Clinical and functional evidence for the pathogenicity of the LRRK2 p.Arg1067Gln variant
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 popu...
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Nature Portfolio
2025-02-01
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| Series: | npj Parkinson's Disease |
| Online Access: | https://doi.org/10.1038/s41531-025-00884-6 |
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| author | Shen-Yang Lim Tzi Shin Toh Jia Wei Hor Jia Lun Lim Lei Cheng Lit Azlina Ahmad-Annuar Yi Wen Tay Jia Nee Foo Ebonne Yulin Ng Kalai Arasu Muthusamy Norlinah Mohamed Ibrahim Khairul Azmi Ibrahim Louis Chew Seng Tan Jannah Zulkefli Anis Nadhirah Khairul Anuar Kirsten Black Pawel Lis Fei Xie Zhidong Cen Kai Shi Lim Katja Lohmann Shalini Padmanabhan Dario R. Alessi Wei Luo Eng King Tan Esther Sammler Ai Huey Tan |
| author_facet | Shen-Yang Lim Tzi Shin Toh Jia Wei Hor Jia Lun Lim Lei Cheng Lit Azlina Ahmad-Annuar Yi Wen Tay Jia Nee Foo Ebonne Yulin Ng Kalai Arasu Muthusamy Norlinah Mohamed Ibrahim Khairul Azmi Ibrahim Louis Chew Seng Tan Jannah Zulkefli Anis Nadhirah Khairul Anuar Kirsten Black Pawel Lis Fei Xie Zhidong Cen Kai Shi Lim Katja Lohmann Shalini Padmanabhan Dario R. Alessi Wei Luo Eng King Tan Esther Sammler Ai Huey Tan |
| author_sort | Shen-Yang Lim |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-4aa6a650a61c4c61af76ac40b5eac11c |
| institution | DOAJ |
| issn | 2373-8057 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | npj Parkinson's Disease |
| spelling | doaj-art-4aa6a650a61c4c61af76ac40b5eac11c2025-08-20T03:04:01ZengNature Portfolionpj Parkinson's Disease2373-80572025-02-011111910.1038/s41531-025-00884-6Clinical and functional evidence for the pathogenicity of the LRRK2 p.Arg1067Gln variantShen-Yang Lim0Tzi Shin Toh1Jia Wei Hor2Jia Lun Lim3Lei Cheng Lit4Azlina Ahmad-Annuar5Yi Wen Tay6Jia Nee Foo7Ebonne Yulin Ng8Kalai Arasu Muthusamy9Norlinah Mohamed Ibrahim10Khairul Azmi Ibrahim11Louis Chew Seng Tan12Jannah Zulkefli13Anis Nadhirah Khairul Anuar14Kirsten Black15Pawel Lis16Fei Xie17Zhidong Cen18Kai Shi Lim19Katja Lohmann20Shalini Padmanabhan21Dario R. Alessi22Wei Luo23Eng King Tan24Esther Sammler25Ai Huey Tan26Division of Neurology, Department of Medicine, Faculty of Medicine, University of MalayaThe Mah Pooi Soo & Tan Chin Nam Centre for Parkinson’s & Related Disorders, Faculty of Medicine, University of MalayaThe Mah Pooi Soo & Tan Chin Nam Centre for Parkinson’s & Related Disorders, Faculty of Medicine, University of MalayaDepartment of Biomedical Science, Faculty of Medicine, University of MalayaDepartment of Physiology, Faculty of Medicine, University of MalayaDepartment of Biomedical Science, Faculty of Medicine, University of MalayaDepartment of Biomedical Science, Faculty of Medicine, University of MalayaLee Kong Chian School of Medicine, Nanyang Technological University SingaporeDepartment of Neurology, National Neuroscience InstituteDivision of Neurosurgery, Faculty of Medicine, University of MalayaDepartment of Medicine, Faculty of Medicine, Universiti Kebangsaan MalaysiaDepartment of Medicine, Hospital Sultanah Nur ZahirahDepartment of Neurology, National Neuroscience InstituteThe Mah Pooi Soo & Tan Chin Nam Centre for Parkinson’s & Related Disorders, Faculty of Medicine, University of MalayaDepartment of Physiology, Faculty of Medicine, University of MalayaMedical Research Council Protein Phosphorylation and Ubiquitylation Unit, University of DundeeMedical Research Council Protein Phosphorylation and Ubiquitylation Unit, University of DundeeDepartment of Neurology, Sir Run Run Shaw Hospital, Zhejiang University School of MedicineDepartment of Neurology, The Second Affiliated Hospital, Zhejiang University School of MedicineDepartment of Biomedical Science, Faculty of Medicine, University of MalayaInstitute of Neurogenetics, University of LuebeckThe Michael J. Fox Foundation for Parkinson’s ResearchMedical Research Council Protein Phosphorylation and Ubiquitylation Unit, University of DundeeDepartment of Neurology, The Second Affiliated Hospital, Zhejiang University School of MedicineDepartment of Neurology, National Neuroscience InstituteMedical Research Council Protein Phosphorylation and Ubiquitylation Unit, University of DundeeDivision of Neurology, Department of Medicine, Faculty of Medicine, University of MalayaAbstract 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.https://doi.org/10.1038/s41531-025-00884-6 |
| spellingShingle | Shen-Yang Lim Tzi Shin Toh Jia Wei Hor Jia Lun Lim Lei Cheng Lit Azlina Ahmad-Annuar Yi Wen Tay Jia Nee Foo Ebonne Yulin Ng Kalai Arasu Muthusamy Norlinah Mohamed Ibrahim Khairul Azmi Ibrahim Louis Chew Seng Tan Jannah Zulkefli Anis Nadhirah Khairul Anuar Kirsten Black Pawel Lis Fei Xie Zhidong Cen Kai Shi Lim Katja Lohmann Shalini Padmanabhan Dario R. Alessi Wei Luo Eng King Tan Esther Sammler Ai Huey Tan Clinical and functional evidence for the pathogenicity of the LRRK2 p.Arg1067Gln variant npj Parkinson's Disease |
| title | Clinical and functional evidence for the pathogenicity of the LRRK2 p.Arg1067Gln variant |
| title_full | Clinical and functional evidence for the pathogenicity of the LRRK2 p.Arg1067Gln variant |
| title_fullStr | Clinical and functional evidence for the pathogenicity of the LRRK2 p.Arg1067Gln variant |
| title_full_unstemmed | Clinical and functional evidence for the pathogenicity of the LRRK2 p.Arg1067Gln variant |
| title_short | Clinical and functional evidence for the pathogenicity of the LRRK2 p.Arg1067Gln variant |
| title_sort | clinical and functional evidence for the pathogenicity of the lrrk2 p arg1067gln variant |
| url | https://doi.org/10.1038/s41531-025-00884-6 |
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