Hostname: page-component-7c8c6479df-p566r Total loading time: 0 Render date: 2024-03-29T12:47:02.633Z Has data issue: false hasContentIssue false

Molecular genetics of color-vision deficiencies

Published online by Cambridge University Press:  05 April 2005

SAMIR S. DEEB
Affiliation:
Departments of Medicine and Genome Sciences, University of Washington, Seattle

Abstract

The normal X-chromosome-linked color-vision gene array is composed of a single long-wave-sensitive (L-) pigment gene followed by one or more middle-wave-sensitive (M-) pigment genes. The expression of these genes to form L- or M-cones is controlled by the proximal promoter and by the locus control region. The high degree of homology between the L- and M-pigment genes predisposed them to unequal recombination, leading to gene deletion or the formation of L/M hybrid genes that explain the majority of the common red–green color-vision deficiencies. Hybrid genes encode a variety of L-like or M-like pigments. Analysis of the gene order in arrays of normal and deutan subjects indicates that only the two most proximal genes of the array contribute to the color-vision phenotype. This is supported by the observation that only the first two genes of the array are expressed in the human retina. The severity of the color-vision defect is roughly related to the difference in absorption maxima (λmax) between the photopigments encoded by the first two genes of the array. A single amino acid polymorphism (Ser180Ala) in the L pigment accounts for the subtle difference in normal color vision and influences the severity of red–green color-vision deficiency.

Blue-cone monochromacy is a rare disorder that involves absence of L- and M-cone function. It is caused either by deletion of a critical region that regulates expression of the L/M gene array, or by mutations that inactivate the L- and M-pigment genes. Total color blindness is another rare disease that involves complete absence of all cone function. A number of mutants in the genes encoding the cone-specific α- and β-subunits of the cGMP-gated cation channel as well as in the α-subunit of transducin have been implicated in this disorder.

Type
Research Article
Copyright
© 2004 Cambridge University Press

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

REFERENCES

Alpern, M. (1979). Lack of uniformity in colour matching. Journal of Physiology 288, 85105.Google Scholar
Arbour, N.C., Zlotogora, J., Knowlton, R.G., Merin, S., Rosenmann, A., Kanis, A.B., Rokhlina, T., Stone, E.M., & Sheffield, V.C. (1997). Homozygosity mapping of achromatopsia to chromosome 2 using DNA pooling. Human Molecular Genetics 6, 689694.CrossRefGoogle Scholar
Asenjo, A.B., Rim, J., & Oprian, D.D. (1994). Molecular determinants of human red/green color discrimination. Neuron 12, 11311138.Google Scholar
Ayyagari, R., Kakuk, L.E., Bingham, E.L., Szczesny, J.J., Kemp, J., Toda, Y., Felius, J., & Sieving, P.A. (2000). Spectrum of color gene deletions and phenotype in patients with blue cone monochromacy. Human Genetics 107, 7582.Google Scholar
Crognale, M.A., Teller, D.Y., Motulsky, A.G., & Deeb, S.S. (1998). Severity of color vision defects: Electroretinographic (ERG), molecular and behavioral studies. Vision Research 38, 33773385.CrossRefGoogle Scholar
Crognale, M.A., Teller, D.Y., Yamaguchi, T., Motulsky, A.G., & Deeb, S.S. (1999). Analysis of red/green color discrimination in subjects with a single X-linked photopigment gene. Vision Research 39, 707719.CrossRefGoogle Scholar
Deeb, S.S. & Kohl, S. (2003). Genetics of color vision deficiencies. Developmental Ophthalmology 37, 170187.Google Scholar
Deeb, S.S., Lindsey, D.T., Hibiya, Y., Sanocki, E., Winderickx, J., Teller, D.Y., & Motulsky, A.G. (1992). Genotype-phenotype relationships in human red/green color-vision defects: Molecular and psychophysical studies. American Journal of Human Genetics 51, 687700.Google Scholar
Feil, R., Aubourg, P., Heilig, R., & Mandel, J.L. (1990). A 195-kb cosmid walk encompassing the human Xq28 color vision pigment genes. Genomics 6, 367373.CrossRefGoogle Scholar
Hayashi, T., Motulsky, A.G., & Deeb, S.S. (1999). Position of a ‘green-red’ hybrid gene in the visual pigment array determines colour-vision phenotype. Nature Genetics 22, 9093.Google Scholar
He, J.C. & Shevell, S.K. (1995). Variation in color matching and discrimination among deuteranomalous trichromats: Theoretical implications of small differences in photopigments. Vision Research 35, 25792588.CrossRefGoogle Scholar
Hess, R.F., Mullen, K.T., Sharpe, L.T., & Zrenner, E. (1989). The photoreceptors in atypical achromatopsia. Journal of Physiology (London) 417, 123149.Google Scholar
Jagla, W.M., Jagle, H., Hayashi, T., Sharpe, L.T., & Deeb, S.S. (2002). The molecular basis of dichromatic color vision in males with multiple red and green visual pigment genes. Human Molecular Genetics 11, 2332.CrossRefGoogle Scholar
Jordan, G. & Mollon, J.D. (1993). A study of women heterozygous for colour deficiencies. Vision Research 33, 14951508.Google Scholar
Kohl, S., Baumann, B., Broghammer, M., Jagle, H., Sieving, P., Kellner, U., Spegal, R., Anastasi, M., Zrenner, E., Sharpe, L.T., & Wissinger, B. (2000). Mutations in the CNGB3 gene encoding the beta-subunit of the cone photoreceptor cGMP-gated channel are responsible for achromatopsia (ACHM3) linked to chromosome 8q21. Human Molecular Genetics 9, 21072116.Google Scholar
Kohl, S., Baumann, B., Rosenberg, T., Kellner, U., Lorenz, B., Vadala, M., Jacobson, S.G., & Wissinger, B. (2002). Mutations in the cone photoreceptor G-protein alpha-subunit gene GNAT2 in patients with achromatopsia. American Journal of Human Genetics 71, 422425.CrossRefGoogle Scholar
Kohl, S., Marx, T., Giddings, I., Jagle, H., Jacobson, S.G., Apfelstedt-Sylla, E., Zrenner, E., Sharpe, L.T., & Wissinger, B. (1998). Total colourblindness is caused by mutations in the gene encoding the alpha-subunit of the cone photoreceptor cGMP-gated cation channel. Nature Genetics 19, 257259.Google Scholar
Merbs, S.L. & Nathans, J. (1992a). Absorption spectra of human cone pigments. Nature 356, 433435.Google Scholar
Merbs, S.L. & Nathans, J. (1992b). Absorption spectra of the hybrid pigments responsible for anomalous color vision. Science 258, 464466.Google Scholar
Motulsky, A.G. & Deeb, S.S. (2001). Color vision and its genetic defects. In The Metabolic and Molecular Bases of Inherited Disease, Vol. IV, eighth edition ed. Scriver, C.R., Beaudet, A.L., Sly, W.S. & Valle, D., pp. 59555976. New York: McGraw-Hill.
Nathans, J., Davenport, C.M., Maumenee, I.H., Lewis, R.A., Hejtmancik, J.F., Litt, M., Lovrien, E., Weleber, R., Bachynski, B., Zwas, F., Traboulsi, E., Klingaman, R., Bech-Hansen, N.T., LaRouche, G.R., Pagon, R.A., Murphey, W.H., & Weleber, R.G. (1989). Molecular genetics of human blue cone monochromacy. Science 245, 831838.Google Scholar
Nathans, J., Maumenee, I.H., Zrenner, E., Sadowski, B., Sharpe, L.T., Lewis, R.A., Hansen, E., Rosenberg, T., Schwartz, M., Heckenlively, J.R., Traboulsi, E., Klingaman, R., Bech-Hansen, N.T., LaRouche, G.R., Pagon, R.A., Murphey, W.H., & Weleber, R.G. (1993). Genetic heterogeneity among blue-cone monochromats. American Journal of Human Genetics 53, 9871000.Google Scholar
Nathans, J., Piantanida, T.P., Eddy, R.L., Shows, T.B., & Hogness, D.S. (1986a). Molecular genetics of inherited variation in human color vision. Science 232, 203210.Google Scholar
Nathans, J., Thomas, D., & Hogness, D.S. (1986b). Molecular genetics of human color vision: The genes encoding blue, green, and red pigments. Science 232, 193202.Google Scholar
Neitz, J. & Jacobs, G.H. (1986). Polymorphism of the long-wave cone in normal human colour vision. Nature 323, 623625.Google Scholar
Neitz, J., Neitz, M., & Jacobs, G.H. (1989). Analysis of fusion gene and encoded photopigment of colour-blind humans. Nature 342, 679682.Google Scholar
Neitz, M., Neitz, J., & Jacobs, G.H. (1991). Spectral tuning of pigments underlying red–green color vision. Science 252, 971974.Google Scholar
Neitz, J., Neitz, M., & Kainz, P.M. (1996). Visual pigment gene structure and the severity of color vision defects. Science 274, 801804.Google Scholar
Peng, C., Rich, E.D., & Varnum, M.D. (2003). Achromatopsia-associated mutation in the human cone photoreceptor cyclic nucleotide-gated channel CNGB3 subunit alters the ligand sensitivity and pore properties of heteromeric channels. Journal of Biological Chemistry 278, 3453334540.CrossRefGoogle Scholar
Sanocki, E., Teller, D.Y., & Deeb, S.S. (1997). Rayleigh match ranges of red/green color-deficient observers: Psychophysical and molecular studies. Vision Research 37, 18971907.CrossRefGoogle Scholar
Sharpe, L.T., Stockman, A., Jagle, H., Knau, H., Klausen, G., Reitner, A., & Nathans, J. (1998). Red, green, and red–green hybrid pigments in the human retina: Correlations between deduced protein sequences and psychophysically measured spectral sensitivities. Journal of Neuroscience 18, 1005310069.Google Scholar
Sharpe, L.T., Stockman, A., Jagle, H., Knau, H., & Nathans, J. (1999a). L, M and L–M hybrid cone photopigments in man: Deriving lambda max from flicker photometric spectral sensitivities. Vision Research 39, 35133525.Google Scholar
Sharpe, L.T., Stockman, A., Jagle, H., & Nathans, J. (1999b). Opsin genes, cone photopigments, color vision, and color blindness. In Color Vision, from Genes to Perception, ed. Gegenfurtener, K.R. & Sharpe, L.T., pp. 351. Cambridge, UK: Cambridge University Press.
Smallwood, P.M., Wang, Y., & Nathans, J. (2002). Role of a locus control region in the mutually exclusive expression of human red and green cone pigment genes. Proceedings of the National Academy of Sciences of the U.S.A. 99, 10081011.CrossRefGoogle Scholar
Sundin, O.H., Yang, J.M., Li, Y., Zhu, D., Hurd, J.N., Mitchell, T.N., Silva, E.D., & Maumenee, I.H. (2000). Genetic basis of total colourblindness among the Pingelapese islanders. Nature Genetics 25, 289293.Google Scholar
Ueyama, H., Li, Y.H., Fu, G.L., Lertrit, P., Atchaneeyasakul, L.O., Oda, S., Tanabe, S., Nishida, Y., Yamade, S., & Ohkubo, I. (2003). An A-71C substitution in a green gene at the second position in the red/green visual-pigment gene array is associated with deutan color-vision deficiency. Proceedings of the National Academy of Sciences of the U.S.A. 100, 33573362.Google Scholar
Vollrath, D., Nathans, J., & Davis, R.W. (1988). Tandem array of human visual pigment genes at Xq28. Science 240, 16691672.Google Scholar
Wang, Y., Macke, J.P., Merbs, S.L., Zack, D.J., Klaunberg, B., Bennett, J., Gearhart, J., & Nathans, J. (1992). A locus control region adjacent to the human red and green visual pigment genes. Neuron 9, 429440.CrossRefGoogle Scholar
Wang, Y., Smallwood, P.M., Cowan, M., Blesh, D., Lawler, A., & Nathans, J. (1999). Mutually exclusive expression of human red and green visual pigment-reporter transgenes occurs at high frequency in murine cone photoreceptors. Proceedings of the National Academy of Sciences of the U.S.A. 96, 52515256.CrossRefGoogle Scholar
Weitz, C.J., Miyake, Y., Shinzato, K., Montag, E., Zrenner, E., Went, L.N., & Nathans, J. (1992a). Human tritanopia associated with two amino acid substitutions in the blue-sensitive opsin. American Journal of Human Genetics 50, 498507.Google Scholar
Weitz, C.J., Went, L.N., & Nathans, J. (1992b). Human tritanopia associated with a third amino acid substitution in the blue-sensitive visual pigment [letter]. American Journal of Human Genetics 51, 444446.Google Scholar
Winderickx, J., Battisti, L., Motulsky, A.G., & Deeb, S.S. (1992a). Selective expression of human X chromosome-linked green opsin genes. Proceedings of the National Academy of Sciences of the U.S.A. 89, 97109714.Google Scholar
Winderickx, J., Battisti, L., Hibiya, Y., Motulsky, A.G., & Deeb, S.S. (1993). Haplotype diversity in the human red and green opsin genes: Evidence for frequent sequence exchange in exon 3. Human Molecular Genetics 2, 14131421.Google Scholar
Winderickx, J., Lindsey, D.T., Sanocki, E., Teller, D.Y., Motulsky, A.G., & Deeb, S.S. (1992b). Polymorphism in red photopigment underlies variation in colour matching. Nature 356, 431433.Google Scholar
Winderickx, J., Sanocki, E., Lindsey, D.T., Teller, D.Y., Motulsky, A.G., & Deeb, S.S. (1992c). Defective colour vision associated with a missense mutation in the human green visual pigment gene. Nature Genetics 1, 251256.Google Scholar
Winick, J.D., Blundell, M.L., Galke, B.L., Salam, A.A., Leal, S.M., & Karayiorgou, M. (1999). Homozygosity mapping of the Achromatopsia locus in the Pingelapese. American Journal of Human Genetics 64, 16791685.Google Scholar
Wissinger, B., Jagle, H., Kohl, S., Broghammer, M., Baumann, B., Hanna, D.B., Hedels, C., Apfelstedt-Sylla, E., Randazzo, G., Jacobson, S.G., Zrenner, E., & Sharpe, L.T. (1998). Human rod monochromacy: Linkage analysis and mapping of a cone photoreceptor expressed candidate gene on chromosome 2q11. Genomics 51, 325331.Google Scholar
Yamaguchi, T., Motulsky, A.G., & Deeb, S.S. (1997). Visual pigment gene structure and expression in human retinae. Human Molecular Genetics 6, 981990.CrossRefGoogle Scholar
Yokoyama, S. (2002). Molecular evolution of color vision in vertebrates. Gene 300, 6978.Google Scholar
Yokoyama, S. & Radlwimmer, F.B. (1999). The molecular genetics of red and green color vision in mammals. Genetics 153, 919932.Google Scholar