Selective expression of human X chromosome-linked green opsin genes.

Missense mutations in the cone opsins have been identified as a relatively common cause of red/green color vision defects, with the most frequent mutation being the substitution of arginine for cysteine at position 203 (C203R). When the corresponding cysteine is mutated in rhodopsin, it disrupts proper folding of the pigment, causing severe, early onset retinitis pigmentosa. While the C203R mutation has been associated with loss of cone function in color vision deficiency, it is not known what happens to cones expressing this mutant opsin. Here, we used high-resolution retinal imaging to examine the cone mosaic in two individuals with genes encoding a middle-wavelength sensitive (M) pigment with the C203R mutation. We found a significant reduction in cone density compared to normal and color-deficient controls, accompanying disruption in the cone mosaic in both individuals, and thinning of the outer nuclear layer. The C203R mosaics were different from that produced by another mutation (LIAVA) previously shown to disrupt the cone mosaic. Comparison of these mosaics provides insight into the timing and degree of cone disruption and has implications for the prospects for restoration of vision loss associated with various cone opsin mutations.color vision ͉ cone mosaic ͉ photopigment ͉ retinal imaging ͉ rhodopsin N ormal human color vision is trichromatic and derives from the presence of three spectrally distinct cone types: long-, middle-, and short-wavelength-sensitive (L, M, and S). Redgreen color vision defects are characterized by the absence of either L or M cone function and they affect about one in 12 Caucasian males. Inherited red-green defects can be linked to disruptions at the X-chromosome opsin gene locus, where the Land M-cone opsin genes reside in a head-to-tail array (1). Most of these disruptions involve gross gene rearrangements (2-6). However, it is becoming appreciated that missense mutations underlie a significant proportion of red-green defects (5-8). This raises the question of what impact these missense mutations have on the viability of the cones.Some insight comes from rhodopsin. There are Ͼ130 distinct rhodopsin mutations, involving at least 89 sites within the molecule (data compiled from refs. 9-17.) With rare exception (e.g., refs. 9 and 18), each of these mutations has been associated with either retinitis pigmentosa (RP) or congenital stationary night blindness. Rhodopsin and the cone opsins have structural similarities and similar functional demands. Thus, it is reasonable to hypothesize that mutations in the cone opsins homologous to those in rhodopsin that cause retinitis pigmentosa would affect the viability of the cones.The most common missense mutation in the cone opsins is a substitution of cytosine for thymine at nucleotide position 1101, which corresponds to a substitution of arginine for cysteine at amino acid position 203 (C203R) (Fig. S1). The corresponding mutation in rhodopsin (C187Y) disrupts proper folding of the pigment, causing severe, early onset retinitis pigmentos...

Section: Discussionmentioning

confidence: 99%

Cone photoreceptor mosaic disruption associated with Cys203Arg mutation in the M-cone opsin

Carroll

Baraas

Wagner-Schuman

et al. 2009

“…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%

“…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 of the array, often an L and an M opsin gene, respectively, through their proximal promoters (4)(5)(6). The choice of the promoters by the LCR is largely a stochastic process (7,8).…”

mentioning

confidence: 99%

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

Tsujimura

Chinen

Kawamura

2007

113

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...

“…Color-normal males always have an array of a red gene at the first position and one or more green genes downstream (3,4). In individuals with more than two pigment genes, only the two upstream genes are thought to be expressed (5,8), although expression of the additional downstream genes has been reported (10,11). In color-deficient European males, protan deficiencies are associated with the presence of a 5Ј redgreen hybrid gene (2,8,9,12), and deutan deficiencies are associated with either a green-gene deletion (2,12) or the presence of a 5Ј green-red hybrid gene (2,8,9,12).…”

mentioning

confidence: 99%

“…T he red͞green visual-pigment genes, which are present in a head-to-tail tandem manner on the long arm of human chromosome X, have been analyzed both in color-normal and colordeficient males (1)(2)(3)(4)(5)(6)(7)(8)(9). Color-normal males always have an array of a red gene at the first position and one or more green genes downstream (3,4).…”

mentioning

confidence: 99%

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

Ueyama

et al. 2003

We studied 247 Japanese males with congenital deutan color-vision deficiency and found that 37 subjects (15.0%) had a normal genotype of a single red gene followed by a green gene(s). Two of them had missense mutations in the green gene(s), but the other 35 subjects had no mutations in either the exons or their flanking introns. However, 32 of the 35 subjects, including all 8 subjects with pigmentcolor defect, a special category of deuteranomaly, had a nucleotide substitution, A؊71C, in the promoter of a green gene at the second position in the red͞green 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 further 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 suggest that the A؊71C substitution in the green gene at the second position is closely associated with deutan color-vision deficiency. In Japanese and presumably other Asian populations further 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.