RAB32 Ser71Arg in autosomal dominant Parkinson's disease: linkage, association, and functional analyses

作者：Emil K. Gustavsson, Jordan Follett, Joanne Trinh, Sandeep Kumar Barodia, Raquel Real, Zhiyong Liu, Melissa Grant‐Peters, Jesse D. Fox, Silke Appel‐Cresswell, A. Jon Stoessl, Alex Rajput, Ali H. Rajput, Roland Auer, Russel Tilney, Marc Sturm, Tobias B. Haack, Suzanne Lesage, Christelle Tesson, Alexis Brice, Carles Vilariño‐Güell, Mina Ryten, Matthew S. Goldberg, Andrew B. West, Michele T Hu, Huw R. Morris, Manu Sharma, Ziv Gan‐Or, Bedia Samancı, Paweł Lis, María Teresa Periñán, Rim Amouri, Samia Ben Sassi, F. Hentati, Francesca Tonelli, Dario R. Alessi, Matthew J. Farrer · 发表于：The Lancet Neurology · 年份：2024 · DOI：10.1016/s1474-4422(24)00121-2 · 被引用次数：113 · 研究领域：Parkinson's Disease Mechanisms and Treatments、Neurological diseases and metabolism、Nuclear Receptors and Signaling

Background Parkinson's disease is a progressive neurodegenerative disorder with multifactorial causes, among which genetic risk factors play a part. The RAB GTPases are regulators and substrates of LRRK2, and variants in the LRRK2 gene are important risk factors for Parkinson's disease. We aimed to explore genetic variability in RAB GTPases within cases of familial Parkinson's disease. Methods We did whole-exome sequencing in probands from families in Canada and Tunisia with Parkinson's disease without a genetic cause, who were recruited from the Centre for Applied Neurogenetics (Vancouver, BC, Canada), an international consortium that includes people with Parkinson's disease from 36 sites in 24 countries. 61 RAB GTPases were genetically screened, and candidate variants were genotyped in relatives of the probands to assess disease segregation by linkage analysis. Genotyping was also done to assess variant frequencies in individuals with idiopathic Parkinson's disease and controls, matched for age and sex, who were also from the Centre for Applied Neurogenetics but unrelated to the probands or each other. All participants were aged 18 years or older. The sequencing and genotyping findings were validated by case–control association analyses using bioinformatic data obtained from publicly available clinicogenomic databases (AMP-PD, GP2, and 100 000 Genomes Project) and a private German clinical diagnostic database (University of Tübingen). Clinical and pathological findings were...