TY - UNPB
T1 - Clinical and functional evidence for the pathogenicity of the LRRK2 p.Arg1067Gln variant
AU - Tan, Ai Huey
AU - Lim, Shen-Yang
AU - Toh, Tzi Shin
AU - Hor, Jia Wei
AU - Lim, Jia Lun
AU - Lit, Lei Cheng
AU - Ahmad-Annuar, Azlina
AU - Tay, Yi Wen
AU - Foo, Jia Nee
AU - Ng, Ebonne
AU - Muthusamy, Kalai Arasu
AU - Ibrahim, Norlinah Mohamed
AU - Ibrahim, Khairul Azmi
AU - Tan, Louis CS
AU - Zulkefli, Jannah
AU - Anuar, Anis Nadhirah Khairul
AU - Black, Kirsten
AU - Lis, Pawel
AU - Xie, Fei
AU - Cen, Zhidong
AU - Lim, Kai Shi
AU - Lohmann, Katja
AU - Padmanabhan, Shalini
AU - Alessi, Dario
AU - Luo, Wei
AU - Tan, Eng-King
AU - Sammler, Esther
PY - 2024/9/17
Y1 - 2024/9/17
N2 - 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.
AB - 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.
U2 - 10.21203/rs.3.rs-4920792/v1
DO - 10.21203/rs.3.rs-4920792/v1
M3 - Preprint
BT - Clinical and functional evidence for the pathogenicity of the LRRK2 p.Arg1067Gln variant
PB - Research Square
ER -