Blue cone monochromatism is characterized by poor central vision and color discrimination, infantile nystagmus, and nearly normal retinal appearance. The psychophysiologic functions of both rods and blue cones are preserved (Lewis et al., 1987). The frequency of achromatopsia is said to be approximately 1 in 100,000 persons. The first detailed description is that given by Huddart (1777). The subject of that report 'could never do more than guess the name of any color; yet he could distinguish white from black, or black from any light or bright color...He had 2 brothers in the same circumstances as to sight; and 2 brothers and sisters who, as well as his parents, had nothing of this defect.' This disorder was previously interpreted as total colorblindness. Information presented by Spivey (1965) indicated that affected persons can see small blue objects on a large yellow field and vice versa. These cases have been variously called partial complete colorblindness, or incomplete achromatopsia. Blackwell and Blackwell (1961) have described achromatopic families in which a few blue cones seemed to be present. See comments of Alpern et al. (1960). Sloan (1964) also had evidence of the presence of a few red cones in cases of otherwise complete achromatopsia. Bromley (1974) showed me a large kindred with this disorder in a typical X-linked recessive pattern.
Lewis et al. (1987) showed linkage of blue cone monochromatism to 2 DNA markers (DXS15 and DXS52) that map in the Xq28 area. Southern blot analysis with clones derived from the red (303900) and green (303800) cone pigment genes showed loss or rearrangement of the cone pigment cluster, but in none of the 3 multigenerational families studied were all pigment genes missing. In all 12 families studied by Nathans et al. (1989), alterations were observed in the red and green visual pigment gene cluster. The alterations fell into 2 classes: one class arose from the wildtype by a 2-step pathway consisting of unequal homologous recombination and point mutation; the second class arose by nonhomologous deletion of genomic DNA adjacent to the red and green pigment gene cluster. These deletions defined a 579-bp region located 4 kb upstream of the red pigment gene and 43 kb upstream of the nearest green pigment gene; this region is essential for the activity of both pigment genes. Most persons with blue cone monochromacy have retinas that appear normal, but, in some, a progressive central retinal dystrophy is observed as they grow older. The dystrophic region corresponds to the fovea, the cone-rich area responsible for high acuity vision, and the immediately surrounding retina. Those individuals with the 2-step alteration presumably started out as dichromats in whom homologous unequal recombination had reduced to 1 the number of genes in the tandem array of cone pigment genes. This is a finding in approximately 1% of Caucasian X chromosomes. In the second step, a mutation inactivated the remaining gene; Nathans et al. (1989) found 2 examples of point mutations. Nathans et al. (1989) made an analogy to 2 forms of thalassemia in which absence of distant upstream sequences results in loss (in cis) of beta-globin gene expression. Within the deleted region are clusters of erythroid-specific deoxyribonuclease I 'hypersensitivity' sites. It has been found in transgenic mice that fragments from these sites confer on a linked human beta-globin gene uniformly high, tissue-specific expression independent of chromosomal position. These observations support a model in which distant sequences act to coordinate tissue-specific gene expression. The fact that 1 patient developed a slowly progressive central retinal dystrophy suggested to Nathans et al. (1989) that, by analogy, some peripheral retinal dystrophies may be caused by mutations in the genes encoding rhodopsin or other rod proteins.
Nathans et al. (1993) examined the tandem array of red and green cone pigment genes on the X chromosome. In 24 subjects, 8 genotypes were found that would be predicted to eliminate the function of all of the genes within the array. As observed in an earlier study, the rearrangements involved either deletion of a locus control region adjacent to the gene array or loss of function via homologous recombination and point mutation. In 15 probands who carried a single gene, an inactivating mutation, cys203 to arg (303800.0001), was found, and both visual pigment genes carried the mutation in 1 subject whose array had 2 genes. This mutation was also found in at least one of the visual pigment genes in 1 subject whose array had multiple genes and in 2 of 321 control subjects, suggesting that preexisting cys203-to-arg mutations constitute a reservoir of chromosomes that are predisposed to generate blue-cone-monochromat genotypes by unequal homologous recombination and/or gene conversion. Two other point mutations were identified: arg247 to ter in a subject with a single red-pigment gene, and pro307 to leu in a subject with a single 5-prime-red/3-prime-green hybrid gene. The observed heterogeneity of genotypes pointed to the existence of multiple 1- and 2-step mutational pathways to blue cone monochromacy.
Nathans et al. (1993) stated that 6 different deletions, ranging in size from 0.6 kb to 55 kb, had been found in, or adjacent to, otherwise typical red-green pigment gene arrays. All of these deletions encompassed a common region between 3.1 kb and 3.7 kb 5-prime of the array. Wang et al. (1992) reported the results of experiments in which sequences 5-prime of the red- and green-pigment array directed expression of a beta-galactosidase reporter gene in transgenic mice, indicating that the region between 3.1 kb and 3.7 kb 5-prime of the array functions as an essential activator of cone-specific gene expression. The existence of a form of blue cone monochromacy due to a change in the genome removed from the color vision genes themselves justifies the inclusion of an asterisked entry distinct from the entries for the CBD (GCP, 303800) and CBP (RCP, 303900) genes.