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      Late-Onset Slowly Progressing Cone/Macular Dystrophy in Patients With the Biallelic Hypomorphic Variant p.Arg1933Ter in RP1

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          Abstract

          Purpose

          Homozygous hypomorphic variants of the RP1 gene, including c.5797C>T, p.Arg1933Ter, have traditionally been considered non-pathogenic. This study aimed to elucidate the clinical manifestations of late-onset, slowly progressive cone/macular dystrophy in patients homozygous for p.Arg1933Ter in the RP1 gene.

          Methods

          Five patients with biallelic p.Arg1933Ter in RP1 were retrospectively recruited, and their clinical profiles were analyzed. Copy number variation analysis and Alu insertion assessment of genes associated with inherited retinal diseases were conducted. The results of comprehensive ophthalmological examinations, multimodal imaging, and full-field electroretinogram tests were analyzed.

          Results

          No specific sequencing errors or structural variations associated with the clinical phenotypes were identified. Alu element insertion in RP1 was not detected. The mean ± SD age at the first visit was 62.2 ± 9.8 years, with symptoms typically starting between 45 and 50 years of age. Two patients exhibited a mild form of cone/macular dystrophy, characterized by a relatively preserved fundus appearance and blurring of the ellipsoid zone on optical coherence tomography. Three patients had late-onset cone/macular dystrophy with significant atrophy.

          Conclusions

          To our knowledge, this study is the first to report that a homozygous hypomorphic variant of RP1, previously considered non-pathogenic, leads to cone/macular dystrophy.

          Translational Relevance

          The study introduces novel possibilities suggesting that the homozygous hypomorphic variant of RP1 may be linked to variant pathogenicity.

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          Most cited references19

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          Alu elements: know the SINEs

          Alu elements are primate-specific repeats and comprise 11% of the human genome. They have wide-ranging influences on gene expression. Their contribution to genome evolution, gene regulation and disease is reviewed.
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            The Mobile Element Locator Tool (MELT): population-scale mobile element discovery and biology

            Mobile element insertions (MEIs) represent ∼25% of all structural variants in human genomes. Moreover, when they disrupt genes, MEIs can influence human traits and diseases. Therefore, MEIs should be fully discovered along with other forms of genetic variation in whole genome sequencing (WGS) projects involving population genetics, human diseases, and clinical genomics. Here, we describe the Mobile Element Locator Tool (MELT), which was developed as part of the 1000 Genomes Project to perform MEI discovery on a population scale. Using both Illumina WGS data and simulations, we demonstrate that MELT outperforms existing MEI discovery tools in terms of speed, scalability, specificity, and sensitivity, while also detecting a broader spectrum of MEI-associated features. Several run modes were developed to perform MEI discovery on local and cloud systems. In addition to using MELT to discover MEIs in modern humans as part of the 1000 Genomes Project, we also used it to discover MEIs in chimpanzees and ancient (Neanderthal and Denisovan) hominids. We detected diverse patterns of MEI stratification across these populations that likely were caused by (1) diverse rates of MEI production from source elements, (2) diverse patterns of MEI inheritance, and (3) the introgression of ancient MEIs into modern human genomes. Overall, our study provides the most comprehensive map of MEIs to date spanning chimpanzees, ancient hominids, and modern humans and reveals new aspects of MEI biology in these lineages. We also demonstrate that MELT is a robust platform for MEI discovery and analysis in a variety of experimental settings.
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              The molecular basis of genetic dominance.

              A O Wilkie (1994)
              Studies of mutagenesis in many organisms indicate that the majority (over 90%) of mutations are recessive to wild type. If recessiveness represents the 'default' state, what are the distinguishing features that make a minority of mutations give rise to dominant or semidominant characters? This review draws on the rapid expansion in knowledge of molecular and cellular biology to classify the molecular mechanisms of dominant mutation. The categories discussed include (1) reduced gene dosage, expression, or protein activity (haploinsufficiency); (2) increased gene dosage; (3) ectopic or temporally altered mRNA expression; (4) increased or constitutive protein activity; (5) dominant negative effects; (6) altered structural proteins; (7) toxic protein alterations; and (8) new protein functions. This provides a framework for understanding the basis of dominant genetic phenomena in humans and other organisms.
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                Author and article information

                Journal
                Transl Vis Sci Technol
                Transl Vis Sci Technol
                TVST
                Translational Vision Science & Technology
                The Association for Research in Vision and Ophthalmology
                2164-2591
                01 August 2024
                August 2024
                : 13
                : 8
                : 2
                Affiliations
                [1 ]Department of Ophthalmology, Seoul National University College of Medicine, Seoul National University Hospital, Seoul, Republic of Korea
                [2 ]Department of Ophthalmology, Seoul National University College of Medicine, Seoul National University Bundang Hospital, Seongnam-si, Gyeonggi-do, Republic of Korea
                [3 ]Precision Medicine Center, Seoul National University Bundang Hospital, Seongnam-si, Gyeonggi-do, Republic of Korea
                Author notes
                [* ] Correspondence: Kwangsic Joo, Department of Ophthalmology, Seoul National University College of Medicine, Seoul National University Bundang Hospital, 173-82 Gumi-ro, Bundang-gu, Seongnam-si, Gyeonggi-do 13620, Republic of Korea. e-mail: namooj@ 123456snubh.org
                Sejoon Lee, Precision Medicine Center, Seoul National University Bundang Hospital, 173-82 Gumi-ro, Bundang-gu, Seongnam-si, Gyeonggi-do 13620, Republic of Korea. e-mail: sejoonlee@ 123456snubh.org
                [*]

                SWC and SJW contributed equally to this article.

                Article
                TVST-23-6452
                10.1167/tvst.13.8.2
                11305420
                39087930
                4b4e7a66-9aea-4b57-969b-05c6fdefde15
                Copyright 2024 The Authors

                This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

                History
                : 09 June 2024
                : 01 December 2023
                Page count
                Pages: 8
                Categories
                Retina
                Retina

                hypomorphic variant,cone dystrophy,macular dystrophy,retinitis pigmentosa,inherited retinal disease,rp1,transposon,alu

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