed in the retina and therefore contribute to the color vision phenotype. The severity of the red-green color vision defects is inversely proportional to the difference between the wavelengths of maximal absorption of the photopigments encoded by the first 2 genes in the array.
Winderickx et al. (1992) found that only a single green pigment gene is expressed in persons with normal color vision. They suggested that a locus control-like element (300824), already known to be located 3.8 kb upstream of the transcription initiation site of the red pigment gene (300822), allows transcription of only a single copy of the green pigment genes, probably the most proximal copy. This finding provided an explanation for the not infrequent presence of 5-prime green-red hybrid genes in individuals with normal color vision. Although such hybrid genes are usually associated with defective color vision, this may not occur when their position in the gene array does not allow expression in retinal cone cells.
The defect of color vision in deuteranomaly (found in 5% of males of European descent) is associated with a 5-prime--green-red--3-prime visual pigment hybrid gene, which may also exist in males with normal color vision. To explain why males with a normal red, a normal green, and a green-red hybrid gene may have either normal or deutan color vision, Winderickx et al. (1992) and Yamaguchi et al. (1997) hypothesized that only the first 2 genes are expressed and deuteranomaly results only if the green-red hybrid gene occupies the second position and is expressed preferentially over normal green-pigment genes occupying more distal positions.
Hayashi et al. (1999) used long-range PCR amplification and studied 10 deutan males (8 deuteranomalous and 2 deuteranopic) with 3 visual pigment genes (red, green, and green-red hybrid) to investigate whether position of the hybrid gene in the array determined gene expression. The green-red hybrid gene was always at the second position (and the first position was always occupied by the red gene) in men with the deutan defect. Conversely, in 2 men with red, green, and green-red hybrid genes and normal color vision, the hybrid gene occupied the third position. When pigment gene mRNA expression was assessed in postmortem retinas of 3 men with the red, green, and green-red genotype, the green-red hybrid gene was expressed only when located in the second position. Since only the first 2 genes are expressed, the retinas of deuteranomals are presumably composed of cones containing red-sensitive pigment and cones containing a red-like--sensitive pigment. The findings of Hayashi et al. (1999) were consistent with the presence of a locus control region (LCR) at the 5-prime end of the X-linked visual pigment gene. This LCR was postulated to form a stable transcriptionally active complex in a stochastic manner with either the red-gene promoter to form red-sensitive pigment, or with the green-gene promoter to form green-sensitive pigment. The LCR is presumably too far removed from the third gene to affect its expression. Another explanation would be that distal gene expression is silenced by elements in the 3-prime-flanking region of the locus. Although the data came from individuals with 3 pigment genes, these findings presumably apply also to lack of expression of visual pigment genes in the fourth or even more distal positions.
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 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.
Up to the time of the report by Winderickx et al. (1992), all red-green color vision defects had been associated with gross rearrangements within the red/green opsin gene array on Xq28. In a male with severe deuteranomaly without a rearrangement of the red/green pigment genes, Winderickx et al. (1992) found that substitution of a highly conserved cysteine by arginine at position 203 (C203R; 300821.0001) in the green pigment opsins accounted for his defect in color vision. Surprisingly, this mutation was found to be fairly common (2%) in the population but apparently was not always expressed.
Ueyama et al. (2003) studied 247 Japanese males with congenital deutan color vision deficiency and found that 37 subjects (15%) had a normal genotype of a single red gene followed by 1 or more green genes. Two of the patients had previously been found to have a missense mutation in 1 or more green pigment genes (300821.0003 and 300821.0004) (Ueyama et al., 2002), but the other 35 had no mutations in either the exons or their flanking introns. However, 32 of the 35 subjects, including all 8 subjects with pigment color defect (a special category of deuteranomaly), had a -71A-C transversion (300821.0005) in the promoter of a green pigment gene at the second position in the red/green visual pigment gene array. Although the -71C substitution was also present in color-normal Japanese males at a frequency of 24.3%, it was never at the second position but always found farther downstream. The substitution was found in 19.4% of Chinese males and 7.7% of Thai males, but rarely in Caucasians or African Americans. These results suggested that the -71A-C substitution is closely associated with deutan color vision deficiency. In Japanese and presumably other Asian populations, farther downstream genes with -71C comprise a reservoir of the visual pigment genes that cause deutan color vision deficiency by unequal crossing-over between the intergenic regions.
Reviews
Nathans (1987) reviewed the molecular biology of colorblindness. Deeb (2005) reviewed the molecular basis of variation in human color vision.
Emery (1988) gave a delightful account of the history of early observations on colorblindness with particular reference to those made by John Dalton (born 1766, died 1844). He pointed out that Dalton's first scientific paper (Dalton, 1798) was concerned with his own affliction of colorblindness, although his reputation rests, of course, on his enunciation of the atomic theory. The Young-Helmholtz theory, which dates from the beginning of the 19th century (Young, 1802), assumed 3 elemental mechanisms for color vision: one with maximal sensitivity for red, a second for green, and a third for blue-violet. It was the genes for these 3 elemental mechanisms that were cloned and characterized by Nathans et al. (1986). As reviewed by Hunt et al. (1995), Dalton judged red sealing wax to be a good match for the outer face of a laurel leaf, and a crimson ribbon matched the color others called 'mud.' In the solar spectrum, he saw only 2 main hues, one of which corresponded to the normal observer's red, orange, yellow, and green, whereas the second corresponded to blue and violet. His brother had the same colorblindness. Dalton supposed that the vitreous humor of his eyes was tinted blue, selectively absorbing longer wavelengths. He instructed that his eyes should be examined after his death, but the examination revealed that the humors were perfectly clear. Hunt et al. (1995) presented the results of analyses on DNA extracted from Dalton's preserved eye tissue, showing that Dalton was a deuteranope, lacking the middlewave photopigment of the retina. Hunt et al. (1995) showed that this diagnosis is compatible with the historical record of Dalton's phenotype, although it contradicts the belief of Thomas Young (1807) that Dalton was a protanope.
The characteristic X-linked recessive pedigree pattern of colorblindness was probably first pointed out by Swiss ophthalmologist Horner in the 1870s (see Thompson, 1986 for a biographic sketch of Horner). Horner's paper on Daltonism appeared in an obscure publication, the annual report of the Canton Zurich, which contained statistics of mortality and morbidity in all hospitals, institutions, etc., and economic aspects for the whole Canton (Horner, 1876). As pointed out by Steinmann (1990), Horner made several perceptive observations on hereditary traits and the advantageous position of the family doctor in observing them. Horner noted: 'I find Luxatio lentis over 3 generations, keratoconus over 2.' In regard to Daltonism, he wrote: 'Its heritability is long since known; Ribot and Darwin mention it, and also that it is more frequent in men. Since I have been able to find very accurate pedigrees which allow the illustration of a certain law, I present here the results of this genealogic study...The table (pedigree)...clearly demonstrates: (1) that there is no colorblind girl; (2) that the colorblind fathers have color-seeing daughters; (3) that the colorblind sons are always descended from color-seeing mothers; (4) that the apparent exception in generation F, where a colorblind father has a colorblind son, is readily explained by the general law, as soon as one takes into account that the mother--color-seeing--is the daughter of a colorblind father, and thus that there is a combination of 2 Daltonian descendents; (5) hence, the general law says: the sons of daughters whose fathers were colorblind, have the greatest chance of being colorblind...that is to say, Daltonism is inherited according to an atavism ('Rueckfalltypus') from grandfather to grandson.' Horner compared the mode of inheritance of Daltonism to that of hemophilia. He concluded by saying, 'If only family doctors, who occasionally know families of successive generations over many decades in great detail, would pay attention to such problems of inheritance, many precious little pearls would be found.' See Kalmus (1965; p. 62) and Bell (1926) for reproduction of Horner's original pedigree of deuteranopia. Rushton (1994) called attention to the fact that Pliny Earle, a Philadelphia physician born in 1809, described the inheritance of colorblindness on the basis of observations in his own family (Earle, 1845). Earle collected information on 5 generations to produce the most extensive family history of colorblindness that had been published up to that time (Sanborn, 1898).
The evolutionary and other significance of the elegant piece of work of Nathans et al. (1986, 1986) was outlined by Botstein (1986).
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