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

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Tác giả: Azlina Ahmad-Annuar, Dario R Alessi, Kirsten Black, Zhidong Cen, Jia Nee Foo, Jia Wei Hor, Khairul Azmi Ibrahim, Anis Nadhirah Khairul Anuar, Jia Lun Lim, Kai Shi Lim, Shen-Yang Lim, Pawel Lis, Lei Cheng Lit, Katja Lohmann, Wei Luo, Norlinah Mohamed Ibrahim, Kalai Arasu Muthusamy, Ebonne Yulin Ng, Shalini Padmanabhan, Esther Sammler, Ai Huey Tan, Eng King Tan, Louis Chew Seng Tan, Yi Wen Tay, Tzi Shin Toh, Fei Xie, Jannah Zulkefli

Ngôn ngữ: eng

Ký hiệu phân loại:

Thông tin xuất bản: United States : NPJ Parkinson's disease , 2025

Mô tả vật lý:

Bộ sưu tập: NCBI

ID: 644207

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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