Genetics of variation in human color vision and the retinal cone mosaic
Introduction
Normal color vision in humans is trichromatic (see Glossary), being based on three classes of cone in the retina that are maximally sensitive to light at ∼420 nm (in the case of short-wave-sensitive, S cones), ∼530 nm (middle-wave-sensitive, M cones) and ∼560 nm (long-wave-sensitive, L cones). It is the ability of neural circuitry to compare light absorbed by these three classes of cone photoreceptor that enables the perception of red, yellow, green and blue colors individually or in various combinations. The synthesis of a single class of photopigment with a distinct absorption spectrum in each photoreceptor cell is fundamental to color vision. Photopigments are G-protein-coupled receptors composed of a protein moiety, opsin, which forms a transmembrane heptahelical bundle within which the chromophore 11-cis retinaldehyde is embedded. Differences in spectral characteristics of the photopigments are dictated by the interaction of amino acid side-chains at key positions in the opsin with the chromophore. Differences at positions 180 (encoded by exon 3), 277 and 285 (encoded by exon 5) account for the majority of the differences between the wavelength of maximal absorption (λmax) of the L and M pigments (Figure 1; for review, see [1••]). In addition, differences at positions 116, 230, 233 and 309 play minor roles [2, 3].
Ser180Ala, a common polymorphism of the L pigment, was shown to play a subtle role in variation in both normal [4] and defective red–green color vision (see below) [5, 6]. The λmax of an L pigment with Ser at position 180 was subsequently shown to be ∼4–7 nm longer than that with Ala when expressed in vitro [2, 3].
Males who have either no functional L-cones (protanopes, ∼1% of all males) or no functional M-cones (deuteranopes, ∼1% of all males) have severe color vision defects. They are referred to as having dichromatic color vision (see Glossary) that is based on functional S cones plus either M or L cones. Males with milder color vision defects have, in addition to S cones, either normal green plus anomalous M-like cones (protanomalous, ∼1%) or normal L plus anomalous M-like cones (deuteranomalous, ∼5% in Northern Europeans and 1–2% in other ethnic groups). These individuals have anomalous trichromatic color vision (see Glossary). The anomalous pigments are L–M chimeras encoded by hybrid genes (see below) [1••]. Loss of S-cone function is very rare and results in tritanopic color vision. The cone spectra of individuals with normal and defective color vision, and a simulation of how the visible spectrum looks to each class are shown in Figure 1. The absorption spectra of cones of anomalous trichromats (protanomalous and deuteranomalous) are shown in Figure 2. A much more severe type of color vision deficiency is blue cone monocromacy, in which individuals have no functional L and M cones.
Section snippets
Genetics of color vision
The cloning by Nathans and colleagues [7] of the genes that encode the S, M and L photoreceptor pigments paved the way for the discovery of the molecular basis of the common red–green color vision deficiencies. The genes encoding the L (OPN1LW [OPSIN 1 LONG-WAVE]) and M (OPNL1MW [OPNLW MIDDLE-WAVE]) photopigments are arranged in a head-to-tail tandem array on the X chromosome at Xq28 (Figure 3a, top array) [7]. The array is composed of a single OPN1LW followed by one or more OPN1MW genes. The
The human retinal cone mosaic
The topography of the S-, M- and L-cone mosaic, and the ratio of L to M cones in the primate retina have recently attracted considerable attention. The relative numbers and arrangement of the three cones are crucial for spatial vision and color perception. S cones are sparse (∼10% of all cones) and arranged randomly in the human retina, and they are absent in the central fovea, the central part of the retina [16]. Previously, the S and (L + M) cone mosaic was determined using psychophysical,
Genetics of cone photoreceptor patterning in the developing retina
Retinal progenitor cells differentiate into either rods or cones (Figure 6). The orphan nuclear receptor NR2E3 plays a crucial role in this decision by inducing rod formation and suppressing the cone pathway. It has been shown that NR2E3 interacts with the cone–rod homeobox transcription factor CRX to directly induce expression of the rhodopsin promoter and repress the S-opsin promoter [27•]. Mutations in NR2E3 were shown to cause the human enhanced S-cone syndrome and increased S-cones in rd7
Conclusions
There is common variation in both normal and defective color vision. Recombination and gene conversion between the juxtaposed, highly homologous OPN1MW an OPN1LW genes underlie this variation.
The ability to define the cone mosaic in the living retina using adaptive optics gives the opportunity in the future to correlate visual performance with the ratio of the three classes of cone and their spatial distribution in the retina. For example, does variance in the L:M ratio have an impact on visual
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
Preparation of this review was supported by a National Institutes of Health (National Eye Institute) grant EY08295.
Glossary
- Anomalous trichromacy
- Trichromatic color vision based on either S, M and an anomalous M-like photoreceptor (protanomaly) or S, L and an anomalous L-like photoreceptor (deuteranomaly). The color vision defect is generally mild but might be severe in certain cases.
- Deutan color vision
- Otherwise known as deuteranopia or deuteranomaly.
- Dichromatic color vision
- Severely defective color vision deficiency based on the presence of only two types of cone photoreceptors, S plus either M (protanopia) or L
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