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<p><i>LRRK2</i>-related Parkinson’s disease (<i>LRRK2</i>-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 <i>LRRK2</i> variants, especially those found in underrepresented populations, remain classified as variants of uncertain significance (VUS). Leveraging on Malaysian, Singaporean, and mainland Chinese PD datasets (<i>n</i> = 4901), we describe 12 Chinese-ancestry patients harboring the <i>LRRK2</i> p.Arg1067Gln variant, more than doubling the number of previously reported cases (total <i>n</i> = 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 <i>LRRK2</i>-PD.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年2月23日

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  • 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

摘要

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.