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

Giovanni Coppola, Subashchandrabose Chinnathambi, Jason Ji Yong Lee, Beth A. Dombroski, Matt C. Baker, Alexandra I. Soto-ortolaza, Suzee E. Lee, Eric Klein, Alden Y. Huang, Renee Sears, Jessica R. Lane, Anna M. Karydas, Robert O. Kenet, Jacek Biernat, Li San Wang, Carl W. Cotman, Charles S. Decarli, Allan I. Levey, John M. Ringman, Mario F. MendezHelena C. Chui, Isabelle Le ber, Alexis Brice, Michelle K. Lupton, Elisavet Preza, Simon Lovestone, John Powell, Neill Graff-radford, Ronald C. Petersen, Bradley F. Boeve, Carol F. Lippa, Eileen H. Bigio, Ian Mackenzie, Elizabeth Finger, Andrew Kertesz, Richard J. Caselli, Marla Gearing, Jorge L. Juncos, Bernardino Ghetti, Salvatore Spina, Yvette M. Bordelon, Wallace W. Tourtellotte, Matthew P. Frosch, Jean Paul G. 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 R. Galasko, Eliezer Masliah, Charles L. White, Juan C. Troncoso, Didier Hannequin, Adam L. Boxer, Michael D. Geschwind, Satish Kumar, Eva Maria Mandelkow, Zbigniew K Wszolek, 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 Barber, Michael M. Barmada, Thomas Beach, Gary W. Beecham, Duane Beekly, David A. Bennett, Eileen H. Bigio, Thomas D. Bird, Deborah Blacker, Bradley F. Boeve, James D. Bowen, Adam Boxer, James R. Burke, Jacqueline Buros, Joseph D. Buxbaum, Nigel J. Cairns, Laura B. Cantwell, Chuanhai Cao, Chris S. Carlson, Regina M. Carney, Minerva M. Carrasquillo, Steven L. Carroll, Helena C. Chui, David G. Clark, Jason Corneveaux, Carl W. Cotman, 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, Dennis W. Dickson, Beth A. Dombroski, Ranjan Duara, William G. Ellis, Nilufer N. Ertekin-Taner, Denis Evans, Kelley M. Faber, Kenneth B. Fallon, Martin R. Farlow, Steven Ferris, Tatiana M. Foroud, Matthew P. Frosch, Douglas R. Galasko, Paul J. Gallins, Mary Ganguli, Marla Gearing, Daniel H. Geschwind, Bernardino Ghetti, John R. Gilbert, Sid Gilman, Bruno Giordani, Jonathan D. Glass, Alison M. Goate, N. 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 A. Kaye, Ronald Kim, Edward H. Koo, Neil W. Kowall, Patricia Kramer, Walter A. Kukull, James J. Lah, Eric B. Larson, Allan I. Levey, Andrew P. Lieberman, Oscar L. Lopez, Kathryn L. Lunetta, Wendy J. Mack, Daniel C. Marson, Eden R. Martin, Frank Martiniuk, Deborah C. Mash, Eliezer Masliah, Wayne C. McCormick, Susan M. McCurry, Andrew N. McDavid, Ann C. McKee, Marsel Mesulam, Bruce L. Miller, Carol A. Miller, Joshua W. Miller, Thomas J. Montine, John C. Morris, Amanda J. Myers, Adam C. Naj, Petra Nowotny, Joseph E. Parisi, Daniel P. Perl, Elaine Peskind, Ronald C. Petersen, Wayne W. Poon, Huntington Potter, Joseph F. Quinn, Ashok Raj, Ruchita A. Rajbhandary, Murray Raskind, Eric M. Reiman, Barry Reisberg, Christiane Reitz, John M. Ringman, Erik D. Roberson, Ekaterina Rogaeva, Roger N. Rosenberg, Mary Sano, Andrew J. Saykin, Julie A. Schneider, Lon S. Schneider, William Seeley, Michael L. Shelanski, Michael A. Slifer, Charles D. Smith, Joshua A. Sonnen, Salvatore Spina, Peter St George-Hyslop, Robert A. Stern, Rudolph E. Tanzi, John Q. Trojanowski, Juan C. Troncoso, Debby W. Tsuang, Vivianna M. Van Deerlin, Badri Narayan Vardarajan, Harry V. Vinters, Jean Paul Vonsattel, Li San Wang, Sandra Weintraub, Kathleen A. Welsh-Bohmer, Jennifer Williamson, Randall L. Woltjer, Steven G. Younkin, Owen A. Ross, Rosa Rademakers, Gerard D. Schellenberg, Bruce L. Miller, Eckhard Mandelkow, Daniel H. Geschwind

Research output: Contribution to journalArticle

142 Scopus citations

Abstract

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 = 2139, OR = 3.0, CI: 1.6-5.6, P = 0.0005) and Alzheimer's disease (AD) (n = 3345, OR = 2.3, CI: 1.3-4.2, P = 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.

Original languageEnglish (US)
Pages (from-to)3500-3512
Number of pages13
JournalHuman molecular genetics
Volume21
Issue number15
DOIs
StatePublished - Aug 2012

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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    Coppola, G., Chinnathambi, S., Lee, J. J. Y., Dombroski, B. A., Baker, M. C., Soto-ortolaza, A. I., Lee, S. E., Klein, E., Huang, A. Y., Sears, R., Lane, J. R., Karydas, A. M., Kenet, R. O., Biernat, J., Wang, L. S., Cotman, C. W., Decarli, C. S., Levey, A. I., Ringman, J. M., ... Geschwind, D. H. (2012). Evidence for a role of the rare p.A152T variant in mapt in increasing the risk for FTD-spectrum and Alzheimer's diseases. Human molecular genetics, 21(15), 3500-3512. https://doi.org/10.1093/hmg/dds161