Author:

Keywords:

Science & Technology, Life Sciences & Biomedicine, Clinical Neurology, Neurosciences & Neurology, Parkinson's disease, LRRK2, mutation, kinase, genetics, GENETICS, ASSOCIATION, MUTATIONS, BINDING, PROTEIN, HEK293 Cells, Humans, Leucine-Rich Repeat Serine-Threonine Protein Kinase-2, Mutation, Parkinson Disease, Protein Serine-Threonine Kinases, 1103 Clinical Sciences, 1106 Human Movement and Sports Sciences, 1109 Neurosciences, Neurology & Neurosurgery, 3202 Clinical sciences, 3209 Neurosciences

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 wild-type, the two new variants, or two known pathogenic mutants (G2019S and R1441G) in HEK-293 T 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. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.