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

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dc.contributor.authorSebate, Boiketloen_ZA
dc.contributor.authorCuttler, Katelynen_ZA
dc.contributor.authorCloete, Rubenen_ZA
dc.contributor.authorBritz, Marcellen_ZA
dc.contributor.authorChristoffels, Alanen_ZA
dc.contributor.authorWilliams, Moniqueen_ZA
dc.contributor.authorCarr, Jonathanen_ZA
dc.contributor.authorBardien, Sorayaen_ZA
dc.date.accessioned2021-04-22T10:08:08Z
dc.date.available2021-04-22T10:08:08Z
dc.date.issued2021
dc.descriptionCITATION: Sebate, B., et al .2021. Prioritization of candidate genes for a South African family with Parkinson’s disease using in-silico tools. PLoS ONE, 16(3):e0249324, doi:10.1371/journal.pone.0249324.
dc.descriptionThe original publication is available at https://journals.plos.org/plosone/
dc.descriptionPublication of this article was funded by the Stellenbosch University Open Access Fund
dc.description.abstractParkinson’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.en_ZA
dc.description.urihttps://journals.plos.org/plosone/article?id=10.1371/journal.pone.0249324
dc.description.versionPublisher's version
dc.format.extent20 pages
dc.identifier.citationSebate, B., et al .2021. Prioritization of candidate genes for a South African family with Parkinson’s disease using in-silico tools. PLoS ONE, 16(3):e0249324, doi:10.1371/journal.pone.0249324
dc.identifier.issn1932-6203 (online)
dc.identifier.otherdoi:10.1371/journal.pone.0249324
dc.identifier.urihttp://hdl.handle.net/10019.1/110246
dc.language.isoen_ZAen_ZA
dc.publisherPublic Library of Science
dc.rights.holderAuthors retain copyright
dc.subjectParkinson’s disease -- Genetic aspects -- South Africaen_ZA
dc.subjectParkinson's disease -- Physiological aspects -- South Africaen_ZA
dc.subjectParkinson's disease -- Psychological aspects -- South Africaen_ZA
dc.subjectFunctional genomics -- Laboratory manualsen_ZA
dc.subjectMovement disordersen_ZA
dc.subjectDyskinesiaen_ZA
dc.subjectDyskinesiasen_ZA
dc.subjectMotor disordersen_ZA
dc.subjectCandidate geneen_ZA
dc.subjectGene prioritizationen_ZA
dc.subjectDisease geneen_ZA
dc.titlePrioritization of candidate genes for a South African family with Parkinson’s disease using in-silico toolsen_ZA
dc.typeArticleen_ZA
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