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

Ai Huey Tan, 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 Ng, Kalai Arasu Muthusamy, Norlinah Mohamed Ibrahim, Khairul Azmi Ibrahim, Louis CS Tan, Jannah Zulkefli, Anis Nadhirah Khairul Anuar, Kirsten Black, Pawel Lis, Fei Xie, Zhidong CenKai Shi Lim, Katja Lohmann, Shalini Padmanabhan, Dario Alessi, Wei Luo, Eng-King Tan, Esther Sammler

Research output: Working paper/PreprintPreprint

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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=4,901), we describe 12 Chinese-ancestry patients harbouring the LRRK2 p.Arg1067Gln variant, more than doubling the number of previously reported cases (total n=23, 87% East Asian, mean age of onset:53.9years). 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 European p.Gly2019Ser variant. Taken together, p.Arg1067Gln should be reclassified from a VUS to pathogenic for causing LRRK2-PD.
Original languageEnglish
PublisherResearch Square
DOIs
Publication statusPublished - 17 Sept 2024

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