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Blue Cone Monochromacy Caused by the C203R Missense Mutation Or Large Deletion Mutations

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Blue Cone Monochromacy Caused by the C203R Missense Mutation Or Large Deletion Mutations Retina Blue Cone Monochromacy Caused by the C203R Missense Mutation or Large Deletion Mutations Alexander Sumaroka,1 Alexandra V. Garafalo,1 Artur V. Cideciyan,1 Jason Charng,1 Alejandro J. Roman,1 Windy Choi,1 Supna Saxena,1 Valeryia Aksianiuk,1 Susanne Kohl,2 Bernd Wissinger,2 and Samuel G. Jacobson1 1Scheie Eye Institute, Department of Ophthalmology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States 2Molecular Genetics Laboratory, Institute for Ophthalmic Research, Centre for Ophthalmology, University of Tuebingen, Tuebingen, Germany Correspondence: Samuel G. Jacob- PURPOSE. To compare the phenotype of blue cone monochromacy (BCM) caused by large son, Scheie Eye Institute, University deletion mutations with those having the C203R missense mutation. of Pennsylvania, 51 N 39th Street, Philadelphia, PA 19104, USA; METHODS. BCM patients with large deletion mutations (n ¼ 21; age range, 5–60 years), and [email protected]. with the C203R missense mutation (n ¼ 13; age range, 5–70 years), were studied with optical coherence tomography, visual acuity, and perimetric sensitivity in a retrospective Submitted: July 15, 2018 Accepted: October 29, 2018 observational case series. Perceptual estimates of spatial resolution driven by rods, S-cones, and L/M-cones were obtained by the choice of chromatic gratings presented on varied Citation: Sumaroka A, Garafalo AV, adapting conditions with a modified microperimeter. Cideciyan AV, et al. Blue cone mono- chromacy caused by the C203R mis- RESULTS. Both genotypes had abnormal foveal photoreceptor structure early in life. Patients sense mutation or large deletion with the C203R mutation, however, had decades-longer persistence of foveal photoreceptor mutations. Invest Ophthalmol Vis Sci. outer nuclear layer thickness and a slower rate of development of inner segment/outer 2018;59:5762–5772. https://doi.org/ segment defects than did patients with large deletion mutations. At late ages, both genotypes 10.1167/iovs.18-25280 had comparably severe losses of central structure. At the rod-rich hot spot, there was no difference in structure between cohorts with age. Grating acuities in all BCM patients were driven by S-cones and rods; the foveal structural differences were not reflected in a difference between cohorts in visual sensitivity and spatial resolution. CONCLUSIONS. A difference in structural phenotype due to the C203R mutation versus large deletion mutations in BCM was detected as a more prolonged persistence of foveal photoreceptor structure in patients with the missense mutation. This should be taken into account in planning natural history studies, selecting outcomes for clinical trials, and defining the time window for possible therapies. Keywords: opsin gene mutations, cones, optical coherence tomography, visual acuity lue cone monochromacy (BCM) is an X-linked disease that The goal of the current study was to compare the B is characterized by impaired red (L, long wavelength) and phenotype of the other common BCM genotype—the C203R green (M, middle wavelength) cone photoreceptor function missense mutation—with that of the large deletion mutations. caused by mutations in the OPN1LW/OPN1MW gene cluster on The results indicate very different disease progressions in chromosome Xq28. Studies of the molecular basis of BCM have BCM due to the two most common types of mutations revealed that different mutational mechanisms can lead to the observed in this disease, and this result warrants consideration 1–7 phenotype of cone photoreceptor dysfunction. in the design of future clinical trials that would include both Two frequently encountered types of mutations causing genotypes. BCM are as follows: (1) large deletions covering the locus control region and/or parts of the OPN1LW and OPN1MW genes or the entire gene cluster, thereby preventing expression METHODS of the OPN1LW/OPN1MW genes; and (2) the C203R missense mutation.1,8,9 We first studied BCM patients with large deletion Human Subjects mutations and have provided evidence that although cone photoreceptor cells are diminished from early life, there are This study was approved by the University of Pennsylvania sufficient numbers remaining across the central retina, albeit Institutional Review Board; informed consent was obtained with shortened outer segments, to suggest the potential value from adults, and assent with parental permission for all of gene augmentation therapy.10 Our next studies inquired children. The study procedures adhered to the tenets of the about possible outcome measures for future clinical trials of Declaration of Helsinki. The cohort included 34 patients therapy and again mainly involve BCM due to deletion (age range, 5–70 years) from 20 families (Table), all of mutations.11,12 whom had a clinical diagnosis of BCM and either a large Copyright 2018 The Authors iovs.arvojournals.org j ISSN: 1552-5783 5762 This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. Downloaded from iovs.arvojournals.org on 09/27/2021 BCM Genotypes IOVS j December 2018 j Vol. 59 j No. 15 j 5763 TABLE. Clinical Characteristics of BCM Patients With Deletion and Missense Mutations Age at Visual Patient/Family in Patient/Family Visits, y Acuity* Refraction† Mutation Class: Mutation Detail Previous Publications‡ Deletion mutations P1/F1 5, 7 20/200 À2.50 Deletion: LCR, OPN1LW (partial) P7/F3 P2/F2 5, 8 20/100 À13.00 Deletion: OPN1LW, OPN1MW (partial) P1/F1 P3/F2 8, 10 20/80 À5.00 Deletion: OPN1LW, OPN1MW (partial) P2/F1 P4/F3 7, 12 20/100 À6.75 Deletion: LCR, OPN1LW P5/F2 P5/F2 11, 13 20/63 À9.25 Deletion: OPN1LW, OPN1MW (partial) P3/F1 P6/F4 13 20/100 À6.00 Deletion: LCR, OPN1LW (partial) n/a P7/F3 12, 16 20/80 À7.25 Deletion: LCR, OPN1LW P6/F2 P8/F5 14, 17 20/100 À4.75 Deletion: LCR, OPN1LW P15/F6 P9/F6 18 20/125 À11.50 Deletion: LCR, OPN1LW P25/F15 P10/F1 10, 19 20/100 À6.25 Deletion: LCR, OPN1LW (partial) P8/F3 P11/F6 24 20/80 À8.75 Deletion: LCR, OPN1LW P26/F15 P12/F1 16, 25 20/80 À9.00 Deletion: LCR, OPN1LW (partial) P9/F3 P13/F1 19, 28, 31 20/100 À7.00 Deletion: LCR, OPN1LW (partial) P10/F3 P14/F7 30 20/250 À10.25 Deletion: LCR, OPN1LW n/a P15/F8 28, 32 20/125 À7.25§ Deletion: LCR, OPN1LW P16/F7 P16/F9 33 20/100 À3.25§ Deletion: LCR, OPN1LW (partial) P17/F8 P17/F10 35, 40 20/80 À6.50 Deletion: LCR, OPN1LW P18/F9 P18/F11 32, 43, 50 20/100 À6.25 Deletion: LCR, OPN1LW P19/F10 P19/F2 48, 50 20/125 À11.00jj Deletion: OPN1LW, OPN1MW (partial) P4/F1 P20/F12 55 20/63 À6.75 Deletion: LCR, OPN1LW P20/F11 P21/F13 60 20/160 À5.00jj Deletion: LCR, OPN1LW, OPN1MW n/a Missense C203R mutation P22/F14 5 20/125 À9.75 Missense: C203R n/a P23/F15 14 20/80 À4.50 Missense: C203R n/a P24/F16 13, 16 20/80 À6.50 Missense: C203R P28/F17 P25/F15 18 20/80 À2.25 Missense: C203R n/a P26/F17 24 20/100 À5.50 Missense: C203R n/a P27/F18 34 20/100 À11.00 Missense: C203R# n/a P28/F18 36 20/100 À6.00 Missense: C203R n/a P29/F16 35, 38 20/80 À6.25 Missense: C203R P29/F17 P30/F19 39, 42 20/100 À1.00 Missense: C203R P27/F16 P31/F15 52 20/80 À6.50 Missense: C203R n/a P32/F18 53 20/100 À1.50 Missense: C203R n/a P33/F14 59 20/160 À9.75¶ Missense: C203R# n/a P34/F20 70 20/100 À9.25 Missense: C203R n/a LCR, locus control region; OPN1LW, long-wave–sensitive opsin-1 gene; OPN1MW, medium-wave–sensitive opsin-1 gene; n/a, not applicable. * Best-corrected visual acuity in the test eye for OCT at most recent visit. † Refractive status of the test eye for OCT at most recent visit, given as spherical equivalent. ‡ Cideciyan et al.,10 (2013); Luo et al.,11 (2015). § Staphyloma limited to optic disc region. jj Foveal atrophic changes. ¶ Chorioretinal atrophic patches outside macula. # Genetic analysis was not performed for these patients, but a family member has the given mutation. deletion mutation in the OPN1LW/OPN1MW gene array Optical Coherence Tomography (n ¼ 21, ages 5–60 years) or the C203R missense mutation (n ¼ 13, ages 5–70 years). Longitudinal data were available OCT imaging was performed in one eye from each of the 34 for 14 patients with the deletion mutation (mean follow-up BCM patients. Cross-sectional images of the retina were duration, 5.7 years; median follow-up duration, 4 years; captured by using mainly spectral-domain OCT (SD-OCT) range of follow-up duration, 2–18 years spanning ages 5–50 devices (RTvue-100; Optovue, Inc., Fremont, CA, USA) and, in years) and for three patients with the C203R mutation a few instances, time-domain OCT (TD-OCT) instruments (patients had 3-year follow-up durations spanning ages 13– (OCT1, OCT3; Carl Zeiss Meditec, Dublin, CA, USA) as 10 42 years). All subjects underwent a complete ophthalmic described. Briefly, overlapping 4.5- or 9-mm scans were exam including best-corrected visual acuity measured with taken along the horizontal and vertical meridians through the the Early Treatment Diabetic Retinopathy Study (ETDRS) fovea. Segmentation analysis was performed with custom methodology. ETDRS acuity of the eye imaged with optical computer programs (MatLab 7.5; MathWorks, Inc., Natick, coherence tomography (OCT) from the most recent visit MA, USA), and signal peaks corresponding to retinal laminae was compared between the two cohorts of patients with were assigned on the basis of previously published work.13–16 different genotypes: the C203R mutation (n ¼ 13) and The foveola was identified as the maximum depression on the deletion mutation (n ¼ 21).
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