Category: Parkinson's Disease: Genetics
Objective: To investigate variants across the RAB GTPase genes in Parkinson’s disease (PD).
Background: The Global Parkinson’s Genetics Program (GP2, http://gp2.org/) is an international collaborative effort that aims to improve our understanding of the genetic architecture of PD. RAB GTPases have been shown to play a crucial role in PD as both regulators and substrates of the LRRK2 protein kinase. Recently, RAB32 p.S71R has been linked to autosomal dominant PD and has been shown to activate LRRK2’s enzymatic activity. This study aimed to identify genetic variants in RAB32 and closely related RAB GTPases and evaluate their potential association with PD.
Method: We analyzed whole-genome sequencing data from 4,713 individuals across 11 genetic ancestry groups within GP2, including 4,098 patients with PD and 390 healthy controls. Variants in RAB29, RAB32, and RAB38 were extracted using Plink, annotated using ANNOVAR, and filtered for coding non-synonymous variants with a gnomAD allele frequency <10-4, which are predicted to be deleterious (CADD, SIFT, Polyphen2).
Results: RAB29 p.R175K was detected in two patients of European descent. RAB32 p.M1? was found in three European patients with early-onset PD. RAB32 p.S71R was detected in four unrelated patients with PD and two additional first-degree relatives with PD of two of these patients. RAB38 p.E181A was found in one Malaysian PD patient of Chinese ancestry, whose daughter has clinically established multiple system atrophy and carries the same variant. RAB38 p.H31R was identified in two Malaysian PD patients of Chinese ancestry, both with a family history of PD. Additional patient screening in a Canadian cohort found RAB38 p.P55S in a young onset patient originating from the Philippines and homozygous for PINK1 p.L347P, and with a dominant pattern of disease inheritance. RAB38 p.P55 substitutions, in vitro, demonstrate a marginal increase in LRRK2 kinase activity.
Conclusion: Given the roles of RAB32 and RAB38, which interact and are functionally redundant in endolysosomal trafficking, variants in RAB38 may contribute to PD. Further segregation analyses and kinase activity assays are warranted to explore the potential effect of all RAB38 variants in PD pathogenesis.
To cite this abstract in AMA style:
C. Gabbert, AJ. Stoessl, AH. Tan, L. Eade, E. Zhunusova, J. Follett, S. Schaake, BS. Malek, C. Shambetova, K. Andersh, YW. Tay, A. Ahmad-Annuar, Z. Gan-Or, M. Ghamgosar Shahkhali, TS. Toh, GP2. Genetics Program, C. Klein, SY. Lim, D. Alessi, M. Farrer, J. Trinh. Rare Variants in RAB GTPases in Parkinson’s Disease [abstract]. Mov Disord. 2025; 40 (suppl 1). https://www.mdsabstracts.org/abstract/rare-variants-in-rab-gtpases-in-parkinsons-disease/. Accessed November 20, 2025.« Back to 2025 International Congress
MDS Abstracts - https://www.mdsabstracts.org/abstract/rare-variants-in-rab-gtpases-in-parkinsons-disease/