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Blue Cone Monochromatism M Michaelides Et Al 3 Eye (2005) 19, 2–10 & 2005 Nature Publishing Group All rights reserved 0950-222X/05 $30.00 www.nature.com/eye 1 1 2 CLINICAL STUDY Blue cone M Michaelides , S Johnson , MP Simunovic , K Bradshaw3, G Holder4, JD Mollon2, AT Moore1 monochromatism: and DM Hunt1 a phenotype and genotype assessment with evidence of progressive loss of cone function in older individuals Abstract Aim To perform a detailed clinical and an inactivating Cys203Arg mutation. The psychophysical assessment of the members of causative mutations were not identified in the three British families affected with blue cone third family. monochromatism (BCM), and to determine the Conclusions The MR test is a useful method molecular basis of disease in these families. of detecting BCM across a wide range of age Methods Affected and unaffected groups; residual tritan colour discrimination is members of three families with BCM were clearly demonstrated and allows BCM to be examined clinically and underwent distinguished from rod monochromatism. 1Institute of Ophthalmology University College London electrophysiological and detailed BCM is usually classified as a stationary cone London, UK psychophysical testing. Blood samples were dysfunction syndrome; however, two of our taken for DNA extraction. The strategy for families show evidence of progression. This is 2Department of molecular analysis was to amplify the coding the first report of progression associated with a Experimental Psychology regions of the long wavelength-sensitive (L) genotype consisting of a single 50-L/M-30 University of Cambridge and middle wavelength-sensitive (M) cone hybrid gene carrying an inactivating mutation. Cambridge, UK opsin genes and the upstream locus control We have confirmed that the Cys203Arg 3Department of region by polymerase chain reaction, and to inactivating mutation is a common sequence Ophthalmology examine these fragments for mutations by change in blue cone monochromats. Addenbrooke’s Hospital direct sequencing. Eye (2005) 19, 2–10. doi:10.1038/sj.eye.6701391 Cambridge, UK Results We have confirmed the reported Published online 16 April 2004 finding of protan-like D-15 arrangements of 4Moorfields Eye Hospital patients with BCM. In addition, we have City Road London, UK Keywords: monochromatism; cone; dysfunction; demonstrated that the Mollon–Reffin (MR) phenotype; genotype Correspondence: Minimal test is a useful colour-discrimination Professor DM Hunt test to aid in the diagnosis of BCM. Affected Institute of Ophthalmology males were shown to fail the protan and Introduction University College London deutan axes, but retained good discrimination 11-43 Bath Street on the tritan axis of the MR test, a compelling London EC1V 9EL, UK In order to derive colour vision, the normal Tel: þ 44 (0)20 7608 6820 evidence for residual colour vision in BCM. human visual system compares the rate of Fax: þ 44 (0)20 7608 6863 This residual tritan discrimination was also quantum catches in three classes of cone, the short E-mail: [email protected] readily detected with HRR plates. In two (S or blue) wavelength-sensitive, middle (M or families, psychophysical testing demonstrated green) wavelength-sensitive and long (L or red) Received: 19 August 2003 evidence for progression of disease. In two wavelength-sensitive cones, which are maximally Accepted: 10 November pedigrees, BCM could be linked to unequal 2003 sensitive to light at 430, 535, and 565 nm, Published online: 16 April crossovers within the opsin gene array that respectively.Thistriadofconetypesprovidesthe 2004 resulted in a single 50-L/M-30 hybrid gene, with physiological substrate for trichromacy.1–3 Blue cone monochromatism M Michaelides et al 3 Each cone class contains its own visual pigment highly efficient at establishing the molecular basis for composed of an opsin protein linked by a Schiff base to BCM.6,7 The mutations in the L- and M-opsin gene array the chromophore retinal. In humans, the L- and M-opsins that cause BCM fall into two classes. In the first class, a are encoded by genes on the X chromosome, and the S- normal L- and M-opsin gene array is inactivated by a opsin by a gene located on chromosome 7.4 There exist deletion in the LCR, located upstream of the L-opsin three types of inherited colour vision deficiency in which gene. A deletion in this region would appear to abolish vision is dichromatic; each type corresponds to a transcription of all genes in the opsin gene array and selective defect in one of the three receptor therefore inactivates both L- and M-cones.10 In the mechanisms.1,2 Protanopia and deuteranopia are second class of mutations, the LCR is preserved, but characterised by defects of the red- and green-sensitive changes within the L- and M-pigment gene array lead to mechanisms, respectively. They are among the common loss of functional pigment production. The most common X-linked disorders of colour vision whose association genotype in this class consists of a single inactivated L/ with alterations in the visual pigment gene cluster at M hybrid gene. The first step in this second mechanism is Xq28 identified those genes as encoding the red- and thought to be unequal crossing over that reduces the green-sensitive visual pigments.4,5 The wild-type number of genes in the array to one, followed by a arrangement of the L- and M-opsin genes consists of a mutation that inactivates the remaining gene. A frequent head-to-tail tandem array of two or more repeat units of inactivating mutation that has been described is the 39 kb on chromosome Xq28 that are 98% identical at the thymine-to-cytosine transition at nucleotide 648, which DNA level.5 This high level of identity would appear to results in a cysteine-to-arginine substitution at codon 203, pre-dispose the L and M-opsin genes to unequal inter- a mutation known to disrupt the folding of cone opsin and intragenic recombination. Transcriptional regulation molecules.11 of the L and M genes is controlled by an upstream locus Our aim was to perform a detailed clinical and control region (LCR).6 In contrast, tritanopia is an psychophysical assessment of members of three British autosomal dominant disorder that is characterised families affected with BCM, and subsequently to by a selective defect of the blue-sensitive mechanism determine the molecular basis of BCM in these families. and is due to dominant mutations in the S-cone opsin gene. Patients and methods Blue cone monochromatism (BCM), or X-linked incomplete achromatopsia, is a rare congenital stationary Affected and unaffected members of three families with cone dysfunction syndrome, affecting less than 1 in BCM were examined clinically and underwent 100 000 individuals, characterised by the absence of L- psychophysical and electrophysiological testing. After and M-cone function.2 Thus, blue-cone monochromats informed consent was obtained, blood samples were possess rod vision and a normal short-wavelength- taken, genomic DNA was isolated from whole blood sensitive cone mechanism. Photopic vision is mediated using an extraction kit (NucleonsBiosciences), and by the blue cones, and without a comparison between molecular genetic analysis was performed. different classes of the cone photoreceptor, affected individuals are reported to have poor colour Clinical assessment discrimination. Mutations in the L- and M-opsin gene array that result in the lack of functional L- and M- The pedigrees of the families studied can be seen in pigments, and thus inactivate the corresponding cones, Figures 1a–c. A full medical and ophthalmic history was have been identified in the majority of BCM cases taken in all examined members. A full ophthalmological studied.6,7 examination was performed. All affected individuals had As in rod monochromacy (RM), BCM typically an ERG performed. Adults had an ERG that conformed presents with reduced visual acuity, pendular to the ISCEV standard, but the children had a modified nystagmus, and photophobia. Visual acuity is of the protocol using skin electrodes. Colour vision testing order of 6/24–6/60. Eccentric fixation may be present included the use of Hardy, Rand and Rittler (HRR) and myopia is a common finding.8 BCM is distinguished plates, SPP2 plates for acquired colour deficiency, from RM via psychophysical or electrophysiological Farnsworth–Munsell (FM) 100-hue test, Farnsworth D- testing. The photopic electroretinogram (ERG) is 15, the Mollon-Reffin (MR) minimal test,12 a profoundly reduced in both, but the S-cone ERG is well computerised colour vision test,13,14 and anomaloscopy. preserved in BCM.9 BCM patients have high The FM 100-hue, Farnsworth D-15 and the MR test Farnsworth–Munsell 100-Hue scores, but have fewer were all performed under CIE Standard Illuminant C errors in the vertical (tritan) axis when compared to RM. from a MacBeth Easel lamp. The MR minimal test is a At the molecular level, mutation analyses have proved saturation discrimination-type test.12 The caps used in Eye Blue cone monochromatism M Michaelides et al 4 this test are of a similar design to those in the D-15 and subject to tap the side of the cap that is coloured. The FM 100-hue tests. The test features a series of caps that lie coloured caps vary in their saturation, so the severity of along protan, deutan, and tritan lines, respectively. In the defect can be assessed. It can be performed by addition, there is one demonstration cap, which does not children as young as 5 years. lie along a dichromatic confusion axis. The remainder of the caps are all neutral, but have varying lightness (there Molecular genetic analysis are a total of nine grey caps). The examiner places one coloured cap among a group of neutral caps and asks the The underlying strategy for molecular analysis was to amplify the coding regions of the L- and M-cone opsin genes and the upstream LCR by PCR, and to examine these fragments for mutations by direct sequencing.
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