ABSTRACT
Background Pathogenic variants in the LRRK2 gene are a common monogenic cause of Parkinson’s disease. However, only seven variants have been confirmed to be pathogenic.
Objectives We identified two novel LRRK2 variants (H230R and A1440P) and performed functional testing.
Methods We transiently expressed wildtype, the two new variants, or two known pathogenic mutants (G2019S and R1441G), in HEK-293T cells, with or without LRRK2 kinase inhibitor treatment. We characterized the phosphorylation and kinase activity of the mutants by western blotting. Thermal shift assays were performed to determine the folding and stability of the LRRK2 proteins.
Results The two variants were found in two large families and segregate with the disease. They display altered LRRK2 phosphorylation and kinase activity.
Conclusions We identified two novel LRRK2 variants which segregate with the disease. The results of functional testing lead us to propose these two variants as novel causative mutations for familial Parkinson’s disease.
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
CONFLICT OF INTEREST The authors declare that there is no conflict of interest.
FUNDING INFORMATION This work was funded by the University of Lille, the “Institut National de la Santé et de la Recherche Médicale” (INSERM), the Lille University Hospital and the Association des Aidants et Malades à Corps de Lewy (A2MCL) charity. This work was also supported by grants from the Programs d’Investissements d’Avenir LabEx (excellence laboratory) DISTALZ (Development of Innovative Strategies for a Transdisciplinary approach to ALZheimer’s disease), the ANR (Agence Nationale de Recherche, France) grant ANR-16-CE16-0012-02 MeTDePaDi, grant ANR-20-CE16-0008 Synapark, grant ANR-21-CE16-0003-01 PARK-PEP, Fondation de France (Maladie de Parkinson, R19199EK), France Parkinson (R16008), and the Michael J. Fox Foundation, grant numbers 6709.03, 10255.03, and 12938.04, and the Protocole Hospitalier de Recherches Cliniques Convergence (CPP/2008/009).