Lim, Shen-Yang and Toh, Tzi Shin and Hor, Jia Wei and Lim, Jia Lun and Lit, Lei Cheng and Ahmad-Annuar, Azlina and Tay, Yi Wen and Foo, Jia Nee and Ng, Ebonne Yulin and Muthusamy, Kalai Arasu and Mohamed Ibrahim, Norlinah and Ibrahim, Khairul Azmi and Tan, Louis Chew Seng and Zulkefli, Jannah and Khairul Anuar, Anis Nadhirah and Black, Kirsten and Lis, Pawel and Xie, Fei and Cen, Zhidong and Lim, Kai Shi and Lohmann, Katja and Padmanabhan, Shalini and Alessi, Dario R. and Luo, Wei and Tan, Eng King and Sammler, Esther and Tan, Ai Huey (2025) Clinical and functional evidence for the pathogenicity of the LRRK2 p.Arg1067Gln variant. NPJ Parkinson's Disease, 11 (1). p. 34. ISSN 2373-8057, DOI https://doi.org/10.1038/s41531-025-00884-6.
Full text not available from this repository.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.
| Item Type: | Article |
|---|---|
| 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 |
| Subjects: | R Medicine > R Medicine (General) |
| Divisions: | Faculty of Medicine Faculty of Medicine > Biomedical Science Department Faculty of Medicine > Physiology Department |
| Depositing User: | Ms. Juhaida Abd Rahim |
| Date Deposited: | 05 May 2025 07:54 |
| Last Modified: | 05 May 2025 07:54 |
| URI: | http://eprints.um.edu.my/id/eprint/47856 |
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