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

September 17, 2024

Monogenic Network

10.21203/rs.3.rs-4920792/v1

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Description

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.

Monogenic Network

The Monogenic Network is comprised of the (i) Data Generation Working Group and the (ii) Data Analysis Working Group, and studies patients and families with known and potential new monogenic causes of Parkinson’s disease.
Learn more about Monogenic Network

Meet the authors

Associate Professor and Consultant Neurologist

Ai Huey Tan, MD, PhD

University of Malaya | Kuala Lumpur, Malaysia

Senior Consultant Neurologist & Professor

Shen-Yang Lim

University of Malaya | Malaysia

Unknown, PhD Student

Tzi Shin Toh

Unknown, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia | Malaysia

PhD Student

HOR (Julian) JIA WEI, BSc

University of Malaya | Kuala Lumpur, Malaysia

Associate Professor

Azlina Ahmad-Annuar

University of Malaya | Malaysia

Member

Yi Wen Tay

University of Malaya | Malaysia

Assistant Professor

Jia Nee Foo

Nanyang Technological University | Singapore

Principal Investigator

Norlinah Mohamed Ibrahim

Universiti Kebangsaan Malaysia | Malaysia

Associated Professor

Katja Lohmann, PhD

University of Luebeck | Germany

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