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

Boiketlo Sebate; Katelyn Cuttler; Ruben Cloete; Marcell Britz; Alan Christoffels; Monique Williams; Jonathan Carr; Soraya Bardien

doi:10.1371/journal.pone.0249324

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

PLoS One. 2021 Mar 26;16(3):e0249324. doi: 10.1371/journal.pone.0249324. eCollection 2021.

Authors

Boiketlo Sebate¹, Katelyn Cuttler¹, Ruben Cloete², Marcell Britz³, Alan Christoffels², Monique Williams⁴, Jonathan Carr⁵, Soraya Bardien¹

Affiliations

¹ Division of Molecular Biology and Human Genetics, Department of Biomedical Sciences, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa.
² South African Medical Research Council Bioinformatics Unit, South African National Bioinformatics Institute, University of the Western Cape, Cape Town, South Africa.
³ Greenacres Medical Centre, Port Elizabeth, South Africa.
⁴ Division of Molecular Biology and Human Genetics, Department of Biomedical Sciences, NRF/DST Centre of Excellence for Biomedical Tuberculosis Research, South African Medical Research Council Centre for Tuberculosis Research, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa.
⁵ Division of Neurology, Department of Medicine, Stellenbosch University, Cape Town, South Africa.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Aged
Computer Simulation*
Female
Humans
Male
Mutation
Parkinson Disease / genetics*
Pedigree*
South Africa

Grants and funding

SB and JC received support from the National Research Foundation of South Africa (Grant Number: 106052) and the South African Medical Research Council (Self-Initiated Research Grant). RC and AC were supported by the South African Research Chairs Initiative of the Department of Science and Technology and National Research Foundation (NRF) of South Africa (award number UID 64751). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.