Functional Analyses of Two Novel LRRK2 Pathogenic Variants in Familial Parkinson's Disease.

Autor: Coku I; University of Lille, Inserm, CHU Lille, U1172-LilNCog (JPARC)-Lille Neuroscience & Cognition, Lille, France., Mutez E; University of Lille, Inserm, CHU Lille, U1172-LilNCog (JPARC)-Lille Neuroscience & Cognition, Lille, France.; University of Lille, Inserm, CHU Lille, Expert Center for Parkinson's Disease, Lille, France., Eddarkaoui S; University of Lille, Inserm, CHU Lille, U1172-LilNCog (JPARC)-Lille Neuroscience & Cognition, Lille, France., Carrier S; University of Lille, Inserm, CHU Lille, U1172-LilNCog (JPARC)-Lille Neuroscience & Cognition, Lille, France., Marchand A; University of Lille, Inserm, CHU Lille, U1172-LilNCog (JPARC)-Lille Neuroscience & Cognition, Lille, France., Deldycke C; University of Lille, Inserm, CHU Lille, U1172-LilNCog (JPARC)-Lille Neuroscience & Cognition, Lille, France., Goveas L; University of Lille, Inserm, CHU Lille, U1172-LilNCog (JPARC)-Lille Neuroscience & Cognition, Lille, France., Baille G; University of Lille, Inserm, CHU Lille, Expert Center for Parkinson's Disease, Lille, France., Tir M; Department of Neurology and Expert Center for Parkinson's Disease, Amiens University Hospital, CHU Amiens-Picardie, Amiens, France., Magnez R; University of Lille, CNRS, Inserm, CHU Lille, UMR9020-U1277-CANTHER-Cancer Heterogeneity Plasticity and Resistance to Therapies, Lille, France., Thuru X; University of Lille, CNRS, Inserm, CHU Lille, UMR9020-U1277-CANTHER-Cancer Heterogeneity Plasticity and Resistance to Therapies, Lille, France., Vermeersch G; Department of Neurology, AZ Sint-Lucas, Bruges, Belgium., Vandenberghe W; Department of Neurology, University Hospitals Leuven, Leuven, Belgium.; Laboratory for Parkinson Research, Department of Neurosciences, KU Leuven, Leuven, Belgium., Buée L; University of Lille, Inserm, CHU Lille, U1172-LilNCog (JPARC)-Lille Neuroscience & Cognition, Lille, France., Defebvre L; University of Lille, Inserm, CHU Lille, U1172-LilNCog (JPARC)-Lille Neuroscience & Cognition, Lille, France.; University of Lille, Inserm, CHU Lille, Expert Center for Parkinson's Disease, Lille, France., Sablonnière B; University of Lille, Inserm, CHU Lille, U1172-LilNCog (JPARC)-Lille Neuroscience & Cognition, Lille, France.; University of Lille, Inserm, CHU Lille, Department of Toxicology and Genopathies, UF Neurobiology, Lille, France., Chartier-Harlin MC; University of Lille, Inserm, CHU Lille, U1172-LilNCog (JPARC)-Lille Neuroscience & Cognition, Lille, France., Taymans JM; University of Lille, Inserm, CHU Lille, U1172-LilNCog (JPARC)-Lille Neuroscience & Cognition, Lille, France., Huin V; University of Lille, Inserm, CHU Lille, U1172-LilNCog (JPARC)-Lille Neuroscience & Cognition, Lille, France.; University of Lille, Inserm, CHU Lille, Department of Toxicology and Genopathies, UF Neurobiology, Lille, France.
Jazyk: angličtina
Zdroj: Movement disorders : official journal of the Movement Disorder Society [Mov Disord] 2022 Aug; Vol. 37 (8), pp. 1761-1767. Date of Electronic Publication: 2022 Jun 16.
DOI: 10.1002/mds.29124
Abstrakt: 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.
(© 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)
Databáze: MEDLINE