Molecular Genetics of Human Blue Cone Monochromacy

Nathans, Jeremy; Davenport, Carol M.; Maumenee, Irene H.; Lewis, Richard A.; Hejtmancik, J. Fielding; Litt, M.; Lovrien, Everett W.; Weleber, Richard G.; Bachynski, Brian N.; Zwas, Fred; Klingaman, Roger L.; Fishman, Gerald A.

doi:10.1126/science.2788922

Cited by 285 publications

(238 citation statements)

References 53 publications

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“…This combination of normal polymorphisms (leucine 153, isoleucine 171, alanine 174, valine 178, alanine 180) has not been observed in the more than 300 L and M pigment genes that we have sequenced from individuals with normal color vision (Neitz & Neitz, unpublished results) and has only been observed in association with blue-cone monochromacy (pedigree H in Nathans et al, 1989). This unusual combination was observed in the affected members of pedigree H who had a single X-chromosome visual pigment gene, and it cosegregated with absence of function of the corresponding cones in 11 of 11 meioses.…”

Section: Resultsmentioning

confidence: 99%

“…1). This mutation was previously identified as being involved in deuteranopia (Bollinger et al, 2001), deuteranomaly (Winderickx et al, 1992), and blue-cone monochromacy (Nathans et al, 1989. It has been shown to disrupt proper folding of the photopigment molecule by preventing the formation of a conserved and essential disulfide bond (Karnik et al, 1988;Karnik & Khorana, 1990;Kazmi et al, 1997).…”

Section: Resultsmentioning

confidence: 99%

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Variety of genotypes in males diagnosed as dichromatic on a conventional clinical anomaloscope

et al. 2004

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The hypothesis that dichromatic behavior on a clinical anomaloscope can be explained by the complement and arrangement of the long- (L) and middle-wavelength (M) pigment genes was tested. It was predicted that dichromacy is associated with an X-chromosome pigment gene array capable of producing only a single functional pigment type. The simplest case of this is when deletion has left only a single X-chromosome pigment gene. The production of a single L or M pigment type can also result from rearrangements in which multiple genes remain. Often, only the two genes at the 5′ end of the array are expressed; thus, dichromacy is also predicted to occur if one of these is defective or encodes a defective pigment, or if both of them encode pigments with identical spectral sensitivities. Subjects were 128 males who accepted the full range of admixtures of the two primary lights as matching the comparison light on a Neitz or Nagel anomaloscope. Strikingly, examination of the L and M pigment genes revealed a potential cause for a color-vision defect in all 128 dichromats. This indicates that the major component of color-vision deficiency could be attributed to alterations of the pigment genes or their regulatory regions in all cases, and the variety of gene arrangements associated with dichromacy is cataloged here. However, a fraction of the dichromats (17 out of 128; 13%) had genes predicted to encode pigments that would result in two populations of cones with different spectral sensitivities. Nine of the 17 were predicted to have two pigments with slightly different spectral peaks (usually ≤ 2.5 nm) and eight had genes which specified pigments identical in peak absorption, but different in amino acid positions previously associated with optical density differences. In other subjects, reported previously, the same small spectral differences were associated with anomalous trichromacy rather than dichromacy. It appears that when the spectral difference specified by the genes is very small, the amount of residual red–green color vision measured varies; some individuals test as dichromats, others test as anomalous trichromats. The discrepancy is probably partly attributable to testing method differences and partly to a difference in performance not perception, but it seems there must also be cases in which other factors, for example, cone ratio, contribute to a person's ability to extract a color signal from a small spectral difference.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Variety of genotypes in males diagnosed as dichromatic on a conventional clinical anomaloscope

et al. 2004

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“…This is analogous to human L-M opsin in which a regulatory region, called LCR, is located upstream of the L-M opsin gene array (4). LCR is necessary for the expression of both L and M opsin genes (20) and preferentially interacts with the closer L-M opsin genes in the array (5,6). The zebrafish 0.5-kb region was designated as RH2-LCR, being the first LCR-type regulator reported for non-primate opsin genes and the first RH2 opsin regulator identified in vertebrates.…”

Section: Discussionmentioning

confidence: 99%

Identification of a locus control region for quadruplicated green-sensitive opsin genes in zebrafish

Tsujimura

Chinen

Kawamura

2007

Proc. Natl. Acad. Sci. U.S.A.

113

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Duplication of opsin genes has a crucial role in the evolution of visual system. Zebrafish have four green-sensitive (RH2) opsin genes (RH2-1, RH2-2, RH2-3, and RH2-4) arrayed in tandem. They are expressed in the short member of the double cones (SDC) but differ in expression areas in the retina and absorption spectra of their encoding photopigments. The shortest and the second shortest wavelength subtypes, RH2-1 and RH2-2, are expressed in the central-to-dorsal retina. The longer wavelength subtype, RH2-3, is expressed circumscribing the RH2-1/RH2-2 area, and the longest subtype, RH2-4, is expressed further circumscribing the RH2-3 area and mainly occupying the ventral retina. The present report shows that a 0.5-kb region located 15 kb upstream of the RH2 gene array is an essential regulator for their expression. When the 0.5-kb region was deleted from a P1-artificial chromosome (PAC) clone encompassing the four RH2 genes and when one of these genes was replaced with a reporter GFP gene, the GFP expression in SDCs was abolished in the zebrafish to which a series of the modified PAC clones were introduced. Transgenic studies also showed that the 0.5-kb region conferred the SDC-specific expression for promoters of a non-SDC (UV opsin) and a nonretinal (keratin 8) gene. Changing the location of the 0.5-kb region in the PAC clone conferred the highest expression for its proximal gene. The 0.5-kb region was thus designated as RH2-LCR analogous to the locus control region of the L-M opsin genes of primates.gene duplication ͉ GFP reporter ͉ transgenesis F unctional differentiation of duplicated genes is important for organismal evolution and is achieved through modifications of not only coding regions but also regulatory mechanisms of the gene expression in the duplicates. The regulatory mechanism for the spatial and the temporal coordination of gene expression among duplicated genes has been a subject of intense interest (1, 2). Gene duplications have an essential role in the evolution of the visual system. The visual opsins in vertebrates are classified into five phylogenetic types that originated before the vertebrate radiation: rod opsin or rhodopsin (RH1); RH1-like, or green cone opsin (RH2); short wavelength-sensitive type 1, or UV-blue cone opsin (SWS1); short wavelength-sensitive type 2, or blue cone opsin (SWS2); and middle-to long-wavelength-sensitive, or redgreen cone opsin (M/LWS) (3). However, the understanding of the regulatory mechanisms for the differential expression among the five types is still fragmentary. Subtypes of the visual opsins, created by more recent gene duplications, provide an excellent model to study the regulatory evolution of duplicated genes. A well documented example is the locus control region (LCR) of the L-M opsin genes (subtypes of M/LWS) arrayed on the X chromosome in the catarrhine primates (Old World monkeys, apes, and humans) (4).The primate L-M opsin LCR is located at Ϸ3.5 kb upstream of the gene array and interacts with only the most proximal or the second proximal gene o...

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“…In the first, mutations occur in a 'locus control region', which lies upstream of the red and green cone pigment genes and which is crucial for their expression. 36 In the second, unequal recombination results in a single X-chromosome-coded opsin gene: a point mutation 36,37 or deletion 38 in this single gene renders its product nonfunctional. The third and final mechanism, described in the minority of blue cone monochromats, occurs in those with two X-chromosome opsin genes, both of which are affected by mutations that result in non-functional gene products.…”

Section: Monochromacymentioning

confidence: 99%