The Genetic Landscape of Parkinsonism-Related Dystonias and Atypical Parkinsonism-Related Syndromes

Díez-Fairén, Mónica; Jerez, Pilar Alvarez; Berghausen, Joos; Bandrés‐Ciga, Sara

doi:10.3390/ijms22158100

Cited by 7 publications

(1 citation statement)

References 106 publications

(122 reference statements)

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“…Especially, dystonia is a prominent symptom for PD patients caused by several genes including PRKN, PINK1, DJ-1, and PLA2G6 (Kasten et al, 2018;Niemann and Jankovic, 2019). Analogously, parkinsonism is commonly seen in subtypes of dystonia caused by genes such as GCH1, TH, TAF1, ATP1A3, and PRKRA (Phukan et al, 2011;Diez-Fairen et al, 2021).…”

Section: Introductionmentioning

confidence: 99%

Genetic analysis of dystonia-related genes in Parkinson's disease

Wang

Zhao

Pan

et al. 2023

Front. Aging Neurosci.

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ObjectiveParkinson's disease (PD) and dystonia are two closely related movement disorders with overlaps in clinical phenotype. Variants in several dystonia-related genes were demonstrated to be associated with PD; however, genetic evidence for the involvement of dystonia-related genes in PD has not been fully studied. Here, we comprehensively investigated the association between rare variants in dystonia-related genes and PD in a large Chinese cohort.MethodsWe comprehensively analyzed the rare variants of 47 known dystonia-related genes by mining the whole-exome sequencing (WES) and whole-genome sequencing (WGS) data from 3,959 PD patients and 2,931 healthy controls. We initially identified potentially pathogenic variants of dystonia-related genes in patients with PD based on different inheritance models. Sequence kernel association tests were conducted in the next step to detect the association between the burden of rare variants and the risk for PD.ResultsWe found that five patients with PD carried potentially pathogenic biallelic variants in recessive dystonia-related genes including COL6A3 and TH. Additionally, we identified 180 deleterious variants in dominant dystonia-related genes based on computational pathogenicity predictions and four of which were considered as potentially pathogenic variants (p.W591X and p.G820S in ANO3, p.R678H in ADCY5, and p.R458Q in SLC2A1). A gene-based burden analysis revealed the increased burden of variant subgroups of TH, SQSTM1, THAP1, and ADCY5 in sporadic early-onset PD, whereas COL6A3 was associated with sporadic late-onset PD. However, none of them reached statistical significance after the Bonferroni correction.ConclusionOur findings indicated that rare variants in several dystonia-related genes are suggestively associated with PD, and taken together, the role of COL6A3 and TH genes in PD is highlighted.

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Section: Introductionmentioning

confidence: 99%

Genetic analysis of dystonia-related genes in Parkinson's disease

Wang

Zhao

Pan

et al. 2023

Front. Aging Neurosci.

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Identification of metabolic pathways and key genes associated with atypical parkinsonism using a systems biology approach

Pasqualotto,

da Silva,

Pellenz

et al. 2024

Metab Brain Dis

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Atypical parkinsonism (AP) is a group of complex neurodegenerative disorders with marked clinical and pathophysiological heterogeneity. The use of systems biology tools may contribute to the characterization of hubbottleneck genes, and the identi cation of its metabolic pathways to broaden the understanding of the bases of these disorders. A systematic search was performed on the DisGeNET database, which integrates data from expert curated repositories, GWAS catalogues, animal models and the scienti c literature. The tools STRING 11.0 and Cytoscape 3.8.2 were used for analysis of protein-protein interaction (PPI) network. The PPI network topography analyses were performed using the CytoHubba 0.1 plugin for Cytoscape. The hub and bottleneck genes were inserted into 4 different sets on the InteractiveVenn. Additional functional enrichment analyses were performed to identify Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways and gene ontology for a described set of genes. The systematic search in the DisGeNET database identi ed 485 genes involved with Atypical Parkinsonism. Superimposing these genes, we detected a total of 31 hub-bottleneck genes. Moreover, our functional enrichment analyses demonstrated the involvement of these hub-bottleneck genes in 3 major KEGG pathways. We identi ed 31 highly interconnected hubbottleneck genes through a systems biology approach, which may play a key role in the pathogenesis of atypical parkinsonism. The functional enrichment analyses showed that these genes are involved in several biological processes and pathways, such as the glial cell development, glial cell activation and cognition, pathways were related to Alzheimer disease and Parkinson disease. As a hypothesis, we highlight as possible key genes for AP the MAPT (microtubule associated protein tau), APOE (apolipoprotein E), SNCA (synuclein alpha) and APP (amyloid beta precursor protein) genes.

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