RT Journal Article SR Electronic T1 Functional analyses of two novel LRRK2 pathogenic variants in familial Parkinson’s disease JF bioRxiv FD Cold Spring Harbor Laboratory SP 2021.12.03.470891 DO 10.1101/2021.12.03.470891 A1 I Coku A1 E Mutez A1 S Eddarkaoui A1 S Carrier A1 A Marchand A1 C Deldycke A1 L Goveas A1 G Baille A1 M Tir A1 R Magnez A1 X Thuru A1 G Vermeersch A1 W Vandenberghe A1 L Buée A1 L Defebvre A1 B Sablonnière A1 MC Chartier-Harlin A1 JM Taymans A1 V Huin YR 2021 UL http://biorxiv.org/content/early/2021/12/03/2021.12.03.470891.abstract AB 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 StatementThe authors have declared no competing interest.