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A Combined in silico, in vitro and Clinical Approach to Characterize Novel Pathogenic Missense Variants in PRPF31 in Retinitis Pigmentosa

At least six different proteins of the spliceosome, including PRPF3, PRPF4, PRPF6, PRPF8, PRPF31, and SNRNP200, are mutated in autosomal dominant retinitis pigmentosa (adRP). These proteins have recently been shown to localize to the base of the connecting cilium of the retinal photoreceptor cells,...

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Autores principales: Wheway, Gabrielle, Nazlamova, Liliya, Meshad, Nervine, Hunt, Samantha, Jackson, Nicola, Churchill, Amanda
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6438860/
https://www.ncbi.nlm.nih.gov/pubmed/30967900
http://dx.doi.org/10.3389/fgene.2019.00248
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author Wheway, Gabrielle
Nazlamova, Liliya
Meshad, Nervine
Hunt, Samantha
Jackson, Nicola
Churchill, Amanda
author_facet Wheway, Gabrielle
Nazlamova, Liliya
Meshad, Nervine
Hunt, Samantha
Jackson, Nicola
Churchill, Amanda
author_sort Wheway, Gabrielle
collection PubMed
description At least six different proteins of the spliceosome, including PRPF3, PRPF4, PRPF6, PRPF8, PRPF31, and SNRNP200, are mutated in autosomal dominant retinitis pigmentosa (adRP). These proteins have recently been shown to localize to the base of the connecting cilium of the retinal photoreceptor cells, elucidating this form of RP as a retinal ciliopathy. In the case of loss-of-function variants in these genes, pathogenicity can easily be ascribed. In the case of missense variants, this is more challenging. Furthermore, the exact molecular mechanism of disease in this form of RP remains poorly understood. In this paper we take advantage of the recently published cryo EM-resolved structure of the entire human spliceosome, to predict the effect of a novel missense variant in one component of the spliceosome; PRPF31, found in a patient attending the genetics eye clinic at Bristol Eye Hospital. Monoallelic variants in PRPF31 are a common cause of autosomal dominant retinitis pigmentosa (adRP) with incomplete penetrance. We use in vitro studies to confirm pathogenicity of this novel variant PRPF31 c.341T > A, p.Ile114Asn. This work demonstrates how in silico modeling of structural effects of missense variants on cryo-EM resolved protein complexes can contribute to predicting pathogenicity of novel variants, in combination with in vitro and clinical studies. It is currently a considerable challenge to assign pathogenic status to missense variants in these proteins.
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spelling pubmed-64388602019-04-09 A Combined in silico, in vitro and Clinical Approach to Characterize Novel Pathogenic Missense Variants in PRPF31 in Retinitis Pigmentosa Wheway, Gabrielle Nazlamova, Liliya Meshad, Nervine Hunt, Samantha Jackson, Nicola Churchill, Amanda Front Genet Genetics At least six different proteins of the spliceosome, including PRPF3, PRPF4, PRPF6, PRPF8, PRPF31, and SNRNP200, are mutated in autosomal dominant retinitis pigmentosa (adRP). These proteins have recently been shown to localize to the base of the connecting cilium of the retinal photoreceptor cells, elucidating this form of RP as a retinal ciliopathy. In the case of loss-of-function variants in these genes, pathogenicity can easily be ascribed. In the case of missense variants, this is more challenging. Furthermore, the exact molecular mechanism of disease in this form of RP remains poorly understood. In this paper we take advantage of the recently published cryo EM-resolved structure of the entire human spliceosome, to predict the effect of a novel missense variant in one component of the spliceosome; PRPF31, found in a patient attending the genetics eye clinic at Bristol Eye Hospital. Monoallelic variants in PRPF31 are a common cause of autosomal dominant retinitis pigmentosa (adRP) with incomplete penetrance. We use in vitro studies to confirm pathogenicity of this novel variant PRPF31 c.341T > A, p.Ile114Asn. This work demonstrates how in silico modeling of structural effects of missense variants on cryo-EM resolved protein complexes can contribute to predicting pathogenicity of novel variants, in combination with in vitro and clinical studies. It is currently a considerable challenge to assign pathogenic status to missense variants in these proteins. Frontiers Media S.A. 2019-03-22 /pmc/articles/PMC6438860/ /pubmed/30967900 http://dx.doi.org/10.3389/fgene.2019.00248 Text en Copyright © 2019 Wheway, Nazlamova, Meshad, Hunt, Jackson and Churchill. http://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 Genetics
Wheway, Gabrielle
Nazlamova, Liliya
Meshad, Nervine
Hunt, Samantha
Jackson, Nicola
Churchill, Amanda
A Combined in silico, in vitro and Clinical Approach to Characterize Novel Pathogenic Missense Variants in PRPF31 in Retinitis Pigmentosa
title A Combined in silico, in vitro and Clinical Approach to Characterize Novel Pathogenic Missense Variants in PRPF31 in Retinitis Pigmentosa
title_full A Combined in silico, in vitro and Clinical Approach to Characterize Novel Pathogenic Missense Variants in PRPF31 in Retinitis Pigmentosa
title_fullStr A Combined in silico, in vitro and Clinical Approach to Characterize Novel Pathogenic Missense Variants in PRPF31 in Retinitis Pigmentosa
title_full_unstemmed A Combined in silico, in vitro and Clinical Approach to Characterize Novel Pathogenic Missense Variants in PRPF31 in Retinitis Pigmentosa
title_short A Combined in silico, in vitro and Clinical Approach to Characterize Novel Pathogenic Missense Variants in PRPF31 in Retinitis Pigmentosa
title_sort combined in silico, in vitro and clinical approach to characterize novel pathogenic missense variants in prpf31 in retinitis pigmentosa
topic Genetics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6438860/
https://www.ncbi.nlm.nih.gov/pubmed/30967900
http://dx.doi.org/10.3389/fgene.2019.00248
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