Portal de Periódicos da CAPES

Evidence for a role of the rare p.A152T variant in MAPT in increasing the risk for FTD-spectrum and Alzheimer's diseases

2012; Oxford University Press; Volume: 21; Issue: 15 Linguagem: Inglês

10.1093/hmg/dds161

1460-2083

Giovanni Coppola, Subashchandrabose Chinnathambi, Jason Ji Yong Lee, Beth A. Dombroski, Matt Baker, Alexandra I. Soto‐Ortolaza, Suzee E. Lee, Eric Klein, Alden Huang, Renee Sears, Jessica Lane, Anna M. Karydas, Robert O. Kenet, Jacek Biernat, Li San Wang, Carl W. Cotman, Charles DeCarli, Allan I. Levey, John M. Ringman, Mario F. Mendez, Helena C. Chui, Isabelle Le Ber, Alexis Brice, Michelle K. Lupton, Elisavet Preza, Simon Lovestone, John Powell, Neill R. Graff‐Radford, Ronald Petersen, Bradley F. Boeve, Carol F. Lippa, Eileen H. Bigio, Ian R. Mackenzie, Elizabeth Finger, Andrew Kertesz, Richard J. Caselli, Marla Gearing, Jorge L. Juncos, Bernardino Ghetti, Salvatore Spina, Yvette Bordelon, Wallace W. Tourtellotte, Matthew P. Frosch, Jean Paul Vonsattel, Chris Zarow, Thomas G. Beach, Roger L. Albin, Andrew P. Lieberman, Virginia M. Lee, John Q. Trojanowski, Vivianna M. Van Deerlin, Thomas D. Bird, Douglas Galasko, Eliezer Masliah, Charles L. White, Juan C. Troncoso, Didier Hannequin, Adam L. Boxer, Michael D. Geschwind, Satish Kumar, Eva‐Maria Mandelkow, Zbigniew K. Wszołek, Ryan J. Uitti, Dennis W. Dickson, Jonathan L. Haines, Richard Mayeux, Margaret A. Pericak‐Vance, Lindsay A. Farrer, Liana G. Apostolova, Steven E. Arnold, Clinton T. Baldwin, Robert C. Barber, M. Michael Barmada, Thomas G. Beach, Gary W. Beecham, Duane Beekly, David A. Bennett, Deborah Blacker, James D. Bowen, Adam Boxer, James R. Burke, Jacqueline L. Buros, Joseph D. Buxbaum, Nigel J. Cairns, Laura B. Cantwell, Chuanhai Cao, Chris Carlson, Regina M. Carney, Minerva M. Carrasquillo, Steven L. Carroll, David G. Clark, Jason J. Corneveaux, Paul K. Crane, Carlos Cruchaga, Jeffrey L. Cummings, Philip L. De Jager, Charles DeCarli, Steven T. DeKosky, F. Yesim Demirci, Ramon Diaz‐Arrastia, Malcolm Dick, Ranjan Duara, William G. Ellis, Nilüfer Ertekin‐Taner, Denis Evans, Kelley M. Faber, Kenneth B. Fallon, Martin R. Farlow, Steven H. Ferris, Tatiana M. Foroud, Paul J. Gallins, Mary Ganguli, Daniel H. Geschwind, John R. Gilbert, Sid Gilman, Bruno Giordani, Jonathan D. Glass, Alison Goate, Neill R. Graff‐Radford, Robert C. Green, John H. Growdon, Hakon Hakonarson, Ronald L. Hamilton, John Hardy, Lindy E. Harrell, Elizabeth Head, Lawrence S. Honig, Matthew J. Huentelman, Christine M. Hulette, Bradley T. Hyman, Gail P. Jarvik, Gregory A. Jicha, Lee Way Jin, Nancy Johnson, Gyungah Jun, M. Ilyas Kamboh, Jason Karlawish, Anna Karydas, John S. K. Kauwe, Jeffrey Kaye, Ronald Kim, Edward H. Koo, Neil W. Kowall, Patricia Kramer, Walter A. Kukull, James J. Lah, Eric B. Larson, Lorna M. Lopez, Kathryn L. Lunetta, Wendy J. Mack, Daniel Marson, Eden R. Martin, Frank Martiniuk, Deborah C. Mash, Wayne C. McCormick, Susan M. McCurry, Andrew McDavid, Ann C. McKee, Marsel Mesulam, Bruce L. Miller, Carol A. Miller, Joshua W. Miller, Thomas J. Montine, John C. Morris, Amanda Myers, Adam C. Naj, Petra Nowotny, Joseph E. Parisi, Daniel P. Perl, Elaine R. Peskind, Wayne W. Poon, Huntington Potter, Joseph F. Quinn, Ashok Raj, Ruchita Rajbhandary, Murray A. Raskind, Eric M. Reiman, ‌Barry Reisberg, Christiane Reitz, Erik D. Roberson, Ekaterina Rogaeva, Roger N. Rosenberg, Mary Sano, Andrew J. Saykin, Julie A. Schneider, Lon S. Schneider, William W. Seeley, Michael L. Shelanski, Michael A. Slifer, Charles D. Smith, Joshua A. Sonnen, Peter St George‐Hyslop, Robert A. Stern, Rudolph E. Tanzi, Debby W. Tsuang, Badri N. Vardarajan, Harry V. Vinters, Jean Paul Vonsattel, Sandra Weıntraub, Kathleen A. Welsh‐Bohmer, Jennifer Williamson, Randall L. Woltjer, Steven G. Younkin, Owen A. Ross, Rosa Rademakers, Daniela Berg, Eckhard Mandelkow,

Parkinson's Disease Mechanisms and Treatments

Rare mutations in the gene encoding for tau (MAPT, microtubule-associated protein tau) cause frontotemporal dementia-spectrum (FTD-s) disorders, including FTD, progressive supranuclear palsy (PSP) and corticobasal syndrome, and a common extended haplotype spanning across the MAPT locus is associated with increased risk of PSP and Parkinson's disease.We identified a rare tau variant (p.A152T) in a patient with a clinical diagnosis of PSP and assessed its frequency in multiple independent series of patients with neurodegenerative conditions and controls, in a total of 15 369 subjects.Tau p.A152T significantly increases the risk for both FTD-s (n 5 2139, OR 5 3.0, CI: 1.6 -5.6, P 5 0.0005) and Alzheimer's disease (AD) (n 5 3345, OR 5 2.3, CI: 1.3 -4.2, P 5 0.004) compared with 9047 controls.Functionally, p.A152T (i) decreases the binding of tau to microtubules and therefore promotes microtubule assembly less efficiently; and (ii) reduces the tendency to form abnormal fibers.However, there is a pronounced increase in the formation of tau oligomers.Importantly, these findings suggest that other regions of the tau protein may be crucial in regulating normal function, as the p.A152 residue is distal to the domains considered responsible for microtubule interactions or aggregation.These data provide both the first genetic evidence and functional studies supporting the role of MAPT p.A152T as a rare risk factor for both FTD-s and AD and the concept that rare variants can increase the risk for relatively common, complex neurodegenerative diseases, but since no clear significance threshold for rare genetic variation has been established, some caution is warranted until the findings are further replicated.