Related Experiment Video

Updated: May 26, 2025

Assaying the Kinase Activity of LRRK2 in vitro
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Assaying the Kinase Activity of LRRK2 in vitro

Published on: January 18, 2012

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

Shen-Yang Lim1,2, Tzi Shin Toh2, Jia Wei Hor2

  • 1Division of Neurology, Department of Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.

NPJ Parkinson'S Disease
|February 23, 2025
PubMed

Insights

The LRRK2 p.Arg1067Gln variant is linked to Parkinson's disease (PD) in East Asian populations. This study reclassifies it as pathogenic, not uncertain, due to increased LRRK2 kinase activity.

Area of Science:

  • Genetics and Neurology
  • Neurodegenerative Diseases

Background:

  • LRRK2-related Parkinson's disease (LRRK2-PD) is a common monogenic form of PD.
  • Many LRRK2 variants remain classified as variants of uncertain significance (VUS), particularly in underrepresented populations.

Purpose of the Study:

  • To investigate the pathogenicity of the LRRK2 p.Arg1067Gln variant.
  • To reclassify the LRRK2 p.Arg1067Gln variant based on new genetic and functional data.

Main Methods:

  • Analysis of large Parkinson's disease datasets from Malaysian, Singaporean, and mainland Chinese populations (n=4901).
  • Genetic association testing to determine variant enrichment in East Asian PD patients compared to controls.
  • Functional assays to measure LRRK2 kinase activity of the p.Arg1067Gln variant.

Main Results:

  • Identified 12 Chinese-ancestry patients with the LRRK2 p.Arg1067Gln variant, increasing known cases by over 100%.
  • The p.Arg1067Gln variant is significantly enriched in East Asian PD patients (OR=8.0, 95% CI: 3.0-20.9).
  • The variant demonstrated a ~2-fold increase in LRRK2 kinase activity compared to wildtype, exceeding that of the known pathogenic p.Gly2019Ser variant.

Conclusions:

  • The LRRK2 p.Arg1067Gln variant is pathogenic and contributes to LRRK2-PD.
  • Reclassification of p.Arg1067Gln from VUS to pathogenic is warranted.
  • This finding has implications for genetic diagnosis and therapeutic strategies in LRRK2-PD.

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