Blue cone monochromatism is a rare X-linked congenital stationary cone dysfunction syndrome characterized by the absence of functional long wavelength-sensitive and medium wavelength-sensitive cones in the retina. Color discrimination is severely impaired from birth, and vision is derived from the remaining preserved blue (S) cones and rod photoreceptors. BCM typically presents with reduced visual acuity, pendular nystagmus, and photophobia. Patients often have myopia (review by Gardner et al., 2009). There is evidence for progression of the disease in some BCM families (Nathans et al., 1989; Ayyagari et al., 2000; Michaelides et al., 2005).
Nathans et al. (1989) studied 12 families with blue cone monochromacy and found alterations in the red and green visual pigment gene cluster in all 12. The alterations fell into 2 classes: one class, seen in 4 families, arose by a 2-step pathway consisting of unequal homologous recombination and point mutation; the second class, present in 8 families, arose by nonhomologous deletion of genomic DNA adjacent to the red and green pigment gene cluster. In these 8 families deletions were of variable sizes, all of which encompassed a common 579-bp region. Two of the deletions were located entirely upstream of the red/green array, removing sequences no closer than 3.8 kb upstream of the red pigment gene transcription start site.
Wang et al. (1992) generated transgenic mice carrying human sequences upstream of the red and green pigment genes fused to a beta-galactosidase reporter. The patterns of transgene expression indicated that the human sequences direct expression to both long and short wave-sensitive cones in the mouse retina, and that a region between 3.1 kb and 3.7 kb 5-prime of the red pigment gene transcription initiation site is essential for expression. Wang et al. (1992) noted that sequences within this region are highly conserved, and suggested a model in which an interaction between the conserved 5-prime region and either the red or the green pigment gene promoter determines which of the 2 genes a given cone expresses.
Winderickx et al. (1992) analyzed the sequence of red- and green-specific mRNA from retinas of individuals with multiple green pigment genes in comparison with the corresponding genomic DNA sequences. The data showed that only a single green pigment gene is expressed, suggesting that the LCR allows transcription of only a single copy of the green pigment genes, probably the most proximal copy.
Nathans et al. (1993) examined the tandem array of red and green cone pigment genes on the X chromosome in 33 unrelated individuals with blue-cone monochromacy or closely related variants of BCM. 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 (Nathans et al., 1989), the rearrangements involved either deletion of the LCR adjacent to the gene array or loss of function via homologous recombination and point mutation. All of the deletions encompassed the common LCR region between 3.1 kb and 3.7 kb 5-prime of the array.
In 9 families segregating X-linked recessive BCM, Ayyagari et al. (2000) found deletions ranging from 6.3 kb to 17.8 kb in the upstream red pigment gene region; all of the deletions included the 600-bp LCR and part or all of the red pigment gene.
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, as is seen in approximately 1% of Caucasian X chromosomes; 3 of the 4 2-step families had a single 5-prime red, 3-prime green hybrid gene, and 1 family had a single red gene. In the second step, a mutation inactivated the remaining gene; Nathans et al. (1989) identified 4 nucleotide changes, including a C203R substitution in the red-green hybrid gene present in 3 families. Regarding the second class of alteration, the authors 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, supporting a model in which distant sequences act to coordinate tissue-specific gene expression. In addition, Nathans et al. (1989) noted that although most persons with blue cone monochromacy have retinas that appear normal, in some patients 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. Nathans et al. (1989) suggested that, by analogy, some peripheral retinal dystrophies may be caused by mutations in the genes encoding rhodopsin (RHO; 180380) or other rod proteins.
Nathans et al. (1993) examined the tandem array of red and green cone pigment genes on the X chromosome in 33 unrelated male patients with BCM or closely related variants of BCM. 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 (Nathans et al., 1989), the rearrangements involved either deletion of the LCR adjacent to the gene array or loss of function via homologous recombination and point mutation. All of the deletions encompassed the common LCR region between 3.1 kb and 3.7 kb 5-prime of the array. In 15 probands who carried a single gene, an inactivating C203R mutation 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 C203R 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 (R247X) in an individual (patient ‘MP’) previously studied by Reitner et al. (1991) with a single red-pigment gene, and pro307 to leu (P307L) in an individual 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 mutation pathways to blue cone monochromacy.
In a Danish family with BCM, Ladekjaer-Mikkelsen et al. (1996) identified an isolated red pigment gene with deletion of exon 4. The authors stated that this was the first intragenic deletion reported among the red and green pigment genes and that it represented a third mechanism underlying the development of BCM.
Ayyagari et al. (2000) studied 10 unrelated families segregating X-linked recessive BCM. Examination of affected individuals revealed progressive macular atrophy in a 56-year-old male patient and his 70-year-old carrier sister. In addition, 4 patients from 3 families had considerable unexplained residual photopic b-wave response on electroretinography (30 to 80% of the clinical low-normal value). Nine of the 10 families had deletions in the upstream red pigment gene region ranging from 6.3 to 17.8 kb; all of the deletions included the 600-bp LCR and part or all of the red gene. The remaining family showed loss of all of the exons of the green pigment gene. Ayyagari et al. (2000) stated that they observed no association between the phenotypes and genotypes in these families.
Michaelides et al. (2005) studied 3 British families with X-linked recessive BCM, 2 of which showed evidence of progression of disease. In 1 of the pedigrees with progressive disease and in the family with typical BCM, the authors identified a single 5-prime-L/M-3-prime hybrid gene that also carried the C203R substitution in exon 4. In the remaining pedigree (‘family A’), the mutational basis of the color vision defect was not identified.
Gardner et al. (2009) analyzed 3 British families with BCM, 1 of which was a family with a slowly progressive phenotype previously described by Michaelides et al. (2005) (‘family A’). In all 3 families, genetic analysis revealed an unequal crossover within the opsin gene array and an inactivating mutation: in 1 family, affected individuals had a single 5-prime-L/M-3-prime hybrid gene with an inactivating C203R mutation, whereas in another family, 11-year-old adopted twin brothers with BCM had a C203R-inactivated hybrid gene followed by a second inactive gene. The family with documented progressive disease was found to have a single hybrid gene lacking exon 2.
The first detailed description of blue cone monochromacy 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.
See comments of Alpern et al. (1960). Blackwell and Blackwell (1961) described affected families in which a few blue cones seemed to be present.
Reitner et al. (1991) performed wavelength discrimination experiments in 5 male patients with blue cone monochromacy and found that within the limited intensity range at which rods and blue cones are simultaneously active, color vision is possible. The authors noted that these findings imply that some rod and cone signals travel by separate pathways to the visual processing stage where wavelength discrimination takes place.
Andreasson and Tornqvist (1991) reported 3 Swedish families with a diagnosis of X-linked achromatopsia, in which affected individuals showed blue cone monochromacy on color vision testing. In 1 family, all 7 patients displayed characteristic BCM, with myopia, low visual acuity, and typical color test results; only 2 of the 7 affected individuals had a measurable b-wave response to 30-Hz flickering light. In contrast, the other 2 families showed better visual acuity, myopia was not obligate, and with the use of a narrow bandpass filter, residual cone b-wave responses were measurable in all 4 patients. Andreasson and Tornqvist (1991) suggested that there might be different types of X-linked achromatopsia, including some with a more benign prognosis.
Michaelides et al. (2005) described 3 British families with X-linked recessive BCM, 2 of which showed evidence of progression of disease: the 60-year-old and 70-year-old maternal grandfathers from families ‘A’ and ‘C,’ respectively, tested as an achromat and a rod monochromat, respectively, and both showed mild macular retinal pigment epithelial (RPE) changes, whereas their respective affected grandsons displayed residual color discrimination and had normal-appearing fundi.