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Prioritization of candidate genes for a South African family with Parkinson’s disease using in-silico tools

Parkinson’s disease (PD) is a neurodegenerative disorder exhibiting Mendelian inheritance in some families. Next-generation sequencing approaches, including whole exome sequencing (WES), have revolutionized the field of Mendelian disorders and have identified a number of PD genes. We recruited a Sou...

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Autores principales: Sebate, Boiketlo, Cuttler, Katelyn, Cloete, Ruben, Britz, Marcell, Christoffels, Alan, Williams, Monique, Carr, Jonathan, Bardien, Soraya
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7997022/
https://www.ncbi.nlm.nih.gov/pubmed/33770142
http://dx.doi.org/10.1371/journal.pone.0249324
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author Sebate, Boiketlo
Cuttler, Katelyn
Cloete, Ruben
Britz, Marcell
Christoffels, Alan
Williams, Monique
Carr, Jonathan
Bardien, Soraya
author_facet Sebate, Boiketlo
Cuttler, Katelyn
Cloete, Ruben
Britz, Marcell
Christoffels, Alan
Williams, Monique
Carr, Jonathan
Bardien, Soraya
author_sort Sebate, Boiketlo
collection PubMed
description Parkinson’s disease (PD) is a neurodegenerative disorder exhibiting Mendelian inheritance in some families. Next-generation sequencing approaches, including whole exome sequencing (WES), have revolutionized the field of Mendelian disorders and have identified a number of PD genes. We recruited a South African family with autosomal dominant PD and used WES to identify a possible pathogenic mutation. After filtration and prioritization, we found five potential causative variants in CFAP65, RTF1, NRXN2, TEP1 and CCNF. The variant in NRXN2 was selected for further analysis based on consistent prediction of deleteriousness across computational tools, not being present in unaffected family members, ethnic-matched controls or public databases, and its expression in the substantia nigra. A protein model for NRNX2 was created which provided a three-dimensional (3D) structure that satisfied qualitative mean and global model quality assessment scores. Trajectory analysis showed destabilizing effects of the variant on protein structure, indicated by high flexibility of the LNS-6 domain adopting an extended conformation. We also found that the known substrate N-acetyl-D-glucosamine (NAG) contributed to restoration of the structural stability of mutant NRXN2. If NRXN2 is indeed found to be the causal gene, this could reveal a new mechanism for the pathobiology of PD.
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spelling pubmed-79970222021-04-06 Prioritization of candidate genes for a South African family with Parkinson’s disease using in-silico tools Sebate, Boiketlo Cuttler, Katelyn Cloete, Ruben Britz, Marcell Christoffels, Alan Williams, Monique Carr, Jonathan Bardien, Soraya PLoS One Research Article Parkinson’s disease (PD) is a neurodegenerative disorder exhibiting Mendelian inheritance in some families. Next-generation sequencing approaches, including whole exome sequencing (WES), have revolutionized the field of Mendelian disorders and have identified a number of PD genes. We recruited a South African family with autosomal dominant PD and used WES to identify a possible pathogenic mutation. After filtration and prioritization, we found five potential causative variants in CFAP65, RTF1, NRXN2, TEP1 and CCNF. The variant in NRXN2 was selected for further analysis based on consistent prediction of deleteriousness across computational tools, not being present in unaffected family members, ethnic-matched controls or public databases, and its expression in the substantia nigra. A protein model for NRNX2 was created which provided a three-dimensional (3D) structure that satisfied qualitative mean and global model quality assessment scores. Trajectory analysis showed destabilizing effects of the variant on protein structure, indicated by high flexibility of the LNS-6 domain adopting an extended conformation. We also found that the known substrate N-acetyl-D-glucosamine (NAG) contributed to restoration of the structural stability of mutant NRXN2. If NRXN2 is indeed found to be the causal gene, this could reveal a new mechanism for the pathobiology of PD. Public Library of Science 2021-03-26 /pmc/articles/PMC7997022/ /pubmed/33770142 http://dx.doi.org/10.1371/journal.pone.0249324 Text en © 2021 Sebate et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Sebate, Boiketlo
Cuttler, Katelyn
Cloete, Ruben
Britz, Marcell
Christoffels, Alan
Williams, Monique
Carr, Jonathan
Bardien, Soraya
Prioritization of candidate genes for a South African family with Parkinson’s disease using in-silico tools
title Prioritization of candidate genes for a South African family with Parkinson’s disease using in-silico tools
title_full Prioritization of candidate genes for a South African family with Parkinson’s disease using in-silico tools
title_fullStr Prioritization of candidate genes for a South African family with Parkinson’s disease using in-silico tools
title_full_unstemmed Prioritization of candidate genes for a South African family with Parkinson’s disease using in-silico tools
title_short Prioritization of candidate genes for a South African family with Parkinson’s disease using in-silico tools
title_sort prioritization of candidate genes for a south african family with parkinson’s disease using in-silico tools
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7997022/
https://www.ncbi.nlm.nih.gov/pubmed/33770142
http://dx.doi.org/10.1371/journal.pone.0249324
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