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A Novel ARL3 Gene Mutation Associated With Autosomal Dominant Retinal Degeneration

Despite major progress in the discovery of causative genes, many individuals and families with inherited retinal degenerations (IRDs) remain without a molecular diagnosis. We applied whole exome sequencing to identify the genetic cause in a family with an autosomal dominant IRD. Eye examinations wer...

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Autores principales: Ratnapriya, Rinki, Jacobson, Samuel G., Cideciyan, Artur V., English, Milton A., Roman, Alejandro J., Sumaroka, Alexander, Sheplock, Rebecca, Swaroop, Anand
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8416110/
https://www.ncbi.nlm.nih.gov/pubmed/34485303
http://dx.doi.org/10.3389/fcell.2021.720782
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author Ratnapriya, Rinki
Jacobson, Samuel G.
Cideciyan, Artur V.
English, Milton A.
Roman, Alejandro J.
Sumaroka, Alexander
Sheplock, Rebecca
Swaroop, Anand
author_facet Ratnapriya, Rinki
Jacobson, Samuel G.
Cideciyan, Artur V.
English, Milton A.
Roman, Alejandro J.
Sumaroka, Alexander
Sheplock, Rebecca
Swaroop, Anand
author_sort Ratnapriya, Rinki
collection PubMed
description Despite major progress in the discovery of causative genes, many individuals and families with inherited retinal degenerations (IRDs) remain without a molecular diagnosis. We applied whole exome sequencing to identify the genetic cause in a family with an autosomal dominant IRD. Eye examinations were performed and affected patients were studied with electroretinography and kinetic and chromatic static perimetry. Sequence variants were analyzed in genes (n = 271) associated with IRDs listed on the RetNet database. We applied a stepwise filtering process involving the allele frequency in the control population, in silico prediction tools for pathogenicity, and evolutionary conservation to prioritize the potential causal variant(s). Sanger sequencing and segregation analysis were performed on the proband and other family members. The IRD in this family is expressed as a widespread progressive retinal degeneration with maculopathy. A novel heterozygous variant (c.200A > T) was identified in the ARL3 gene, leading to the substitution of aspartic acid to valine at position 67. The Asp67 residue is evolutionary conserved, and the change p.Asp67Val is predicted to be pathogenic. This variant was segregated in affected members of the family and was absent from an unaffected individual. Two previous reports of a de novo missense mutation in the ARL3 gene, each describing a family with two affected generations, are the only examples to date of autosomal dominant IRD associated with this photoreceptor gene. Our results, identifying a novel pathogenic variant in ARL3 in a four-generation family with a dominant IRD, augment the evidence that the ARL3 gene is another cause of non-syndromic retinal degeneration.
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spelling pubmed-84161102021-09-04 A Novel ARL3 Gene Mutation Associated With Autosomal Dominant Retinal Degeneration Ratnapriya, Rinki Jacobson, Samuel G. Cideciyan, Artur V. English, Milton A. Roman, Alejandro J. Sumaroka, Alexander Sheplock, Rebecca Swaroop, Anand Front Cell Dev Biol Cell and Developmental Biology Despite major progress in the discovery of causative genes, many individuals and families with inherited retinal degenerations (IRDs) remain without a molecular diagnosis. We applied whole exome sequencing to identify the genetic cause in a family with an autosomal dominant IRD. Eye examinations were performed and affected patients were studied with electroretinography and kinetic and chromatic static perimetry. Sequence variants were analyzed in genes (n = 271) associated with IRDs listed on the RetNet database. We applied a stepwise filtering process involving the allele frequency in the control population, in silico prediction tools for pathogenicity, and evolutionary conservation to prioritize the potential causal variant(s). Sanger sequencing and segregation analysis were performed on the proband and other family members. The IRD in this family is expressed as a widespread progressive retinal degeneration with maculopathy. A novel heterozygous variant (c.200A > T) was identified in the ARL3 gene, leading to the substitution of aspartic acid to valine at position 67. The Asp67 residue is evolutionary conserved, and the change p.Asp67Val is predicted to be pathogenic. This variant was segregated in affected members of the family and was absent from an unaffected individual. Two previous reports of a de novo missense mutation in the ARL3 gene, each describing a family with two affected generations, are the only examples to date of autosomal dominant IRD associated with this photoreceptor gene. Our results, identifying a novel pathogenic variant in ARL3 in a four-generation family with a dominant IRD, augment the evidence that the ARL3 gene is another cause of non-syndromic retinal degeneration. Frontiers Media S.A. 2021-08-17 /pmc/articles/PMC8416110/ /pubmed/34485303 http://dx.doi.org/10.3389/fcell.2021.720782 Text en Copyright © 2021 Ratnapriya, Jacobson, Cideciyan, English, Roman, Sumaroka, Sheplock and Swaroop. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Cell and Developmental Biology
Ratnapriya, Rinki
Jacobson, Samuel G.
Cideciyan, Artur V.
English, Milton A.
Roman, Alejandro J.
Sumaroka, Alexander
Sheplock, Rebecca
Swaroop, Anand
A Novel ARL3 Gene Mutation Associated With Autosomal Dominant Retinal Degeneration
title A Novel ARL3 Gene Mutation Associated With Autosomal Dominant Retinal Degeneration
title_full A Novel ARL3 Gene Mutation Associated With Autosomal Dominant Retinal Degeneration
title_fullStr A Novel ARL3 Gene Mutation Associated With Autosomal Dominant Retinal Degeneration
title_full_unstemmed A Novel ARL3 Gene Mutation Associated With Autosomal Dominant Retinal Degeneration
title_short A Novel ARL3 Gene Mutation Associated With Autosomal Dominant Retinal Degeneration
title_sort novel arl3 gene mutation associated with autosomal dominant retinal degeneration
topic Cell and Developmental Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8416110/
https://www.ncbi.nlm.nih.gov/pubmed/34485303
http://dx.doi.org/10.3389/fcell.2021.720782
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