RAB32 Ser71Arg

The research record

This is the project's file for this landmark, as written and checked. Sources are listed at the end; anything not yet confirmed is marked "Not yet verified".

Who

Emil Gustavsson (first author), Matthew Farrer (senior author, University of Florida), Dario Alessi, Francesca Tonelli, Huw Morris, Manu Sharma, Ziv Gan-Or, the Global Parkinson's Genetics Program and others. The paper lists funding from the US National Institutes of Health, the Canada Excellence Research Chairs programme, Aligning Science Across Parkinson's, the Michael J. Fox Foundation and the UK Medical Research Council. A preprint appeared in January 2024; the paper is Lancet Neurology 2024;23:603–614 (June issue).

What happened

The team sequenced the protein-coding DNA of 130 probands (the first affected person in each family) from Canada and Tunisia and screened 61 RAB genes (RAB proteins are traffic controllers for cell compartments, and some are tagged by LRRK2, see landmark 37). RAB32 c.213C>G (p.Ser71Arg) followed the disease through three families (nine affected). Genotyping 2,604 more patients and 344 controls found five more carriers, and databases (6,043 cases, 62,549 controls) another eight, from Canada, Italy, Poland, Turkey, Tunisia, Germany, the UK and the USA; carriers shared one haplotype. Overall odds ratio: 13.17 (95% CI 2.15–87.23). Mean onset was 54.6 years; penetrance was incomplete. In cells, Arg71 raised LRRK2 kinase activity about twofold compared with Ser71. One autopsy showed sparse tangles but no Lewy bodies.

Why it moved us toward a cure

It adds a second inherited cause that feeds into LRRK2 activity (the first was VPS35, landmark 36). That raises the possibility that several causes converge on overactive LRRK2 and that LRRK2 inhibitors (landmark 7) may suit more than LRRK2 mutation carriers. The authors also suggest a link to the cell's innate immune defences.

It parallels RAB29, another Rab protein that switches LRRK2 on (landmark 228).

Outcome

Advanced (changed from open on 20 Oct 2026): independent groups have since confirmed it and built on it. Hop and colleagues (Nature Genetics 2024, DOI 10.1038/s41588-024-01787-7) found the same variant in about 0.7% of 2,184 familial cases against 0.004% of 69,775 controls (odds ratio 65.5), in three families, and again saw higher LRRK2 activity. Groups in France, Italy and Germany reported further carriers in 2024–25 (for example Cogan et al., Movement Disorders, DOI 10.1002/mds.30024; Radefeldt et al., DOI 10.1002/mds.30041, which traces one founder event and finds carriers under 50 without symptoms, consistent with incomplete penetrance). A 2025 review of 83 patients found typical dopamine-responsive Parkinson's with a median onset of 54 (Kleinz et al., DOI 10.1002/mds.70037), and RAB32 is now in the causal-gene list of GP2's 2026 study across 11 ancestries (Lange et al., Lancet Neurol, DOI 10.1016/S1474-4422(26)00198-5). Caveats stand: the original linkage evidence was modest (non-parametric Z score 1.95, p = 0.03), the original odds ratio is very imprecise, the one autopsy lacked Lewy bodies, and the variant is very rare. No RAB32-directed therapy exists.

Sources

• Gustavsson et al., Lancet Neurol 2024;23:603–614, DOI 10.1016/S1474-4422(24)00121-2, PMID 38614108 (UCL Discovery) · MRC PPU record. No correction or retraction is listed; PubMed lists a commentary and four letters (Oct 2024) with an author reply.
• Preprint, "A pathogenic variant in RAB32 causes autosomal dominant Parkinson's disease and activates LRRK2 kinase" (medRxiv, 18 Jan 2024)
• Hop et al., Nat Genet 2024, DOI 10.1038/s41588-024-01787-7 · Radefeldt et al., Mov Disord, DOI 10.1002/mds.30041 · Kleinz et al., Mov Disord 2025, DOI 10.1002/mds.70037 (abstracts read via Europe PMC)
• Not yet verified: full texts; whether any RAB32 carrier has joined a LRRK2 trial.