Kirsten Black
Current Organizations / Institutes
The organizations/institutes from the scholar's latest article
Research Subjects
Kirsten Black has a total of 26 co-authors. Here are the top co-authors by number of shared publications:
- Alexander Zimprich
Department of Neurology, Medical University of Vienna, Vienna 1090, Austria
1 shared publication - Allison Ann Dilliott
Department of Human Genetics, McGill University, Canada
1 shared publication Anna Saari
Medical Research Council Protein Phosphorylation and Ubiquitylation Unit (MRC-PPU), Faculty of Life Sciences, University of Dundee, Dundee DD1 5EH, United Kingdom
1 shared publication- Anthea Cheung
Medical Research Council Protein Phosphorylation and Ubiquitylation Unit (MRC-PPU), Faculty of Life Sciences, University of Dundee, Dundee DD1 5EH, United Kingdom
1 shared publication Benjamin Riebenbauer
Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, 72076, Germany
1 shared publication- Christine Klein
Institute of Neurogenetics, University of Luebeck
1 shared publication
Latest Publications
- Open Access
Large-scale functional annotation establishes a reference framework for human LRRK2 variants
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.
Open AccessLarge-scale functional annotation establishes a reference framework for human LRRK2 variants
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.