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Clinical and functional evidence for the pathogenicity of the LRRK2 p.Arg1067Gln variant

Lim SY 1 , Toh TS 2 , Hor JW 2 , Lim JL 3 , Lit LC 4 , Ahmad-Annuar A 3 Show all authors , Tay YW 3 , Foo JN 5 , Ng EY 6 , Muthusamy KA 7 , Mohamed Ibrahim N 8 , Ibrahim KA 9 , Tan LCS 6 , Zulkefli J 2 , Khairul Anuar AN 4 , Black K 10 , Lis P 10 , Xie F 11 , Cen Z 12 , Lim KS 3 , Lohmann K 13 , Padmanabhan S 14 , Alessi DR 10 , Luo W 12 , Tan EK 6 , Sammler E 15 , Tan AH 16

Affiliations 

  • 1 Division of Neurology, Department of Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
  • 2 The Mah Pooi Soo & Tan Chin Nam Centre for Parkinson's & Related Disorders, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
  • 3 Department of Biomedical Science, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
  • 4 Department of Physiology, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
  • 5 Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, Singapore, Singapore
  • 6 Department of Neurology, National Neuroscience Institute, Singapore, Singapore
  • 7 Division of Neurosurgery, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia
  • 8 Department of Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
  • 9 Department of Medicine, Hospital Sultanah Nur Zahirah, Kuala Terengganu, Terengganu, Malaysia
  • 10 Medical Research Council Protein Phosphorylation and Ubiquitylation Unit, University of Dundee, Dundee, UK
  • 11 Department of Neurology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, PR China
  • 12 Department of Neurology, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, PR China
  • 13 Institute of Neurogenetics, University of Luebeck, Luebeck, Germany
  • 14 The Michael J. Fox Foundation for Parkinson's Research, New York, NY, USA
  • 15 Medical Research Council Protein Phosphorylation and Ubiquitylation Unit, University of Dundee, Dundee, UK. e.m.sammler@dundee.ac.uk
  • 16 Division of Neurology, Department of Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia. aihuey.tan@gmail.com
NPJ Parkinsons Dis, 2025 Feb 23;11(1):34.
PMID: 39988587 DOI: 10.1038/s41531-025-00884-6

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 ~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.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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