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Candidate Genetic Modifiers for RPGR Retinal Degeneration

PURPOSE: To define genetic variants associated with variable severity of X-linked progressive retinal atrophy 1 (XLPRA1) caused by a five-nucleotide deletion in canine RPGR exon ORF15. METHODS: A genome-wide association study (GWAS) was performed in XLPRA1 phenotype informative pedigree. Whole genom...

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Autores principales: Appelbaum, Tatyana, Murgiano, Leonardo, Becker, Doreen, Santana, Evelyn, Aguirre, Gustavo D.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Association for Research in Vision and Ophthalmology 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7745631/
https://www.ncbi.nlm.nih.gov/pubmed/33326016
http://dx.doi.org/10.1167/iovs.61.14.20
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author Appelbaum, Tatyana
Murgiano, Leonardo
Becker, Doreen
Santana, Evelyn
Aguirre, Gustavo D.
author_facet Appelbaum, Tatyana
Murgiano, Leonardo
Becker, Doreen
Santana, Evelyn
Aguirre, Gustavo D.
author_sort Appelbaum, Tatyana
collection PubMed
description PURPOSE: To define genetic variants associated with variable severity of X-linked progressive retinal atrophy 1 (XLPRA1) caused by a five-nucleotide deletion in canine RPGR exon ORF15. METHODS: A genome-wide association study (GWAS) was performed in XLPRA1 phenotype informative pedigree. Whole genome sequencing (WGS) was used for mutational analysis of genes within the candidate genomic region. Retinas of normal and mutant dogs were used for gene expression, gene structure, and RNA duplex analyses. RESULTS: GWAS followed by haplotype phasing identified an approximately 4.6 Mb candidate genomic interval on CFA31 containing seven protein-coding genes expressed in retina (ROBO1, ROBO2, RBM11, NRIP1, HSPA13, SAMSN1, and USP25). Furthermore, we identified and characterized two novel lncRNAs, ROBO1-AS and ROBO2-AS, that display overlapping gene organization with axon guidance pathway genes ROBO1 and ROBO2, respectively, producing sense-antisense gene pairs. Notably, ROBO1-AS and ROBO2-AS act in cis to form lncRNA/mRNA duplexes with ROBO1 and ROBO2, respectively, suggesting important roles for these lncRNAs in the ROBO regulatory network. A subsequent WGS identified candidate genes within the genomic region on CFA31 that might be implicated in modifying severity of XLPRA1. This approach led to discovery of genetic variants in ROBO1, ROBO1-AS, ROBO2-AS, and USP25 that are strongly associated with the XLPRA1 moderate phenotype. CONCLUSIONS: The study provides new insights into the genetic basis of phenotypic variation in severity of RPGR(orf15)-associated retinal degeneration. Our findings suggest an important role for ROBO pathways in disease progression further expanding on our previously reported changes of ROBO1 expression in XLPRA1 retinas.
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spelling pubmed-77456312020-12-23 Candidate Genetic Modifiers for RPGR Retinal Degeneration Appelbaum, Tatyana Murgiano, Leonardo Becker, Doreen Santana, Evelyn Aguirre, Gustavo D. Invest Ophthalmol Vis Sci Genetics PURPOSE: To define genetic variants associated with variable severity of X-linked progressive retinal atrophy 1 (XLPRA1) caused by a five-nucleotide deletion in canine RPGR exon ORF15. METHODS: A genome-wide association study (GWAS) was performed in XLPRA1 phenotype informative pedigree. Whole genome sequencing (WGS) was used for mutational analysis of genes within the candidate genomic region. Retinas of normal and mutant dogs were used for gene expression, gene structure, and RNA duplex analyses. RESULTS: GWAS followed by haplotype phasing identified an approximately 4.6 Mb candidate genomic interval on CFA31 containing seven protein-coding genes expressed in retina (ROBO1, ROBO2, RBM11, NRIP1, HSPA13, SAMSN1, and USP25). Furthermore, we identified and characterized two novel lncRNAs, ROBO1-AS and ROBO2-AS, that display overlapping gene organization with axon guidance pathway genes ROBO1 and ROBO2, respectively, producing sense-antisense gene pairs. Notably, ROBO1-AS and ROBO2-AS act in cis to form lncRNA/mRNA duplexes with ROBO1 and ROBO2, respectively, suggesting important roles for these lncRNAs in the ROBO regulatory network. A subsequent WGS identified candidate genes within the genomic region on CFA31 that might be implicated in modifying severity of XLPRA1. This approach led to discovery of genetic variants in ROBO1, ROBO1-AS, ROBO2-AS, and USP25 that are strongly associated with the XLPRA1 moderate phenotype. CONCLUSIONS: The study provides new insights into the genetic basis of phenotypic variation in severity of RPGR(orf15)-associated retinal degeneration. Our findings suggest an important role for ROBO pathways in disease progression further expanding on our previously reported changes of ROBO1 expression in XLPRA1 retinas. The Association for Research in Vision and Ophthalmology 2020-12-16 /pmc/articles/PMC7745631/ /pubmed/33326016 http://dx.doi.org/10.1167/iovs.61.14.20 Text en Copyright 2020 The Authors http://creativecommons.org/licenses/by-nc-nd/4.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
spellingShingle Genetics
Appelbaum, Tatyana
Murgiano, Leonardo
Becker, Doreen
Santana, Evelyn
Aguirre, Gustavo D.
Candidate Genetic Modifiers for RPGR Retinal Degeneration
title Candidate Genetic Modifiers for RPGR Retinal Degeneration
title_full Candidate Genetic Modifiers for RPGR Retinal Degeneration
title_fullStr Candidate Genetic Modifiers for RPGR Retinal Degeneration
title_full_unstemmed Candidate Genetic Modifiers for RPGR Retinal Degeneration
title_short Candidate Genetic Modifiers for RPGR Retinal Degeneration
title_sort candidate genetic modifiers for rpgr retinal degeneration
topic Genetics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7745631/
https://www.ncbi.nlm.nih.gov/pubmed/33326016
http://dx.doi.org/10.1167/iovs.61.14.20
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