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

Lara M. Lange; Kristin Levine; Susan H. Fox; Connie Marras; Nazish Ahmed; Nicole Kuznetsov; Dan Vitale; Hirotaka Iwaki; Katja Lohmann; Luca Marsili; Alberto J. Espay; Peter Bauer; Christian Beetz; Jessica Martin; Stewart A. Factor; Lenora A. Higginbotham; Honglei Chen; Hampton Leonard; Mike A. Nalls; Niccolo E. Mencacci; Huw R. Morris; Andrew B. Singleton; Christine Klein; Cornelis Blauwendraat; Zih Hua Fang; Masharip Atadzhanov; Toan Nguyen; Duan Nguyen; Mathew Koretsky; Mary B. Makarious; Faraz Faghri; Thomas Beach; Tao Xie; Sonya Dumanis; Ruth Walker; Roy Alcalay; Roger Albin; Steven Lubbe; Megan J. Puckelwartz; Matthew Farrer; Marissa Dean; Lisa Shulman; Lauren Ruffrage; Lana M. Chahine; Kenneth Marek; Katerina Markopoulou; Karl Kieburtz; Karen Nuytemans; Kamalini Ghosh Galvelis; Rejko Krüger; the Global Parkinson’s Genetics Program (GP2)

doi:10.1038/s41531-025-00896-2

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

Lara M. Lange^*, Kristin Levine, Susan H. Fox, Connie Marras, Nazish Ahmed, Nicole Kuznetsov, Dan Vitale, Hirotaka Iwaki, Katja Lohmann, Luca Marsili, Alberto J. Espay, Peter Bauer, Christian Beetz, Jessica Martin, Stewart A. Factor, Lenora A. Higginbotham, Honglei Chen, Hampton Leonard, Mike A. Nalls, Niccolo E. MencacciHuw R. Morris, Andrew B. Singleton, Christine Klein, Cornelis Blauwendraat, Zih Hua Fang^*, Masharip Atadzhanov, Toan Nguyen, Duan Nguyen, Mathew Koretsky, Mary B. Makarious, Faraz Faghri, Thomas Beach, Tao Xie, Sonya Dumanis, Ruth Walker, Roy Alcalay, Roger Albin, Steven Lubbe, Megan J. Puckelwartz, Matthew Farrer, Marissa Dean, Lisa Shulman, Lauren Ruffrage, Lana M. Chahine, Kenneth Marek, Katerina Markopoulou, Karl Kieburtz, Karen Nuytemans, Kamalini Ghosh Galvelis, Rejko Krüger, the Global Parkinson’s Genetics Program (GP2)

^*Corresponding author for this work

Research output: Contribution to journal › Article › Research › peer-review

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.

Original language	English
Article number	58
Pages (from-to)	58
Journal	npj Parkinson's Disease
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41531-025-00896-2
Publication status	Published - 25 Mar 2025
Externally published	Yes

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Lange, L. M., Levine, K., Fox, S. H., Marras, C., Ahmed, N., Kuznetsov, N., Vitale, D., Iwaki, H., Lohmann, K., Marsili, L., Espay, A. J., Bauer, P., Beetz, C., Martin, J., Factor, S. A., Higginbotham, L. A., Chen, H., Leonard, H., Nalls, M. A., ... the Global Parkinson’s Genetics Program (GP2) (2025). The LRRK2 p.L1795F variant causes Parkinson’s disease in the European population. npj Parkinson's Disease, 11(1), 58. Article 58. https://doi.org/10.1038/s41531-025-00896-2

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title = "The LRRK2 p.L1795F variant causes Parkinson{\textquoteright}s disease in the European population",

abstract = "LRRK2-PD represents the most common form of autosomal dominant Parkinson{\textquoteright}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.",

author = "Lange, {Lara M.} and Kristin Levine and Fox, {Susan H.} and Connie Marras and Nazish Ahmed and Nicole Kuznetsov and Dan Vitale and Hirotaka Iwaki and Katja Lohmann and Luca Marsili and Espay, {Alberto J.} and Peter Bauer and Christian Beetz and Jessica Martin and Factor, {Stewart A.} and Higginbotham, {Lenora A.} and Honglei Chen and Hampton Leonard and Nalls, {Mike A.} and Mencacci, {Niccolo E.} and Morris, {Huw R.} and Singleton, {Andrew B.} and Christine Klein and Cornelis Blauwendraat and Fang, {Zih Hua} and Masharip Atadzhanov and Toan Nguyen and Duan Nguyen and Mathew Koretsky and Makarious, {Mary B.} and Faraz Faghri and Thomas Beach and Tao Xie and Sonya Dumanis and Ruth Walker and Roy Alcalay and Roger Albin and Steven Lubbe and Puckelwartz, {Megan J.} and Matthew Farrer and Marissa Dean and Lisa Shulman and Lauren Ruffrage and Chahine, {Lana M.} and Kenneth Marek and Katerina Markopoulou and Karl Kieburtz and Karen Nuytemans and Galvelis, {Kamalini Ghosh} and Rejko Kr{\"u}ger and {the Global Parkinson{\textquoteright}s Genetics Program (GP2)}",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2025.",

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doi = "10.1038/s41531-025-00896-2",

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Lange, LM, Levine, K, Fox, SH, Marras, C, Ahmed, N, Kuznetsov, N, Vitale, D, Iwaki, H, Lohmann, K, Marsili, L, Espay, AJ, Bauer, P, Beetz, C, Martin, J, Factor, SA, Higginbotham, LA, Chen, H, Leonard, H, Nalls, MA, Mencacci, NE, Morris, HR, Singleton, AB, Klein, C, Blauwendraat, C, Fang, ZH, Atadzhanov, M, Nguyen, T, Nguyen, D, Koretsky, M, Makarious, MB, Faghri, F, Beach, T, Xie, T, Dumanis, S, Walker, R, Alcalay, R, Albin, R, Lubbe, S, Puckelwartz, MJ, Farrer, M, Dean, M, Shulman, L, Ruffrage, L, Chahine, LM, Marek, K, Markopoulou, K, Kieburtz, K, Nuytemans, K, Galvelis, KG, Krüger, R & the Global Parkinson’s Genetics Program (GP2) 2025, 'The LRRK2 p.L1795F variant causes Parkinson’s disease in the European population', npj Parkinson's Disease, vol. 11, no. 1, 58, pp. 58. https://doi.org/10.1038/s41531-025-00896-2

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T1 - The LRRK2 p.L1795F variant causes Parkinson’s disease in the European population

AU - Lange, Lara M.

AU - Levine, Kristin

AU - Fox, Susan H.

AU - Marras, Connie

AU - Ahmed, Nazish

AU - Kuznetsov, Nicole

AU - Vitale, Dan

AU - Iwaki, Hirotaka

AU - Lohmann, Katja

AU - Marsili, Luca

AU - Espay, Alberto J.

AU - Bauer, Peter

AU - Beetz, Christian

AU - Martin, Jessica

AU - Factor, Stewart A.

AU - Higginbotham, Lenora A.

AU - Chen, Honglei

AU - Leonard, Hampton

AU - Nalls, Mike A.

AU - Mencacci, Niccolo E.

AU - Morris, Huw R.

AU - Singleton, Andrew B.

AU - Klein, Christine

AU - Blauwendraat, Cornelis

AU - Fang, Zih Hua

AU - Atadzhanov, Masharip

AU - Nguyen, Toan

AU - Nguyen, Duan

AU - Koretsky, Mathew

AU - Makarious, Mary B.

AU - Faghri, Faraz

AU - Beach, Thomas

AU - Xie, Tao

AU - Dumanis, Sonya

AU - Walker, Ruth

AU - Alcalay, Roy

AU - Albin, Roger

AU - Lubbe, Steven

AU - Puckelwartz, Megan J.

AU - Farrer, Matthew

AU - Dean, Marissa

AU - Shulman, Lisa

AU - Ruffrage, Lauren

AU - Chahine, Lana M.

AU - Marek, Kenneth

AU - Markopoulou, Katerina

AU - Kieburtz, Karl

AU - Nuytemans, Karen

AU - Galvelis, Kamalini Ghosh

AU - Krüger, Rejko

AU - the Global Parkinson’s Genetics Program (GP2)

PY - 2025/3/25

Y1 - 2025/3/25

N2 - 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.

AB - 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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UR - https://pubmed.ncbi.nlm.nih.gov/40133296/

U2 - 10.1038/s41531-025-00896-2

DO - 10.1038/s41531-025-00896-2

M3 - Article

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VL - 11

SP - 58

JO - npj Parkinson's Disease

JF - npj Parkinson's Disease

IS - 1

M1 - 58

ER -

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

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