Objective: Our aim was to identify whether a novel putative pathogenic variant in RAB32, a gene recently associated with familial forms of Parkinson’s Disease (PD), is present in individuals from Latin America.

Background: More than 20 different genes have been associated with familial forms of PD. A recent study[1] has found a novel variant (c.213C>G; p.Ser71Arg; rs200251693) in the RAB32 gene co-segregating with autosomal dominant inheritance pattern in three pedigrees with multi-incidental parkinsonism and present in additional unrelated individuals (coming from North America, Africa, Europe, and the Middle East). Interestingly, 15/16 carriers were all associated with the same consensus haplotype across nine variants in Chr 6. Belonging to the RAB GTPase family, RAB32 interacts with LRRK2, converging in common signaling pathways[2].

Method: We screened 2,864 affected and unaffected individuals (1817 affected, 1047 control) from the Latin American Research consortium on the Genetics of Parkinson’s disease (LARGE-PD) with available genotyping data from the GDA+Neuroboost array for the presence of the haplotype associated with the variant. Data was phased using Eagle inferencing, based on reference hg38. The alleles associated with the haplotype were extracted[1] using an in-house script to find all nine variants on the phased VCF file. We then performed TaqMan RT-PCR probing for the RAB32 SNP to identify presence or absence of the variant in those with the haplotype.

Results: We identified 15 LARGE-PD samples that exhibited the associated haplotype. Based on reported pedigrees, three of these individuals had reported familial history of PD, eight had no known familial history of PD, and four had no available pedigrees. The samples originated from eight Latin American sites. Of the 15 samples, eleven were affected at the date of collection and four were unaffected. The TaqMan indicated that the RAB32 c.213C>G variant was not present in any of the 15 samples analyzed with the assay.

Conclusion: We did not identify any p.S71R carriers amongst those LARGE-PD individuals carrying the consensus haplotype. This warrants further investigation within Latin American populations as variant carriers in a different haplotype or different variants in the same gene could be found.

References: [1] Emil K. Gustavsson, Jordan Follett, Joanne Trinh, Sandeep K. Barodia, Raquel Real, Zhiyong Liu, Melissa Grant-Peters, Jesse D. Fox, Silke Appel-Cresswell, A. Jon Stoessl, Alex Rajput, Ali H. Rajput, Roland Auer, Russel Tilney, Marc Sturm, Tobias B. Haack, Suzanne Lesage, Christelle Tesson, Alexis Brice, Carles Vilariño-Güell, Mina Ryten, Matthew S. Goldberg, Andrew B. West, Michele T. Hu, Huw R. Morris, Manu Sharma, Ziv Gan-Or, Bedia Samanci, Pawel Lis, Teresa Tocino, Rim Amouri, Samia Ben Sassi, Faycel Hentati, Global Parkinson’s Genetics Program (GP2), Francesca Tonelli, Dario R. Alessi, Matthew J. Farrer (2024). A pathogenic variant in RAB32 causes autosomal dominant Parkinson’s disease and activates LRRK2 kinase
medRxiv 2024.01.17.24300927; doi: https://doi.org/10.1101/2024.01.17.24300927

[2] Emma McGrath, Dieter Waschbüsch, Brian M. Baker & Amir R. Khan (2021). LRRK2 binds to the Rab32 subfamily in a GTP-dependent manner via its armadillo domain
Small GTPases, 12:2, 133-146, DOI: 10.1080/21541248.2019.1666623

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MDS Abstracts - https://www.mdsabstracts.org/abstract/screening-for-newly-pd-associated-rab32-p-s71r-variant-in-latin-america/