Prioritization of candidate genes for a South African family with Parkinson’s disease using in-silico tools
Date
2021
Journal Title
Journal ISSN
Volume Title
Publisher
Public Library of Science
Abstract
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.
Description
CITATION: 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.
The original publication is available at https://journals.plos.org/plosone/
Publication of this article was funded by the Stellenbosch University Open Access Fund
The original publication is available at https://journals.plos.org/plosone/
Publication of this article was funded by the Stellenbosch University Open Access Fund
Keywords
Parkinson’s disease -- Genetic aspects -- South Africa, Parkinson's disease -- Physiological aspects -- South Africa, Parkinson's disease -- Psychological aspects -- South Africa, Functional genomics -- Laboratory manuals, Movement disorders, Dyskinesia, Dyskinesias, Motor disorders, Candidate gene, Gene prioritization, Disease gene
Citation
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