Functional and Structural Characterization of LRRK2 p.V1447L in Parkinson’s Disease
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Background
Gain-of-kinase-function variants in LRRK2 are a leading cause for Parkinson’s disease (PD).
Objectives
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 in addition to other variants in close proximity to V1447.
Methods
We measured LRRK2-dependent Rab10 phosphorylation in neutrophils and monocytes of a LRRK2 p.V1447L carrier with PD. We deployed structural modelling and evaluated the impact of additional LRRK2 variants at and around LRRK2 V1447.
Results
LRRK2 p.V1447L strongly activates LRRK2 kinase activity. We identified additional variants in the LRRK2 ROC:COR B interface with critical impact on kinase activity and show that different substitutions at the same residue can have opposing effects.
Conclusions
We recommend reclassifying LRRK2 p.V1447L from VUS to likely pathogenic. Our study expands the range of putative Loss-of-kinase function variants to LRRK2 missense variants.
