Functional and Structural Characterization of LRRK2 p.V1447L in Parkinson's Disease

Gain-of-kinase-function variants in LRRK2 are a leading cause of monogenic Parkinson's disease (PD). We tested the functional impact of a novel LRRK2 variant p.V1447L identified in a young-onset PD patient in vivo in peripheral blood, as well as in a robust cellular assay, alongside other variants in close proximity to V1447. We measured LRRK2-dependent Rab10 phosphorylation in neutrophils and monocytes of a LRRK2 p.V1447L carrier with PD. We performed structural mapping and evaluated the potential impact of other LRRK2 variants at and around LRRK2 V1447. LRRK2 p.V1447L strongly increases LRRK2 kinase activity. We identified additional variants in the LRRK2 ROC:CORB interface with critical impact on kinase activity and demonstrated that different substitutions at the same residue can have opposing effects. We recommend reclassifying LRRK2 p.V1447L from variant of uncertain significance to likely pathogenic. Our study expands the range of putative loss-of-kinase function variants to LRRK2 missense variants.