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

Lange, Lara M., Levine, Kristin, Fox, Susan H., Marras, Connie, Ahmed, Nazish, Kuznetsov, Nicole, Vitale, Dan, Iwaki, Hirotaka, Lohmann, Katja, Marsili, Luca, Espay, Alberto J., Bauer, Peter, Beetz, Christian, Martin, Jessica, Factor, Stewart A., Higginbotham, Lenora A., Chen, Honglei, Leonard, Hampton, Nalls, Mike A., Mencacci, Niccolo E., Morris, Huw R., Singleton, Andrew B., Klein, Christine, Blauwendraat, Cornelis, Fang, Zih-Hua, Gatto, Emilia M., Kauffman, Marcelo, Khachatryan, Samson, Tavadyan, Zaruhi, Shepherd, Claire E., Hunter, Julie, Kumar, Kishore, Ellis, Melina, Rentería, Miguel E., Koks, Sulev, Zimprich, Alexander, Schumacher-Schuh, Artur F., Rieder, Carlos, Awad, Paula Saffie, Tumas, Vitor, Camargos, Sarah, Fon, Edward A., Monchi, Oury, Fon, Ted, Galleguillos, Benjamin Pizarro, Olguin, Patricio, Miranda, Marcelo, Bustamante, Maria Leonor, Chana, Pedro, Tang, Beisha, Shang, Huifang, Guo, Jifeng, Chan, Piu, Luo, Wei, Arboleda, Gonzalo, Orozco, Jorge, del Rio, Marlene Jimenez, Hernandez, Alvaro, Salama, Mohamed, Kamel, Walaa A., Zewde, Yared Z., Brice, Alexis, Corvol, Jean-Christophe, Westenberger, Ana, Vollstedt, Eva-Juliane, Madoev, Harutyun, Trinh, Joanne, Junker, Johanna, Illarionova, Anastasia, Mollenhauer, Brit, Hopfner, Franziska, Höglinger, Günter, Sharma, Manu, Gasser, Thomas, Groppa, Sergiu, Akpalu, Albert, Xiromerisiou, Georgia, Hadjigorgiou, Georgios, Dadiotis, Efthymios, Dagklis, Ioannis, Tarnanas, Ioannis, Stefanis, Leonidas, Stamelou, Maria, Medina, Alex, Chan, Germaine Hiu-Fai, Cheung, Nelson Yuk-Fai, Ip, Nancy, Chan, Phillip, Zhou, Xiaopu, Kishore, Asha, KP, Divya, Pal, Pramod, Kukkle, Prashanth Lingappa, Rajan, Roopa, Borgohain, Rupam, Salari, Mehri, Quattrone, Andrea, Gagliardi, Monica, Valente, Enza Maria, Avenali, Micol, Annesi, Grazia, Parnetti, Lucilla, Schirinzi, Tommaso, Funayama, Manabu, Hattori, Nobutaka, Shiraishi, Tomotaka, Karimova, Altynay, Kaishibayeva, Gulnaz, Shambetova, Cholpon, Krüger, Rejko, Tan, Ai Huey, Ahmad-Annuar, Azlina, Lim, Shen-Yang, Tay, Yi Wen, Norlinah, Mohamed Ibrahim, Murad, Nor Azian Abdul, Azmin, Shahrul, Mohamed, Wael, Martinez-Ramirez, Daniel, Rodriguez-Violante, Mayela, Reyes-Pérez, Paula, Tserensodnom, Bayasgalan, Ojha, Rajeev, Anderson, Tim J., Pitcher, Toni L., Sanyaolu, Arinola, Okubadejo, Njideka, Ojo, Oluwadamilola, Aasly, Jan O., Pihlstrøm, Lasse, Tan, Manuela, Ur-Rehman, Shoaib, Cornejo-Olivas, Mario, Doquenia, Maria Leila, Rosales, Raymond, Vinuela, Angel, Iakovenko, Elena, Mubarak, Bashayer Al, Umair, Muhammad, Tan, Eng-King, Foo, Jia Nee, Amod, Ferzana, Carr, Jonathan, Bardien, Soraya, Jeon, Beomseok, Kim, Yun Joong, Cubo, Esther, Alvarez, Ignacio, Hoenicka, Janet, Beyer, Katrin, Periñan, Maria Teresa, Pastor, Pau, El-Sadig, Sarah, Brolin, Kajsa, Zweier, Christiane, Krack, Paul, Tinkhauser, Gerd, Lin, Chin-Hsien, Kung, Pin-Jui, Wu, Hsiu-Chuan, Wu, Ruey-Meei, Wu, Yihru, Amouri, Rim, Ben Sassi, Samia, Ba?ak, A. Nazl?, Çakmak, Özgür Öztop, Ertan, Sibel, Genc, Gencer, Noyce, Alastair, Dey, Sumit, Martínez-Carrasco, Alejandro, Schrag, Anette, Schapira, Anthony, Stafford, Eleanor J., Houlden, Henry, Hardy, John, Mok, Kin Ying, Rizig, Mie, Wood, Nicholas, Okunoye, Olaitan, Kaiyrzhanov, Rauan, Weil, Rimona, Jasaityte, Simona, Obese, Vida, Carroll, Camille, Bale, Claire, Grosset, Donald, Williams, Nigel ORCID: https://orcid.org/0000-0003-1177-6931, Lewis, Patrick Alfryn, Love, Seth, Stott, Simon, Pantazis, Caroline B., Andersh, Kate, Screven, Laurel, Bandres-Ciga, Sara, Sarmiento, Ignacio Juan Keller, O?Grady, Alyssa, Siddiqi, Bernadette, Casey, Bradford, Fiske, Brian, Comart, Charisse, Solle, Justin C., Murphy, Kaileigh, Kuhl, Maggie, Louie, Naomi, Chowdhury, Sohini, Sherer, Todd, Sobering, Andrew K., Jonas, Cabell, Cruchaga, Carlos, Ibanez, Laura, Wegel, Claire, Foroud, Tatiana, Hall, Deborah, Hernandez, Dena, Kim, Jonggeol Jeff, Song, Yeajin, Shiamim, Ejaz, Riley, Ekemini, Serrano, Geidy E., Mata, Ignacio F., Inca-Martinez, Miguel, Williamson, Jared, Jankovic, Joseph, Shulman, Joshua, Galvelis, Kamalini Ghosh, Nuytemans, Karen, Kieburtz, Karl, Markopoulou, Katerina, Marek, Kenneth, Chahine, Lana M., Ruffrage, Lauren, Shulman, Lisa, Dean, Marissa, Farrer, Matthew, Puckelwartz, Megan J., Lubbe, Steven, Albin, Roger, Alcalay, Roy, Walker, Ruth, Dumanis, Sonya, Xie, Tao, Beach, Thomas, Faghri, Faraz, Makarious, Mary B., Koretsky, Mathew, Nguyen, Duan, Nguyen, Toan and Atadzhanov, Masharip 2025. The LRRK2 p.L1795F variant causes Parkinson's disease in the European population. npj Parkinson's Disease 11 (1) , 58. 10.1038/s41531-025-00896-2

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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.

Item Type:	Article
Status:	Published
Schools:	Schools > Medicine
Publisher:	Nature Research
ISSN:	2373-8057
Date of First Compliant Deposit:	6 May 2025
Date of Acceptance:	25 March 2025
Last Modified:	07 May 2025 11:17
URI:	https://orca.cardiff.ac.uk/id/eprint/178076

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