Chapter 238

## Abstract

Abstract

1. Color vision has intrigued scientists for several hundred years. Red-green color vision defects are common and among the first recognized X-linked traits. The molecular genetics of the visual pigments mediating normal and defective color vision have been elucidated and provide the basis for an understanding of the genetic basis of normal and abnormal color vision.

2. The retina is a displaced part of the brain and includes four different photoreceptors: rods containing rhodopsin and cones containing photopigments sensitive to either blue (short-wave), green (middle-wave), or red (long-wave). Normal color vision is trichromatic and is subserved by these three cone pigments. Rhodopsin is used for dim-light vision, whereas the various cone photopigments mediate vision in bright light and color vision. The photopigments have characteristic absorption maxima with wide regions of overlap. The four human visual pigments are similar in their amino acid sequences and are members of the heptahelical transmembrane receptor family that includes olfactory receptors. The red and green pigments differ by at most 15 amino acids. Differences at three residues (180, 277, and 285) largely account for spectral differences between these pigments.

3. The autosomal genes for rhodopsin and the blue pigment are located at chromosome 3q21–24 and 7q31.3–q32, respectively. The red-green pigment gene complex maps to a subterminal site on the long arm of the X chromosome (Xq28) linked to the loci for adrenoleukodystrophy, glucose-6-phosphate deficiency, and hemophilia. The red-green gene arrays are composed of a single red pigment gene (six exons) and one or more green pigment genes (six exons) located downstream (3′) of the red gene. About 25 percent of male Caucasians have a single green pigment gene, whereas the rest have two, three, or more green pigment genes. Almost half of Japanese and African-American males only have a single green pigment gene. The high homology of the red and green opsin genes (including introns) predisposes to unequal crossover and accounts for the numerical polymorphism. Gene expression studies suggest that only the two most proximal among several pigment genes are expressed in the retina. The ratio of red to green pigment mRNAs in human retinas varies widely (1–10, with a mode of 4).

4. Illegitimate recombination between the red and green pigment genes causes deletions or the formation of hybrid genes and explains the genetic basis of the majority of color vision defects. The deletion of green pigment genes leaves a single red pigment gene that is characteristically associated with deuteranopia (G). Affected individuals are dichromatic because they completely lack functional green cones. The finding of severe trichromatic deuteranomaly (G′) in a few individuals with this genetic makeup remains unexplained.

5. Exon 5 (which includes two residues that account for two-thirds of the spectral difference between the red and green pigments) plays a major role in spectral tuning. The recombinational exchange of exon 5 produces hybrid pigments with large spectral shifts and corresponding effects on color vision.

6. 5′ Green–red 3′ hybrid genes with or without additional green genes usually are associated with deuteranomaly—a milder type of color vision defect with a red-shifted absorption maximum for the green pigment. Individuals with 5′ green–red 3′ hybrid genes who have normal color vision carry the variant gene in a more downstream location of the gene array, where it is not expressed.

7. 5′ Red–green 3′ fusion genes are always associated with protan abnormalities (R or R′). Those who have a single hybrid gene only are always protanopic (R) and are therefore dichromats. Those who have additional normal green genes are either protanopic (R) or protanomalous (R′) (i.e., a milder defect with slightly green-shifted absorption maximum of the red pigment) depending on whether Ala (protanopia) or Ser (protanomaly) is present at position 180 of the hybrid pigment.

8. A rare cause of red-green color vision defect (1/64 among color-defective males) is a point mutation of a critical cysteine residue of the green pigment (C203R).

9. A single-amino-acid polymorphism (serine/alanine) at position 180 of the X-linked red pigment gene occurs in different ethnic groups. Serine occupies this position in 64 percent of Caucasians, 80 percent of African-Americans, and 84 percent of Japanese. Individuals with with normal color vision (who have the serine variant) perceive red color as a deeper red than those who have alanine at position 180, as shown by color matching. The Ser/Ala polymorphism also affects the spectral sensitivities of various hybrid genes.

10. Tritan or blue pigment abnormalities are caused by missense mutations in the blue pigment gene and are transmitted (some with incomplete penetrance) as autosomal dominant traits.

11. The detection of color vision is often based on plate tests that require color discrimination of shapes or numbers. The standard test for detection of subtypes of color vision defects is quantitative anomaloscopy using color matching.

12. Subjective color perception is most severely compromised in dichromats (i.e., in deuteranopes and particularly in protanopes), who cannot discriminate between colors in the red-green region of the spectrum. More subtle abnormalities are seen in trichromatic subjects with deuteranomaly and protanomaly, whose color discrimination capacities are weakened but not absent. Tasks requiring practical color discrimination may be performed adequately even by some fairly severely affected persons who test as abnormal on various color vision test systems such as color plate tests.

13. Blue cone monochromacy is a rare disease that manifests as complete functional absence of red and green cone function. It can be caused by deletion of a critical regulatory element upstream (5′) of the red-green gene complex that is required for expression of both the red and the green gene(s). Alternate causes involve point mutations of a single red-green hybrid gene that completely abolishes its function. The C203R mutation is frequently involved.

14. Complete achromatopsia, or red monochromacy, is another rare disease that involves complete functional absence of red, green, and blue cone function. A number of mutants with gene encoding the α subunit of cone c-AMP-gated cation channels have been implicated in this disorder.

15. Deuteranomaly is the most common defect in Caucasian populations (4–5 percent). The other defects (protanopia, protanomaly, deuteranopia) have frequencies of about 1 percent each. The frequency of color vision defects in most other populations is lower, ranging around 3 to 4 percent among Japanese and those of African descent, and is largely accounted for by fewer deuteranomalous individuals. The relatively high frequency of human color vision defects mainly results from unequal crossover between the highly homologous red and green pigment genes in this multigene complex. The high frequency of deuteranomalous individuals is unexplained. The role of selection to explain population differences in deuteranomaly remains undefined.

16. Female heterozygotes for the X-linked color vision defects are common in Caucasians (about 15 percent) and usually do not manifest color vision defects. Compound transheterozygotes for protan and deutan defects have normal color vision. Compound transheterozygotes for protanomaly/protanopia as well as those for deuteranomaly/deuteranopia will manifest with the milder of the two defects (i.e., anomaly), as expected on molecular grounds.

17. There is a high frequency (19 percent) of green-red fusion genes among African-Americans that are not expressed as color vision defects. About one-third of Africans have a phenotypically silent polymorphism manifesting as a shortened red pigment gene that resembles the normal (shortened) green pigment gene by lacking a block of three Alu repeat elements. This homology may predispose to more illegitimate recombination and possibly explain the higher frequency of green-red fusion genes in this population.

18. The evolution of the color vision gene complex has been elucidated. Rhodopsin was the first product of the undifferentiated ancestral gene (800 million years ago). Three hundred million years later, the blue gene developed from the single middle-wave gene, and only 30 million years ago, the red and green genes diverged from each other. Further duplication of the green pigment genes then occurred.

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