Clinical and functional evidence for the pathogenicity of the LRRK2 p.Arg1067Gln variant
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 ~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.
Authors
- Katja Lohmann (ORCID: https://orcid.org/0000-0002-5121-1460)
- Jia Wei Hor (ORCID: https://orcid.org/0000-0002-8306-5453)
- Azlina Ahmad (ORCID: https://orcid.org/0000-0002-9000-793X)
- Khairul Azmi Ibrahim (ORCID: https://orcid.org/0000-0002-2109-1138)
- Lei Cheng Lit (ORCID: https://orcid.org/0000-0002-3210-4491)
- Paweł Lis (ORCID: https://orcid.org/0000-0002-4978-7671)
- Kalai Arasu Muthusamy (ORCID: https://orcid.org/0000-0001-6149-9149)
- Jannah Zulkefli (ORCID: https://orcid.org/0000-0003-4153-4562)
- Jia Nee Foo (ORCID: https://orcid.org/0000-0001-9899-2308)
- Shalini Padmanabhan (ORCID: https://orcid.org/0000-0002-6933-416X)
- Tzi Shin Toh (ORCID: https://orcid.org/0000-0003-2434-2147)
- Eng‐King Tan (ORCID: https://orcid.org/0000-0003-2977-9743)
- Shen‐Yang Lim (ORCID: https://orcid.org/0000-0002-6942-2522)
- Anis Nadhirah Khairul Anuar (ORCID: https://orcid.org/0000-0001-7075-2871)
- Dario R. Alessi (ORCID: https://orcid.org/0000-0002-2140-9185)
- Zhidong Cen (ORCID: https://orcid.org/0000-0003-3155-5781)
- Louis C.S. Tan (ORCID: https://orcid.org/0000-0002-8415-401X)
- Yi Wen Tay (ORCID: https://orcid.org/0000-0002-9319-0768)
- Jia Lun Lim (ORCID: https://orcid.org/0000-0003-4485-7674)
- Esther Sammler (ORCID: https://orcid.org/0000-0003-3218-7116)
- Ai Huey Tan (ORCID: https://orcid.org/0000-0002-2979-3839)
- Wei Luo (ORCID: https://orcid.org/0000-0001-6951-7698)
- Fei Xie (ORCID: https://orcid.org/0000-0003-3674-8216)
- Norlinah Mohamed Ibrahim
- Kirsten Black
- Kai Shi Lim
- Ebonne Yulin Ng
Institutions
- Ministry of Health (MY)
- Agency for Science, Technology and Research (SG)
- Nanyang Technological University (SG)
- University of Dundee (GB)
- Sir Run Run Shaw Hospital (CN)
- Michael J. Fox Foundation (US)
- University of Malaya (MY)
- Hospital Sultanah Nur Zahirah (MY)
- MRC Protein Phosphorylation and Ubiquitylation Unit (GB)
- Institute for Medical Research (MY)
- National Neuroscience Institute (SG)
- Second Affiliated Hospital of Zhejiang University (CN)
- Genome Institute of Singapore (SG)
- Zhejiang University (CN)
- National University of Malaysia (MY)
- Medical Research Council (GB)
- University of Lübeck (DE)
Publication Details
- Journal
- npj Parkinson s Disease
- Published
- 2025-02-23
- DOI
- https://doi.org/10.1038/s41531-025-00884-6
- Citations
- 8
- Primary Topic
- Parkinson's Disease Mechanisms and Treatments
- Type
- article
- Field-Weighted Citation Impact
- 11.11
Funders
- Michael J. Fox Foundation for Parkinson's Research
- University of Dundee
- Universiti Malaya
- Medical Research Council
- National Medical Research Council
- Science and Technology Program of Zhejiang Province