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      Cone Dystrophy in Patient with Homozygous RP1L1 Mutation

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          Abstract

          The purpose of this study was to determine whether an autosomal recessive cone dystrophy was caused by a homozygous RP1L1 mutation. A family including one subject affected with cone dystrophy and four unaffected members without evidence of consanguinity underwent detailed ophthalmic evaluations. The ellipsoid and interdigitation zones on the spectral-domain optical coherence tomography images were disorganized in the proband. The proband had a reduced amplitude of cone and flicker full-field electroretinograms (ERGs). Focal macular ERGs and multifocal ERGs were severely reduced in the proband. A homozygous RP1L1 mutation (c.3628T>C, p.S1210P) was identified in the proband. Family members who were heterozygous for the p.S1210P mutation had normal visual acuity and normal results of clinical evaluations. To investigate other putative pathogenic variant(s), a next-generation sequencing (NGS) approach was applied to the proband. NGS identified missense changes in the heterozygous state of the PCDH15, RPGRIP1, and GPR98 genes. None of these variants cosegregated with the phenotype and were predicted to be benign reinforcing the putative pathogenicity of the RP1L1 homozygous mutation. The AO images showed a severe reduction of the cone density in the proband. Our findings indicate that a homozygous p.S1210P exchange in the RP1L1 gene can cause cone dystrophy.

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          Most cited references 41

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          Comprehensive statistical study of 452 BRCA1 missense substitutions with classification of eight recurrent substitutions as neutral.

          Genetic testing for hereditary cancer syndromes contributes to the medical management of patients who may be at increased risk of one or more cancers. BRCA1 and BRCA2 testing for hereditary breast and ovarian cancer is one such widely used test. However, clinical testing methods with high sensitivity for deleterious mutations in these genes also detect many unclassified variants, primarily missense substitutions. We developed an extension of the Grantham difference, called A-GVGD, to score missense substitutions against the range of variation present at their position in a multiple sequence alignment. Combining two methods, co-occurrence of unclassified variants with clearly deleterious mutations and A-GVGD, we analysed most of the missense substitutions observed in BRCA1. A-GVGD was able to resolve known neutral and deleterious missense substitutions into distinct sets. Additionally, eight previously unclassified BRCA1 missense substitutions observed in trans with one or more deleterious mutations, and within the cross-species range of variation observed at their position in the protein, are now classified as neutral. The methods combined here can classify as neutral about 50% of missense substitutions that have been observed with two or more clearly deleterious mutations. Furthermore, odds ratios estimated for sets of substitutions grouped by A-GVGD scores are consistent with the hypothesis that most unclassified substitutions that are within the cross-species range of variation at their position in BRCA1 are also neutral. For most of these, clinical reclassification will require integrated application of other methods such as pooled family histories, segregation analysis, or validated functional assay.
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            The arrangement of the three cone classes in the living human eye.

            Human colour vision depends on three classes of receptor, the short- (S), medium- (M), and long- (L) wavelength-sensitive cones. These cone classes are interleaved in a single mosaic so that, at each point in the retina, only a single class of cone samples the retinal image. As a consequence, observers with normal trichromatic colour vision are necessarily colour blind on a local spatial scale. The limits this places on vision depend on the relative numbers and arrangement of cones. Although the topography of human S cones is known, the human L- and M-cone submosaics have resisted analysis. Adaptive optics, a technique used to overcome blur in ground-based telescopes, can also overcome blur in the eye, allowing the sharpest images ever taken of the living retina. Here we combine adaptive optics and retinal densitometry to obtain what are, to our knowledge, the first images of the arrangement of S, M and L cones in the living human eye. The proportion of L to M cones is strikingly different in two male subjects, each of whom has normal colour vision. The mosaics of both subjects have large patches in which either M or L cones are missing. This arrangement reduces the eye's ability to recover colour variations of high spatial frequency in the environment but may improve the recovery of luminance variations of high spatial frequency.
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              Improvements on Littmann's method of determining the size of retinal features by fundus photography.

              Littmann's formula relating the size of a retinal feature to its measured image size on a telecentric fundus camera film is widely used. It requires only the corneal radius, ametropia, and Littmann's factor q obtained from nomograms or tables. These procedures are here computerized for practitioners' convenience. Basic optical principles are discussed, showing q to be a constant fraction of the theoretical ocular dimension k', the distance from the eye's second principal point to the retina. If the eye's axial length is known, three new methods of determining q become available: (a) simply reducing the axial length by a constant 1.82 mm; (b) constructing a personalized schematic eye, given additional data; (c) ray tracing through this eye to extend calculations to peripheral retinal areas. Results of all these evaluations for 12 subjects of known ocular dimensions are presented for comparison. Method (a), the simplest, is arguably the most reliable. It shows good agreement with Littmann's supplementary procedure when the eye's axial length is known.
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                Author and article information

                Journal
                Biomed Res Int
                Biomed Res Int
                BMRI
                BioMed Research International
                Hindawi Publishing Corporation
                2314-6133
                2314-6141
                2015
                29 January 2015
                : 2015
                Affiliations
                1Department of Ophthalmology, Nippon Medical School, Chiba Hokuso Hospital, Inzai, Chiba 270-1694, Japan
                2INSERM, U968, 75012 Paris, France
                3Sorbonne Universités, UPMC Université Paris 06, UMR_S 968, Institut de la Vision, 75012 Paris, France
                4CNRS, UMR_7210, 75012 Paris, France
                5Honjo Daiichi Hospital, Yurihonjo, Akita 015-0834, Japan
                6Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts, DHU ViewMaintain, INSERM-DHOS CIC 1423, 75012 Paris, France
                7Department of Ophthalmology, Nippon Medical School, Bunkyo-ku, Tokyo 113-8602, Japan
                Author notes

                Academic Editor: Atsushi Mizota

                Article
                10.1155/2015/545243
                4322316
                Copyright © 2015 Sachiko Kikuchi et al.

                This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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