Evidence map›Paper›PMID 38614108›Full record

ArticleThe Lancet. Neurology2024

RAB32 Ser71Arg in autosomal dominant Parkinson's disease: linkage, association, and functional analyses.

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 and 27 more

Open access · hybridAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in The Lancet. Neurology, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 66 papers.

0numbers the graph read from it
0cells of the map it votes in
66citing papers in PubMed
36.2field-weighted citation impact, top 1% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

66 citing papers in PubMed, 100 citations in OpenAlex.

  1. Article
  2. Article
  3. Species-dependent activities of the PINK1-parkin axis.Translational neurodegeneration · 2026
    Review
  4. The Global Parkinson's Disease Genetics (GP2) Genome Browser.Movement disorders : official journal of the Movement Disorder Society · 2026
    Article
  5. Article
  6. Review
  7. Review
  8. Article
  9. Review
  10. Genetic and environmental risk factors of Parkinsonism.Journal of neural transmission (Vienna, Austria : 1996) · 2026
    Review
  11. Article
  12. Review
  13. Article
  14. Review
  15. Review
  16. Article
  17. Elucidating the molecular interplay between LRRK2 and Rab GTPases.bioRxiv : the preprint server for biology · 2026
    Article
  18. Article
  19. Review
  20. Review

6 more citing papers are in PubMed but not listed here.

4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

37 authors at 14 institutions in 8 countries.

Emil K GustavssonDepartment of Genetics and Genomic Medicine, Great Ormond Street Institute of Child Health, University College London, London, UK; Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada; Aligning Science Across Parkinson's Collaborative Research Network, Chevy Chase, MD, USA.
Jordan FollettMcKnight Brain Institute, Department of Neurology, University of Florida, Gainesville, FL, USA; Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada.
Joanne TrinhInstitute of Neurogenetics, University of Lübeck, Lübeck, Germany; Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada.
Sandeep K BarodiaDepartment of Neurology, Center for Neurodegeneration and Experimental Therapeutics, University of Alabama at Birmingham, Birmingham, AL, USA.
Raquel RealDepartment of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, University College London, London, UK; UCL Movement Disorders Centre, University College London, London, UK; Aligning Science Across Parkinson's Collaborative Research Network, Chevy Chase, MD, USA.
Zhiyong LiuDepartment of Neurology, Center for Neurodegeneration and Experimental Therapeutics, University of Alabama at Birmingham, Birmingham, AL, USA.
Melissa Grant-PetersDepartment of Genetics and Genomic Medicine, Great Ormond Street Institute of Child Health, University College London, London, UK; Aligning Science Across Parkinson's Collaborative Research Network, Chevy Chase, MD, USA.
Jesse D FoxDepartment of Medical Genetics, University of British Columbia, Vancouver, BC, Canada.
Silke Appel-CresswellPacific Parkinson's Research Centre, Djavad Mowafaghian Centre for Brain Health, Division of Neurology, University of British Columbia, Vancouver, BC, Canada.
A Jon StoesslPacific Parkinson's Research Centre, Djavad Mowafaghian Centre for Brain Health, Division of Neurology, University of British Columbia, Vancouver, BC, Canada.
Alex RajputMovement Disorders Program, Division of Neurology, University of Saskatchewan and Saskatchewan Health Authority, Saskatoon, SK, Canada.
Ali H RajputMovement Disorders Program, Division of Neurology, University of Saskatchewan and Saskatchewan Health Authority, Saskatoon, SK, Canada.
Roland AuerDepartment of Pathology, University of Saskatchewan and Saskatchewan Health Authority, Saskatoon, SK, Canada.
Russel TilneyDepartment of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, University College London, London, UK; UCL Movement Disorders Centre, University College London, London, UK.
Marc SturmInstitute for Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.
Tobias B HaackInstitute for Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.
Suzanne LesageSorbonne Université, Institut du Cerveau-Paris Brain Institute-ICM, Inserm, CNRS, Paris, France.
Christelle TessonSorbonne Université, Institut du Cerveau-Paris Brain Institute-ICM, Inserm, CNRS, Paris, France.
Alexis BriceSorbonne Université, Institut du Cerveau-Paris Brain Institute-ICM, Inserm, CNRS, Paris, France; Assistance Publique Hôpitaux de Paris, Hôpital Pitié-Salpêtrière, Département de Neurologie, Centre d'Investigation Clinique Neurosciences, DMU Neuroscience, Paris, France.
Carles Vilariño-GüellDepartment of Medical Genetics, University of British Columbia, Vancouver, BC, Canada.
Mina RytenDepartment of Genetics and Genomic Medicine, Great Ormond Street Institute of Child Health, University College London, London, UK; NIHR Great Ormond Street Hospital Biomedical Research Centre, University College London, London, UK; Aligning Science Across Parkinson's Collaborative Research Network, Chevy Chase, MD, USA.
Matthew S GoldbergDepartment of Neurology, Center for Neurodegeneration and Experimental Therapeutics, University of Alabama at Birmingham, Birmingham, AL, USA.
Andrew B WestDuke Center for Neurodegeneration and Neurotherapeutics, Department of Pharmacology and Cancer Biology, Duke University, Durham, NC, USA.
Michele T HuDivision of Neurology, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.
Huw R MorrisDepartment of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, University College London, London, UK; UCL Movement Disorders Centre, University College London, London, UK; Aligning Science Across Parkinson's Collaborative Research Network, Chevy Chase, MD, USA.
Manu SharmaCentre for Genetic Epidemiology, Institute for Clinical Epidemiology and Applied Biometry, University of Tübingen, Tübingen, Germany.
Ziv Gan-OrThe Neuro, Montreal Neurological Institute-Hospital, Montreal, QC, Canada; Department of Neurology and Neurosurgery, and Department of Human Genetics, McGill University, Montreal, QC, Canada.
Bedia SamanciBehavioural Neurology and Movement Disorders Unit, Department of Neurology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey.
Pawel LisMRC Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dundee, UK; Aligning Science Across Parkinson's Collaborative Research Network, Chevy Chase, MD, USA.
Maria Teresa PeriñanQueen Mary College, University of London, London, UK.
Rim AmouriService de Neurologie, Institut National de Neurologie, La Rabta, Tunis, Tunisia.
Samia Ben SassiService de Neurologie, Institut National de Neurologie, La Rabta, Tunis, Tunisia.
Faycel HentatiService de Neurologie, Institut National de Neurologie, La Rabta, Tunis, Tunisia.
Global Parkinson's Genetics Program (GP2)
Francesca TonelliMRC Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dundee, UK; Aligning Science Across Parkinson's Collaborative Research Network, Chevy Chase, MD, USA.
Dario R AlessiMRC Protein Phosphorylation and Ubiquitylation Unit, School of Life Sciences, University of Dundee, Dundee, UK; Aligning Science Across Parkinson's Collaborative Research Network, Chevy Chase, MD, USA.
Matthew J FarrerMcKnight Brain Institute, Department of Neurology, University of Florida, Gainesville, FL, USA; Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada. Electronic address: m.farrer@ufl.edu.
University of British Columbia · CACentre National de la Recherche Scientifique · FRInstitut National de Santé Publique · TNSaskatchewan Health Authority · CAUniversity of Alabama at Birmingham · USUniversity of Dundee · GBUniversity of Tübingen · DEGreat Ormond Street Hospital · GBKing's College London · GBQueen Mary University of London · GBDuke University · USIstanbul University · TRMontreal Neurological Institute and Hospital · CAUniversity of Oxford · GB

Funding

Genetics and Molecular Biology of ParkinsonismP50NS040256 · NINDS · MAYO CLINIC JACKSONVILLE · PI DICKSON, DENNIS WILLIAM · 2004 to 2009
$8.9M
Mechanisms of LRRK2 Mediated NeurotoxicityR01NS064934 · NINDS · UNIVERSITY OF ALABAMA AT BIRMINGHAM · PI WEST, ANDREW B · 2010 to 2025
$6.3M
MORRIS K. UDALL PARKINSONS DISEASE RESEARCH CENTER OF EXP01NS040256 · NINDS · MAYO CLINIC COLL OF MED, JACKSONVILLE · PI DICKSON, DENNIS WILLIAM · 1999 to 2003
$5.2M
Genotype/Phenotype Studies of Parkinson's Disease in TunisiaR21NS064885 · NINDS · MAYO CLINIC JACKSONVILLE · PI FARRER, MATTHEW J, HENTATI, FAYCAL · 2009 to 2009
$153k
NINDS NIH HHS P01 NS040256NINDS NIH HHS P50 NS040256NINDS NIH HHS R01 NS064934NINDS NIH HHS R21 NS064885Wellcome Trust
6 · The paper itself

Abstract

backgroundParkinson's disease is a progressive neurodegenerative disorder with multifactorial causes, among which genetic risk factors play a part. The RAB GTPases are regulators and substrates of LRRK2, and variants in the LRRK2 gene are important risk factors for Parkinson's disease. We aimed to explore genetic variability in RAB GTPases within cases of familial Parkinson's disease.

methodsWe did whole-exome sequencing in probands from families in Canada and Tunisia with Parkinson's disease without a genetic cause, who were recruited from the Centre for Applied Neurogenetics (Vancouver, BC, Canada), an international consortium that includes people with Parkinson's disease from 36 sites in 24 countries. 61 RAB GTPases were genetically screened, and candidate variants were genotyped in relatives of the probands to assess disease segregation by linkage analysis. Genotyping was also done to assess variant frequencies in individuals with idiopathic Parkinson's disease and controls, matched for age and sex, who were also from the Centre for Applied Neurogenetics but unrelated to the probands or each other. All participants were aged 18 years or older. The sequencing and genotyping findings were validated by case-control association analyses using bioinformatic data obtained from publicly available clinicogenomic databases (AMP-PD, GP2, and 100 000 Genomes Project) and a private German clinical diagnostic database (University of Tübingen). Clinical and pathological findings were summarised and haplotypes were determined. In-vitro studies were done to investigate protein interactions and enzyme activities.

findingsBetween June 1, 2010, and May 31, 2017, 130 probands from Canada and Tunisia (47 [36%] female and 83 [64%] male; mean age 72·7 years [SD 11·7; range 38-96]; 109 White European ancestry, 18 north African, two east Asian, and one Hispanic] underwent whole-exome sequencing. 15 variants in RAB GTPase genes were identified, of which the RAB32 variant c.213C>G (Ser71Arg) cosegregated with autosomal dominant Parkinson's disease in three families (nine affected individuals; non-parametric linkage Z score=1·95; p=0·03). 2604 unrelated individuals with Parkinson's disease and 344 matched controls were additionally genotyped, and five more people originating from five countries (Canada, Italy, Poland, Turkey, and Tunisia) were identified with the RAB32 variant. From the database searches, in which 6043 individuals with Parkinson's disease and 62 549 controls were included, another eight individuals were identified with the RAB32 variant from four countries (Canada, Germany, UK, and USA). Overall, the association of RAB32 c.213C>G (Ser71Arg) with Parkinson's disease was significant (odds ratio [OR] 13·17, 95% CI 2·15-87·23; p=0·0055; I

interpretationRAB32 Ser71Arg is a novel genetic risk factor for Parkinson's disease, with reduced penetrance. The variant was found in individuals with Parkinson's disease from multiple ethnic groups, with the same haplotype. In-vitro assays show that RAB32 Arg71 activates LRRK2 kinase, which indicates that genetically distinct causes of familial parkinsonism share the same mechanism. The discovery of RAB32 Ser71Arg also suggests several genetically inherited causes of Parkinson's disease originated to control intracellular immunity. This shared aetiology should be considered in future translational research, while the global epidemiology of RAB32 Ser71Arg needs to be assessed to inform genetic counselling.

fundingNational Institutes of Health, the Canada Excellence Research Chairs program, Aligning Science Across Parkinson's, the Michael J Fox Foundation for Parkinson's Research, and the UK Medical Research Council.

Indexed as

Parkinson Diseaserab GTP-Binding ProteinsAdultAgedCanadaCase-Control StudiesExome SequencingFemaleGenetic LinkageGenetic Predisposition to DiseaseGenotypeHumansLeucine-Rich Repeat Serine-Threonine Protein Kinase-2MaleMiddle AgedTunisiaLeucine-Rich Repeat Serine-Threonine Protein Kinase-2Rab32 protein, humanrab GTP-Binding Proteins

Identifiers

PMID38614108
PMCPMC11096864
OpenAlexW4394695501

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.