Functional Analyses of Two Novel LRRK2 Pathogenic Variants in Familial Parkinson's Disease.
LRRK2
Parkinson's disease
genetics
kinase
mutation
Journal
Movement disorders : official journal of the Movement Disorder Society
ISSN: 1531-8257
Titre abrégé: Mov Disord
Pays: United States
ID NLM: 8610688
Informations de publication
Date de publication:
08 2022
08 2022
Historique:
revised:
20
04
2022
received:
03
12
2021
accepted:
13
05
2022
pubmed:
17
6
2022
medline:
20
8
2022
entrez:
16
6
2022
Statut:
ppublish
Résumé
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. We identified two novel LRRK2 variants (H230R and A1440P) and performed functional testing. 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. The two variants were found in two large families and segregate with the disease. They display altered LRRK2 phosphorylation and kinase activity. 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.
Sections du résumé
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.
Identifiants
pubmed: 35708213
doi: 10.1002/mds.29124
pmc: PMC9543145
doi:
Substances chimiques
LRRK2 protein, human
EC 2.7.11.1
Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
EC 2.7.11.1
Protein Serine-Threonine Kinases
EC 2.7.11.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1761-1767Informations de copyright
© 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
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