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R1514Q substitution in Lrrk2 is not a pathogenic Parkinson's disease mutation

2006; Wiley; Volume: 22; Issue: 2 Linguagem: Inglês

10.1002/mds.21233

1531-8257

William C. Nichols, Diane K. Marek, Michael W. Pauciulo, Nathan Pankratz, Cheryl Halter, Alice Rudolph, Clifford W. Shults, Joanne Wojcieszek, Tatiana Foroud, Clifford W. Shults, Frederick J. Marshall, David Oakes, Alice Rudolph, Aileen Shinaman, Karen Marder, P.M. Conneally, Tatiana M. Foroud, C. A. Halter, Kelly Lyons, Eric Siemers, Stewart A. Factor, Donald S. Higgins, Steven N. Evans, Holly A. Shill, Mark Stacy, J. Danielson, L. Marlor, Kathy Williamson, Joseph Jankovic, Christine Hunter, David K. Simon, Paula D. Ryan, Lisa Scollins, Rachel Saunders‐Pullman, Karyn Boyar, C. Costan-Toth, Erich Ohmann, Lewis Sudarsky, Caroline Joubert, Joseph H. Friedman, Kelvin L. Chou, Hubert Fernandez, Michelle Lannon, Néstor Gálvez-Jiménez, A. Podichetty, Peter A. LeWitt, Margaret M. DeAngelis, C. O’Brien, Lauren Seeberger, Colleen Dingmann, Dale P. Judd, James A. Fraser, Juliette Harris, John M. Bertoni, Charles M. Peterson, S. Chouinard, Michel Panisset, Jacqueline A. Hall, H. Poiffaut, Vittorio Calabrese, Pasquale Roberge, J. Wojcieszek, Joann Belden, D. Jennings, Kenneth Marek, Susan Mendick, Stephen G. Reich, Boadie W. Dunlop, Mandar Jog, C. Horn, J. Rao, Megan Cook, Ryan J. Uitti, Martin Turk, T. Ajax, J. Mannetter, Kapil D. Sethi, James W. Carpenter, Keith L. Ligon, Sushma Narayan, L. Woodward, Karen Blindauer, Jacques Petit, Lawrence Elmer, Emily Aiken, Keith L. Davis, Christoph Schell, Samantha L. Wilson, M. Veličković, William C. Koller, Simon Phipps, Andrew Feigin, Mark Forrest Gordon, Jörg Hamann, Elisa Licari, M. Marotta-Kollarus, Barbara Shannon, R. Winnick, T. Simuni, Alexander Tobias Kaczmarek, Karen Williams, Markus Wolff, M. Fernandez, Jean Hubble, Sandra K. Kostyk, A. Campbell, Carson Reider, Richard Camicioli, J. Carter, Paul A. Andrews, Samuel H. Morehouse, Christian D. Stone, Tilak Mendis, David A. Grimes, Paul A. Gray, K.F. Haas, James P. Sutton, B. Hutchinson, Jennifer Young, Alex Rajput, Lynell W. Klassen, Theresa Shirley, B. V. Manyam, Patricia Simpson, Jacqueline Whetteckey, Brian Wulbrecht, Daniel Truong, Mona Pathak, N. Luong, Thien Tra, Anh Tran, Josh N. Vo, Anthony E. Lang, Galit Kleiner‐Fisman, Ana Nieves, Julie So, Gerald D. Podskalny, Louise Giffin, Paul Atchison, Christopher Allen, W. R. Wayne Martin, Marguerite Wieler, Oksana Suchowersky, Małgorzata Klimek, Neal Hermanowicz, Shari Niswonger, Deborah Fontaine, Michael J. Aminoff, Chadwick W. Christine, Mariann DiMinno, J. Hevezi, Aparna Dalvi, Un Jung Kang, Judith A. Richman, Shirley Uy, Alok Sahay, Donna Schwieterman, Maureen A. Leehey, Samantha Culver, T. Derian, T. Demarcaida, S. Belber, Robert L. Rodnitzky, Jon Dobson, Rajesh Pahwa, Tracy L. Gales, Stephanie Thomas, Lisa M. Shulman, William J. Weiner, Kelly Dustin, Carlos Singer, Lisette Zelaya, Paul Tuite, Volker Hagen, Susan Rolandelli, Robyn Schacherer, Gordon Gilbert, Joan Stehle Werner, Carmen Serrano, Susana Roque, Roger Kurlan, Debra Berry, Irenita Gardiner, Robert A. Hauser, Juan Sanchez‐Ramos, Theresa A. Zesiewicz, H. Delgado, Karen Price, Patricia Rodríguez, Ronald Pfeiffer, Lori Davis, Brenda Pfeiffer, Richard B. Dewey, Bruce E. Hayward, Martha Meacham, Francis O. Walker, Victoria Hunt, Brad A. Racette, L. Good, Melissa M. Rundle, Alexander Watts, Aiguo Wang, T F Ross, Sue Bennett, Daniel Kamp, Elaine Julian-Baros,

Lysosomal Storage Disorders Research

Mutations in LRRK2 were first reported as causing Parkinson's disease (PD) in late 2004. Since then, approximately a dozen LRRK2 substitutions have been identified that are believed to be pathogenic mutations. The substitution of adenine for guanine at nucleotide 4541 (4541G>A) in LRRK2 was recently reported. This substitution resulted in the replacement of an arginine at position 1514 with a glutamine (R1514Q). Although this substitution was not found in a large cohort of controls, its pathogenicity could not be verified. We have now genotyped the R1514Q substitution in a sample of 954 PD patients from 429 multiplex PD families. This substitution was identified in 1.8% of the PD patients; however, the majority of the PD sibships segregating this substitution were discordant for this putative mutation. In addition, the R1514Q substitution was detected in 1.4% of neurologically evaluated, control individuals. These data suggest that the R1514Q variant is not a pathogenic LRRK2 mutation. We believe it is imperative that the causative nature of any newly identified genetic variant be determined before it is included in any panel for diagnostic testing.