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

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

doi:10.1038/s41531-025-00884-6

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

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 LimKatja Lohmann, Shalini Padmanabhan, Dario R. Alessi, Wei Luo, Eng King Tan, Esther Sammler (Lead / Corresponding author), Ai Huey Tan (Lead / Corresponding author)

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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.

Original language	English
Article number	34
Number of pages	9
Journal	NPJ Parkinson's disease
Volume	11
Issue number	1
Early online date	23 Feb 2025
DOIs	https://doi.org/10.1038/s41531-025-00884-6
Publication status	E-pub ahead of print - 23 Feb 2025

ASJC Scopus subject areas

Neurology
Clinical Neurology
Cellular and Molecular Neuroscience

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Lim, S. Y., Toh, T. S., Hor, J. W., Lim, J. L., Lit, L. C., Ahmad-Annuar, A., Tay, Y. W., Foo, J. N., Ng, E. Y., Muthusamy, K. A., Mohamed Ibrahim, N., Ibrahim, K. A., Tan, L. C. S., Zulkefli, J., Khairul Anuar, A. N., Black, K., Lis, P., Xie, F., Cen, Z., ... Tan, A. H. (2025). Clinical and functional evidence for the pathogenicity of the LRRK2 p.Arg1067Gln variant. NPJ Parkinson's disease, 11(1), Article 34. Advance online publication. https://doi.org/10.1038/s41531-025-00884-6

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title = "Clinical and functional evidence for the pathogenicity of the LRRK2 p.Arg1067Gln variant",

abstract = "LRRK2-related Parkinson{\textquoteright}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 \textasciitilde{}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.",

author = "Lim, \{Shen Yang\} and Toh, \{Tzi Shin\} and Hor, \{Jia Wei\} and Lim, \{Jia Lun\} and Lit, \{Lei Cheng\} and Azlina Ahmad-Annuar 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 Jannah Zulkefli and \{Khairul Anuar\}, \{Anis Nadhirah\} and Kirsten Black and Pawel Lis and Fei Xie and Zhidong Cen and Lim, \{Kai Shi\} and Katja Lohmann and Shalini Padmanabhan and Alessi, \{Dario R.\} and Wei Luo and Tan, \{Eng King\} and Esther Sammler and Tan, \{Ai Huey\}",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2025.",

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doi = "10.1038/s41531-025-00884-6",

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Lim, SY, Toh, TS, Hor, JW, Lim, JL, Lit, LC, Ahmad-Annuar, A, Tay, YW, Foo, JN, Ng, EY, Muthusamy, KA, Mohamed Ibrahim, N, Ibrahim, KA, Tan, LCS, Zulkefli, J, Khairul Anuar, AN, Black, K, Lis, P, Xie, F, Cen, Z, Lim, KS, Lohmann, K, Padmanabhan, S, Alessi, DR, Luo, W, Tan, EK, Sammler, E & Tan, AH 2025, 'Clinical and functional evidence for the pathogenicity of the LRRK2 p.Arg1067Gln variant', NPJ Parkinson's disease, vol. 11, no. 1, 34. https://doi.org/10.1038/s41531-025-00884-6

TY - JOUR

T1 - Clinical and functional evidence for the pathogenicity of the LRRK2 p.Arg1067Gln variant

AU - Lim, Shen Yang

AU - Toh, Tzi Shin

AU - Hor, Jia Wei

AU - Lim, Jia Lun

AU - Lit, Lei Cheng

AU - Ahmad-Annuar, Azlina

AU - Tay, Yi Wen

AU - Foo, Jia Nee

AU - Ng, Ebonne Yulin

AU - Muthusamy, Kalai Arasu

AU - Mohamed Ibrahim, Norlinah

AU - Ibrahim, Khairul Azmi

AU - Tan, Louis Chew Seng

AU - Zulkefli, Jannah

AU - Khairul Anuar, Anis Nadhirah

AU - Black, Kirsten

AU - Lis, Pawel

AU - Xie, Fei

AU - Cen, Zhidong

AU - Lim, Kai Shi

AU - Lohmann, Katja

AU - Padmanabhan, Shalini

AU - Alessi, Dario R.

AU - Luo, Wei

AU - Tan, Eng King

AU - Sammler, Esther

AU - Tan, Ai Huey

PY - 2025/2/23

Y1 - 2025/2/23

N2 - 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.

AB - 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.

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DO - 10.1038/s41531-025-00884-6

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ER -

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

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