BACKGROUND: Leucine-rich repeat kinase 2 (LRRK2) p.L1795F variant was proposed as a genetic risk factor for Parkinson's disease (PD). However, its prevalence, phenotype, and origin remain unknown. OBJECTIVE: The aim was to evaluate the frequency and phenotype of p.L1795F in early-onset PD (EOPD) and familial PD compared to healthy controls (HC) in Central Europe. METHODS: Whole-exome sequencing was used to screen 219 EOPD and familial PD patients of Central Europeans compared to HC. Sanger sequencing assessed segregation. Detailed clinical phenotype was evaluated for all positive carriers. RESULTS: p.L1795F was identified in 1.37% (3/219) and 3.23% of familial cases (3/93), with no carriers among HCs (0/303). Segregation analysis confirmed association with PD. Carriers were traced to the eastern Slovak-Hungarian region. It also appears to be associated with a more aggressive phenotype. CONCLUSION: Our data indicate that p.L1795F contributes to PD in Central Europe. Further exploration in larger cohorts is warranted to establish its contribution to global PD risk.

2nd Department of Neurology Comenius University in Bratislava Faculty of Medicine University Hospital Bratislava Bratislava Slovak Republic

Department of Clinical and Movement Neurosciences UCL Queen Square Institute of Neurology University College London London United Kingdom

Department of Clinical Neurosciences Scientific Park MEDIPARK P J Safarik University Kosice Slovak Republic

Department of Medical and Clinical Biochemistry Faculty of Medicine P J Safarik University in Kosice Kosice Slovak Republic

Department of Neurodegenerative Disease UCL Queen Square Institute of Neurology London United Kingdom

Department of Neurology 2nd Faculty of Medicine Charles University and Motol University Hospital Prague Czech Republic

Department of Neurology and Centre of Clinical Neuroscience 1st Faculty of Medicine Charles University and General University Hospital Prague Prague Czech Republic

Department of Neurology and HUN REN PTE Clinical Neuroscience MR Research Group University of Pecs Medical School Pécs Hungary

Department of Neurology Jessenius Faculty of Medicine Comenius University and University Hospital Martin Martin Slovak Republic

Department of Neurology P J Safarik University Kosice Slovak Republic

Department of Neurology Semmelweis University Budapest Hungary

Department of Neurology Silesian Centre of Neurology Katowice Katowice Poland

Department of Neurology University Hospital of L Pasteur Kosice Slovak Republic

Department of Neurology University of Szeged Szeged Hungary

Department of Neurology Zvolen Hospital Zvolen Slovak Republic

Department of Neuromuscular Diseases UCL Queen Square Institute of Neurology London United Kingdom

Division of Molecular Biology and Biochemistry Gottfried Schatz Research Center Medical University of Graz Graz Austria

Institute of Normal and Pathological Physiology Centre of Experimental Medicine Slovak Academy of Sciences Bratislava Slovak Republic

Royal Veterinary College London United Kingdom

Res Sq. 2024 May 29:rs.3.rs-4378197. doi: 10.21203/rs.3.rs-4378197/v1. PubMed

Zobrazit více v PubMed

Pitz V, Makarious MB, Bandrés‐Ciga S, et al. Analysis of rare Parkinson's disease variants in millions of people. Res Sq 2024;10(1):11. 10.1038/s41531-023-00608-8. PubMed DOI PMC

Kalogeropulou AF, Purlyte E, Tonelli F, et al. Impact of 100 LRRK2 variants linked to Parkinson's disease on kinase activity and microtubule binding. Biochem J 2022;479:1759–1783. PubMed PMC

Nichols WC, Elsaesser VE, Pankratz N, et al. LRRK2 mutation analysis in Parkinson disease families with evidence of linkage to PARK8. Neurology 2007;69(18):1737–1744. 10.1212/01.wnl.0000278115.50741.4e. PubMed DOI

Benitez BA, Davis AA, Jin SC, et al. Resequencing analysis of five mendelian genes and the top genes from genome‐wide association studies in Parkinson's disease. Mol Neurodegener 2016;11:29. PubMed PMC

Skorvanek M, Rizig M, Athanasiou‐Fragkouli A, et al. LRRK2 mutations in Parkinson's disease patients from Central Europe: a case control study. Parkinsonism Relat Disord 2021;83:110–112. PubMed

Ostrozovicova M, Dusek P, Grofik M, et al. Central European group on Genetics of movement Disorders. Eur J Neurol 2024;31:e16165. PubMed PMC

Postuma RB, Berg D, Stern M, et al. MDS clinical diagnostic criteria for Parkinson's disease. Mov Disord 2015;30:1591–1601. PubMed

Myasnikov A, Zhu H, Hixson P, et al. Structural analysis of the full‐length human LRRK2. Cell 2021;184:3519–3527.e10. PubMed PMC

Illés A, Csabán D, Grosz Z, et al. The Role of Genetic Testing in the Clinical Practice and Research of Early‐Onset Parkinsonian Disorders in a Hungarian Cohort: Increasing Challenge in Genetic Counselling, Improving Chances in Stratification for Clinical Trials. Front Genet 2019;10:1061. 10.3389/fgene.2019.01061. PubMed DOI PMC

Simpson C, Vinikoor‐Imler L, Nassan FL, Shirvan J, Lally C, Dam T, Maserejian N. Prevalence of ten LRRK2 variants in Parkinson's disease: a comprehensive review. Parkinsonism Relat Disord 2022;98:103–113. PubMed

Chao K. GnomAD v4.0; https://gnomad.broadinstitute.org/news/2023-11-gnomad-v4-0/.

No title . https://pdgenetics.shinyapps.io/VariantBrowser.

Pitz V, Makarious MB, Bandres‐Ciga S, et al. Analysis of rare Parkinson's disease variants in millions of people. NPJ Parkinsons Dis 2024;10:1–10. PubMed PMC

Minton K. Predicting variant pathogenicity with AlphaMissense. Nat Rev Genet 2023;24:804. PubMed

Tolosa E, Vila M, Klein C, Rascol O. LRRK2 in Parkinson disease: challenges of clinical trials. Nat Rev Neurol 2020;16:97–107. PubMed

Golub Y, Berg D, Calne DB, et al. Genetic factors influencing age at onset in LRRK2‐linked Parkinson disease. Parkinsonism Relat Disord 2009;15:539–541. PubMed

Gan‐Or Z, Bar‐Shira A, Mirelman A, Gurevich T, Giladi N, Orr‐Urtreger A. The age at motor symptoms onset in LRRK2‐associated Parkinson's disease is affected by a variation in the MAPT locus: a possible interaction. J Mol Neurosci 2012;46:541–544. PubMed