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. 2025 Mar 25;11(1):58.
doi: 10.1038/s41531-025-00896-2.

The LRRK2 p.L1795F variant causes Parkinson's disease in the European population

Lara M Lange  1   2   3 , Kristin Levine  4   5 , Susan H Fox  6 , Connie Marras  6 , Nazish Ahmed  6 , Nicole Kuznetsov  4   5 , Dan Vitale  4   5 , Hirotaka Iwaki  7   4   5 , Katja Lohmann  8 , Luca Marsili  9 , Alberto J Espay  9 , Peter Bauer  10 , Christian Beetz  10 , Jessica Martin  5 , Stewart A Factor  11 , Lenora A Higginbotham  11 , Honglei Chen  12 , Hampton Leonard  4   5 , Mike A Nalls  4   5 , Niccolo E Mencacci  13 , Huw R Morris  14   15 , Andrew B Singleton  7   5 , Christine Klein  8   16 , Cornelis Blauwendraat  7   5 , Zih-Hua Fang  17 ; Global Parkinson’s Genetics Program (GP2)
Collaborators, Affiliations

The LRRK2 p.L1795F variant causes Parkinson's disease in the European population

Lara M Lange et al. NPJ Parkinsons Dis. .

Abstract

LRRK2-PD represents the most common form of autosomal dominant Parkinson's disease. We identified the LRRK2 p.L1795F variant in three families and six additional unrelated cases using genetic data from over 50,000 individuals. Carriers with available genotyping data shared a common haplotype. The clinical presentation resembles other LRRK2-PD forms. Combined with published functional evidence showing strongly enhanced LRRK2 kinase activity, we provide evidence that LRRK2 p.L1795F is pathogenic.

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Conflict of interest statement

Competing interests: L.M.L., N.A., K. Lo., and L.A.H. declare no competing interests. C.M. receives research funding from the Michael J Fox Foundation, the Parkinson’s Foundation (US) and holds the Catherine Manson Chair in Movement Disorders, funded by the Mayvon Foundation. D.V., H.L.L., H.I., K.Le., and M.A.N.’s participation in this project was part of a competitive contract awarded to DataTecnica LLC by the National Institutes of Health to support open science research. M.A.N. also currently serves on the scientific advisory board for Character Bio Inc plus is a scientific founder at Neuron23 Inc and owns stock. L.M. has received honoraria from the International Association of Parkinsonism and Related Disorders (IAPRD) Society for social media and web support, and personal compensation as a consultant/scientific advisory board member for Acadia. He has received a grant (collaborative research agreement) from the International Parkinson and Movement Disorders Society for the MDS-UTRS Validation Program (Role: PI), Non-Profit. A.J.E. has received grant support from the NIH and the Michael J Fox Foundation; personal compensation as a consultant/scientific advisory board member for Neuroderm, Amneal, Acadia, Avion Pharmaceuticals, Acorda, Kyowa Kirin, Supernus (formerly, USWorldMeds), NeuroDiagnostics, Inc (SYNAPS Dx), Intrance Medical Systems, Inc., Praxis Precision Medicines, and Herantis Pharma; and publishing royalties from Lippincott Williams & Wilkins, Cambridge University Press, and Springer. He co-founded REGAIN Therapeutics and is co-inventor of the patent “Compositions and methods for treatment and/or prophylaxis of proteinopathies. P.B. and C.B. are employees of CENTOGENE GmbH. S.A.F. received honoraria from Lundbeck, Biogen, Takeda, and Neurocrine and grants from Medtronics, Boston Scientific, Sun Pharmaceuticals Advanced Research Company, Aspen, Biohaven, Neurocrine, Voyager, Prilenia Therapeutics, CHDI Foundation, Michael J. Fox Foundation, NIH 1 P50 NS123103-01, NIH 1R01NS125294-01, and the Parkinson Foundation. Finally, he reports royalties from Demos, Blackwell Futura, Springer for textbooks, and Uptodate. N.E.M receives salary and research support from the NIH (1K08NS131581), the Parkinson’s Foundation and the Aligning Science Across Parkinson’s (ASAP) Global Parkinson’s Genetics Program (GP2). He serves as a member of the PDGENEration steering committee. H.R.M. is employed by UCL. In the last months, he reports paid consultancies from Roche, Aprinoia, AI Therapeutics and Amylyx; lecture fees/honoraria from BMJ, Kyowa Kirin, and the Movement Disorders Society; and research Grants from Parkinson’s UK, Cure Parkinson’s Trust, PSP Association, Medical Research Council, and the Michael J Fox Foundation. H.R.M. is also a co-applicant on a patent application related to C9ORF72 - Method for diagnosing a neurodegenerative disease (PCT/GB2012/052140). A.B.S. is an Associate Editor of Movement Disorders. He is an unpaid member of the Scientific Advisory Board of Cajal Neuroscience. C.K. has received grant support from The Michael J. Fox Foundation for Parkinson’s Research and the Aligning Science Across Parkinson’s Initiative. She serves as a medical advisor to Centogene, Retromer Therapeutics, and Takeda and received speakers’ honoraria from Bial and Desitin. Z-H.F. is supported by the Aligning Science Across Parkinson’s (ASAP) Global Parkinson’s Genetics Program (GP2) and receives GP2 salary support from The Michael J. Fox Foundation for Parkinson’s Research. K.Lo., S.F., and A.B.S. are Associate Editors of npj Parkinson’s disease. They were not involved in the journal’s review of or decisions related to this manuscript.

Figures

Fig. 1
Fig. 1. Pedigrees of identified families in this study.
Pedigree of Family GP2-FAM-1 (A), CANADA-FAM-1 (B), and AMP-FAM-1 (C) with the LRRK2 p.L1795F variant. The pedigrees were drawn based on reported family history and may be incomplete. The index cases are indicated with arrows. Affected individuals are indicated by black symbols: circles (female) and squares (male). Diamond is where sex is undefined. Unaffected individuals are indicated by open symbols. Unaffected variant carriers are indicated by open symbols with a dot in the middle. A diagonal line indicates deceased individuals. Red circle indicates individuals with genetic data available (WGS data for GP2-FAM-1 and AMP-FAM-1, single gene testing for CANADA-FAM-1). Heterozygous mutant (m) and wild-type (wt) genotypes are indicated with corresponding age at the sample collection (age) and age at motor symptom onset (if known; AAO). A The mother of GP2-FAM-1 index was reported to have eight additional siblings (#), several of whom are clinically affected with PD; however, no detailed family history is available for these relatives. B One maternal aunt (II-1) of the CANADA-FAM-1 index was reported to have had Alzheimer’s disease (##).
Fig. 2
Fig. 2. Overlapping identity-by-descent segments spanning LRRK2 p.L1795F variant among the variant carriers with genotyping data.
Each line represents an IBD segment inferred between a unique pair of individuals. IBD segments are colored based on whether both individuals in a pair belong to the same family (GP2-FAM-1) or are considered unrelated (UR). FS indicates an IBD segment between full siblings, 2nd degree refers to a segment between a pair of second-degree relatives, and PO represents a segment between a parent and offspring. The vertical grey line marks the genomic position of the LRRK2 p.L1795F variant.
Fig. 3
Fig. 3. Study design.
Figure created with BioRender.com.
See this image and copyright information in PMC

Update of

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