Clinical and functional evidence for the pathogenicity of the LRRK2 p.Arg1067Gln variant
Document Type
Article
Publication Date
2-1-2025
Abstract
LRRK2-related Parkinson's disease (LRRK2-PD) is the most frequent form of monogenic PD worldwide, with important therapeutic opportunities, exemplified by the advancement in LRRK2 kinase inhibition studies/trials. However, many LRRK2 variants, especially those found in underrepresented populations, remain classified as variants of uncertain significance (VUS). Leveraging on Malaysian, Singaporean, and mainland Chinese PD datasets (n = 4901), we describe 12 Chinese-ancestry patients harboring the LRRK2 p.Arg1067Gln variant, more than doubling the number of previously reported cases (total n = 23, 87% East Asian, mean age of onset: 53.9 years). We determine that this variant is enriched in East Asian PD patients compared to population controls (OR = 8.0, 95% CI: 3.0-20.9), and provide supportive data for its co-segregation with PD, albeit with incomplete penetrance. Utilizing established experimental workflows, this variant showed increased LRRK2 kinase activity, by similar to 2-fold compared to wildtype and higher than the p.Gly2019Ser variant. Taken together, p.Arg1067Gln should be reclassified from a VUS to pathogenic for causing LRRK2-PD.
Divisions
fac_med,biomedsc,physiodept
Funders
Michael J. Fox Foundation for Parkinson's Research (Michael J. Fox Foundation),Michael J Fox Foundation (MJFF-010188) ; (MJFF-021041) ; (MJFF-022659),University of Dundee, United Kingdom (SCAF/18/01),Personal CSO Scottish Senior Clinical Academic Fellowship (2024C03100),Global Parkinson's Genetics Program - Science and Technology Program of Zhejiang Province (PD LCG 000207),National Medical Research Council, Singapore
Publication Title
NPJ Parkinson's Disease
Volume
11
Issue
1
Publisher
Nature Portfolio
Publisher Location
HEIDELBERGER PLATZ 3, BERLIN, 14197, GERMANY