Large-scale functional annotation establishes a reference framework for human LRRK2 variants
Year: 2026
Type: preprint
Abstract: Pathogenic variants in leucine-rich repeat kinase 2 ( LRRK2 ) 1 are among the most frequent monogenic causes of Parkinson’s disease (PD) 2 and act through a gain-of-function mechanism of increased kinase activity. LRRK2 -targeted therapies are in clinical development, but interpretation of the rapidly expanding catalogue of rare LRRK2 variants remains a barrier to translation. Here, we present functionally annotated data on >350 LRRK2 coding variants using a standardized cellular assay with Rab10 phosphorylation as a readout of kinase activity and integrated these data with curated genetic and clinical annotations from the Movement Disorders Society Genetic Mutation Database (MDSGene). Variants differed in activation magnitude, ranging from modest increases (e.g., p.G2019S) to strongly activating substitutions such as p.Y1699C or p.L1795F. Activating variants occurred across the full length of LRRK2, although the largest effects clustered within the ROC–COR regulatory hub, where structural analysis identified subdomains forming an allosteric scaffold controlling kinase output. All known/established pathogenic variants showed increased activity, whereas benign and likely benign variants remained within the wild-type range. Functional effect sizes correlated with pathway activation in patient-derived immune cells, altogether providing a framework for ACMG-based variant interpretation in which kinase activation can support PS3 functional evidence for reclassification of variants.
Source: medRxiv
Authors: Anthea Cheung, Neringa Pratuseviciute, Kirsten Black, Pawel Lis, Toan Phung, Melanie Cavin, Gabriel Morel, Anna Saari, Vincent Huin, Simone Zittel-Dirks, Francesca Tonelli, Benjamin Riebenbauer, Thomas Gasser, Javier Ruiz-Martinez, Global Parkinson’s Genetics Program (GP2), Huw R. Morris, Lara M Lange, Allison Dilliott, Orly Goldstein, Shachar Shani, Lionel Arnaud, Alexander Zimprich, Walter Pirker, Christine Klein, Roy Alcalay, Katja Lohmann, Dario R. Alessi, Esther Sammler
Institutions: University of Dundee, MRC Protein Phosphorylation and Ubiquitylation Unit, Medical Research Council, Inserm, Université de Lille, Centre Hospitalier Universitaire de Lille, Centre de Recherche Jean Pierre Aubert, Lille Neurosciences & Cognition, University Medical Center Hamburg-Eppendorf, Hertie Institute for Clinical Brain Research, University of Tübingen, Universitätsklinikum Tübingen, Biomedical Research Networking Center on Neurodegenerative Diseases, Biogipuzkoa Health Research Institute, Centro de Investigación Biomédica en Red, UCL Queen Square Institute of Neurology, University College London, National Institutes of Health, Wiener Krankenanstaltenverbund, National Institute on Aging, Parkinson's Foundation, Tel Aviv Sourasky Medical Center, Tel Aviv University, Sorbonne Université, Assistance Publique – Hôpitaux de Paris, Medical University of Vienna, University of Lübeck, Columbia University Irving Medical Center
Language: English
Subfield: Neurology
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7166140440
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