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 JiYong 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. Mendez & 210 others Helena 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 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

118 Citations (Scopus)

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
Article numberdds161
Pages (from-to)3500-3512
Number of pages13
JournalHuman Molecular Genetics
Volume21
Issue number15
DOIs
StatePublished - Jan 1 2012

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Progressive Supranuclear Palsy
Frontotemporal Dementia
Microtubule-Associated Proteins
Microtubules
tau Proteins
Alzheimer Disease
Neurodegenerative Diseases
Haplotypes
Parkinson Disease
Mutation
Genes

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)
  • Molecular Biology

Cite this

Coppola, G., Chinnathambi, S., Lee, J. J., Dombroski, B. A., Baker, M. C., Soto-ortolaza, A. I., ... 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. [dds161]. https://doi.org/10.1093/hmg/dds161

Evidence for a role of the rare p.A152T variant in mapt in increasing the risk for FTD-spectrum and Alzheimer's diseases. / Coppola, Giovanni; Chinnathambi, Subashchandrabose; Lee, Jason JiYong; Dombroski, Beth A.; Baker, Matt C.; Soto-ortolaza, Alexandra I.; Lee, Suzee E.; Klein, Eric; Huang, Alden Y.; Sears, Renee; Lane, Jessica R.; Karydas, Anna M.; Kenet, Robert O.; Biernat, Jacek; Wang, Li San; Cotman, Carl W.; Decarli, Charles S.; Levey, Allan I.; Ringman, John M.; Mendez, Mario F.; Chui, Helena C.; Le ber, Isabelle; Brice, Alexis; Lupton, Michelle K.; Preza, Elisavet; Lovestone, Simon; Powell, John; Graff-radford, Neill; Petersen, Ronald C.; Boeve, Bradley F.; Lippa, Carol F.; Bigio, Eileen H.; Mackenzie, Ian; Finger, Elizabeth; Kertesz, Andrew; Caselli, Richard J.; Gearing, Marla; Juncos, Jorge L.; Ghetti, Bernardino; Spina, Salvatore; Bordelon, Yvette M.; Tourtellotte, Wallace W.; Frosch, Matthew P.; Vonsattel, Jean Paul G; Zarow, Chris; Beach, Thomas G.; Albin, Roger L.; Lieberman, Andrew P.; Lee, Virginia M.; Trojanowski, John Q.; Van deerlin, Vivianna M.; Bird, Thomas D.; Galasko, Douglas R.; Masliah, Eliezer; White, Charles L.; Troncoso, Juan C.; Hannequin, Didier; Boxer, Adam L.; Geschwind, Michael D.; Kumar, Satish; Mandelkow, Eva Maria; Wszolek, Zbigniew K.; Uitti, Ryan J.; Dickson, Dennis W.; Haines, Jonathan L.; Mayeux, Richard; Pericak-Vance, Margaret A; Farrer, Lindsay A.; Apostolova, Liana G.; Arnold, Steven E.; Baldwin, Clinton T.; Barber, Robert; Barmada, Michael M.; Beach, Thomas; Beecham, Gary W; Beekly, Duane; Bennett, David A.; Bigio, Eileen H.; Bird, Thomas D.; Blacker, Deborah; Boeve, Bradley F.; Bowen, James D.; Boxer, Adam; Burke, James R.; Buros, Jacqueline; Buxbaum, Joseph D.; Cairns, Nigel J.; Cantwell, Laura B.; Cao, Chuanhai; Carlson, Chris S.; Carney, Regina M.; Carrasquillo, Minerva M.; Carroll, Steven L.; Chui, Helena C.; Clark, David G.; Corneveaux, Jason; Cotman, Carl W.; Crane, Paul K.; Cruchaga, Carlos; Cummings, Jeffrey L.; De Jager, Philip L.; DeCarli, Charles; DeKosky, Steven T.; Demirci, F. Yesim; Diaz-Arrastia, Ramon; Dick, Malcolm; Dickson, Dennis W.; Dombroski, Beth A.; Duara, Ranjan; Ellis, William G.; Ertekin-Taner, Nilufer N.; Evans, Denis; Faber, Kelley M.; Fallon, Kenneth B.; Farlow, Martin R.; Ferris, Steven; Foroud, Tatiana M.; Frosch, Matthew P.; Galasko, Douglas R.; Gallins, Paul J.; Ganguli, Mary; Gearing, Marla; Geschwind, Daniel H.; Ghetti, Bernardino; Gilbert, John; Gilman, Sid; Giordani, Bruno; Glass, Jonathan D.; Goate, Alison M.; Graff-Radford, N. R.; Green, Robert C.; Growdon, John H.; Hakonarson, Hakon; Hamilton, Ronald L.; Hardy, John; Harrell, Lindy E.; Head, Elizabeth; Honig, Lawrence S.; Huentelman, Matthew J.; Hulette, Christine M.; Hyman, Bradley T.; Jarvik, Gail P.; Jicha, Gregory A.; Jin, Lee Way; Johnson, Nancy; Jun, Gyungah; Kamboh, M. Ilyas; Karlawish, Jason; Karydas, Anna; Kauwe, John S K; Kaye, Jeffrey A.; Kim, Ronald; Koo, Edward H.; Kowall, Neil W.; Kramer, Patricia; Kukull, Walter A.; Lah, James J.; Larson, Eric B.; Levey, Allan I.; Lieberman, Andrew P.; Lopez, Oscar L.; Lunetta, Kathryn L.; Mack, Wendy J.; Marson, Daniel C.; Martin, Eden R; Martiniuk, Frank; Mash, Deborah C; Masliah, Eliezer; McCormick, Wayne C.; McCurry, Susan M.; McDavid, Andrew N.; McKee, Ann C.; Mesulam, Marsel; Miller, Bruce L.; Miller, Carol A.; Miller, Joshua W.; Montine, Thomas J.; Morris, John C.; Myers, Amanda J; Naj, Adam C.; Nowotny, Petra; Parisi, Joseph E.; Perl, Daniel P.; Peskind, Elaine; Petersen, Ronald C.; Poon, Wayne W.; Potter, Huntington; Quinn, Joseph F.; Raj, Ashok; Rajbhandary, Ruchita A.; Raskind, Murray; Reiman, Eric M.; Reisberg, Barry; Reitz, Christiane; Ringman, John M.; Roberson, Erik D.; Rogaeva, Ekaterina; Rosenberg, Roger N.; Sano, Mary; Saykin, Andrew J.; Schneider, Julie A.; Schneider, Lon S.; Seeley, William; Shelanski, Michael L.; Slifer, Michael A.; Smith, Charles D.; Sonnen, Joshua A.; Spina, Salvatore; George-Hyslop, Peter St; Stern, Robert A.; Tanzi, Rudolph E.; Trojanowski, John Q.; Troncoso, Juan C.; Tsuang, Debby W.; Van Deerlin, Vivianna M.; Vardarajan, Badri Narayan; Vinters, Harry V.; Vonsattel, Jean Paul; Wang, Li San; Weintraub, Sandra; Welsh-Bohmer, Kathleen A.; Williamson, Jennifer; Woltjer, Randall L.; Younkin, Steven G.; Ross, Owen A.; Rademakers, Rosa; Schellenberg, Gerard D.; Miller, Bruce L.; Mandelkow, Eckhard; Geschwind, Daniel H.

In: Human Molecular Genetics, Vol. 21, No. 15, dds161, 01.01.2012, p. 3500-3512.

Research output: Contribution to journalArticle

Coppola, G, Chinnathambi, S, Lee, JJ, Dombroski, BA, Baker, MC, Soto-ortolaza, AI, Lee, SE, Klein, E, Huang, AY, Sears, R, Lane, JR, Karydas, AM, Kenet, RO, Biernat, J, Wang, LS, Cotman, CW, Decarli, CS, Levey, AI, Ringman, JM, Mendez, MF, Chui, HC, Le ber, I, Brice, A, Lupton, MK, Preza, E, Lovestone, S, Powell, J, Graff-radford, N, Petersen, RC, Boeve, BF, Lippa, CF, Bigio, EH, Mackenzie, I, Finger, E, Kertesz, A, Caselli, RJ, Gearing, M, Juncos, JL, Ghetti, B, Spina, S, Bordelon, YM, Tourtellotte, WW, Frosch, MP, Vonsattel, JPG, Zarow, C, Beach, TG, Albin, RL, Lieberman, AP, Lee, VM, Trojanowski, JQ, Van deerlin, VM, Bird, TD, Galasko, DR, Masliah, E, White, CL, Troncoso, JC, Hannequin, D, Boxer, AL, Geschwind, MD, Kumar, S, Mandelkow, EM, Wszolek, ZK, Uitti, RJ, Dickson, DW, Haines, JL, Mayeux, R, Pericak-Vance, MA, Farrer, LA, Apostolova, LG, Arnold, SE, Baldwin, CT, Barber, R, Barmada, MM, Beach, T, Beecham, GW, Beekly, D, Bennett, DA, Bigio, EH, Bird, TD, Blacker, D, Boeve, BF, Bowen, JD, Boxer, A, Burke, JR, Buros, J, Buxbaum, JD, Cairns, NJ, Cantwell, LB, Cao, C, Carlson, CS, Carney, RM, Carrasquillo, MM, Carroll, SL, Chui, HC, Clark, DG, Corneveaux, J, Cotman, CW, Crane, PK, Cruchaga, C, Cummings, JL, De Jager, PL, DeCarli, C, DeKosky, ST, Demirci, FY, Diaz-Arrastia, R, Dick, M, Dickson, DW, Dombroski, BA, Duara, R, Ellis, WG, Ertekin-Taner, NN, Evans, D, Faber, KM, Fallon, KB, Farlow, MR, Ferris, S, Foroud, TM, Frosch, MP, Galasko, DR, Gallins, PJ, Ganguli, M, Gearing, M, Geschwind, DH, Ghetti, B, Gilbert, J, Gilman, S, Giordani, B, Glass, JD, Goate, AM, Graff-Radford, NR, Green, RC, Growdon, JH, Hakonarson, H, Hamilton, RL, Hardy, J, Harrell, LE, Head, E, Honig, LS, Huentelman, MJ, Hulette, CM, Hyman, BT, Jarvik, GP, Jicha, GA, Jin, LW, Johnson, N, Jun, G, Kamboh, MI, Karlawish, J, Karydas, A, Kauwe, JSK, Kaye, JA, Kim, R, Koo, EH, Kowall, NW, Kramer, P, Kukull, WA, Lah, JJ, Larson, EB, Levey, AI, Lieberman, AP, Lopez, OL, Lunetta, KL, Mack, WJ, Marson, DC, Martin, ER, Martiniuk, F, Mash, DC, Masliah, E, McCormick, WC, McCurry, SM, McDavid, AN, McKee, AC, Mesulam, M, Miller, BL, Miller, CA, Miller, JW, Montine, TJ, Morris, JC, Myers, AJ, Naj, AC, Nowotny, P, Parisi, JE, Perl, DP, Peskind, E, Petersen, RC, Poon, WW, Potter, H, Quinn, JF, Raj, A, Rajbhandary, RA, Raskind, M, Reiman, EM, Reisberg, B, Reitz, C, Ringman, JM, Roberson, ED, Rogaeva, E, Rosenberg, RN, Sano, M, Saykin, AJ, Schneider, JA, Schneider, LS, Seeley, W, Shelanski, ML, Slifer, MA, Smith, CD, Sonnen, JA, Spina, S, George-Hyslop, PS, Stern, RA, Tanzi, RE, Trojanowski, JQ, Troncoso, JC, Tsuang, DW, Van Deerlin, VM, Vardarajan, BN, Vinters, HV, Vonsattel, JP, Wang, LS, Weintraub, S, Welsh-Bohmer, KA, Williamson, J, Woltjer, RL, Younkin, SG, Ross, OA, Rademakers, R, Schellenberg, GD, Miller, BL, Mandelkow, E & Geschwind, DH 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, vol. 21, no. 15, dds161, pp. 3500-3512. https://doi.org/10.1093/hmg/dds161
Coppola G, Chinnathambi S, Lee JJ, Dombroski BA, Baker MC, Soto-ortolaza AI et al. 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. 2012 Jan 1;21(15):3500-3512. dds161. https://doi.org/10.1093/hmg/dds161
Coppola, Giovanni ; Chinnathambi, Subashchandrabose ; Lee, Jason JiYong ; Dombroski, Beth A. ; Baker, Matt C. ; Soto-ortolaza, Alexandra I. ; Lee, Suzee E. ; Klein, Eric ; Huang, Alden Y. ; Sears, Renee ; Lane, Jessica R. ; Karydas, Anna M. ; Kenet, Robert O. ; Biernat, Jacek ; Wang, Li San ; Cotman, Carl W. ; Decarli, Charles S. ; Levey, Allan I. ; Ringman, John M. ; Mendez, Mario F. ; Chui, Helena C. ; Le ber, Isabelle ; Brice, Alexis ; Lupton, Michelle K. ; Preza, Elisavet ; Lovestone, Simon ; Powell, John ; Graff-radford, Neill ; Petersen, Ronald C. ; Boeve, Bradley F. ; Lippa, Carol F. ; Bigio, Eileen H. ; Mackenzie, Ian ; Finger, Elizabeth ; Kertesz, Andrew ; Caselli, Richard J. ; Gearing, Marla ; Juncos, Jorge L. ; Ghetti, Bernardino ; Spina, Salvatore ; Bordelon, Yvette M. ; Tourtellotte, Wallace W. ; Frosch, Matthew P. ; Vonsattel, Jean Paul G ; Zarow, Chris ; Beach, Thomas G. ; Albin, Roger L. ; Lieberman, Andrew P. ; Lee, Virginia M. ; Trojanowski, John Q. ; Van deerlin, Vivianna M. ; Bird, Thomas D. ; Galasko, Douglas R. ; Masliah, Eliezer ; White, Charles L. ; Troncoso, Juan C. ; Hannequin, Didier ; Boxer, Adam L. ; Geschwind, Michael D. ; Kumar, Satish ; Mandelkow, Eva Maria ; Wszolek, Zbigniew K. ; Uitti, Ryan J. ; Dickson, Dennis W. ; Haines, Jonathan L. ; Mayeux, Richard ; Pericak-Vance, Margaret A ; Farrer, Lindsay A. ; Apostolova, Liana G. ; Arnold, Steven E. ; Baldwin, Clinton T. ; Barber, Robert ; Barmada, Michael M. ; Beach, Thomas ; Beecham, Gary W ; Beekly, Duane ; Bennett, David A. ; Bigio, Eileen H. ; Bird, Thomas D. ; Blacker, Deborah ; Boeve, Bradley F. ; Bowen, James D. ; Boxer, Adam ; Burke, James R. ; Buros, Jacqueline ; Buxbaum, Joseph D. ; Cairns, Nigel J. ; Cantwell, Laura B. ; Cao, Chuanhai ; Carlson, Chris S. ; Carney, Regina M. ; Carrasquillo, Minerva M. ; Carroll, Steven L. ; Chui, Helena C. ; Clark, David G. ; Corneveaux, Jason ; Cotman, Carl W. ; Crane, Paul K. ; Cruchaga, Carlos ; Cummings, Jeffrey L. ; De Jager, Philip L. ; DeCarli, Charles ; DeKosky, Steven T. ; Demirci, F. Yesim ; Diaz-Arrastia, Ramon ; Dick, Malcolm ; Dickson, Dennis W. ; Dombroski, Beth A. ; Duara, Ranjan ; Ellis, William G. ; Ertekin-Taner, Nilufer N. ; Evans, Denis ; Faber, Kelley M. ; Fallon, Kenneth B. ; Farlow, Martin R. ; Ferris, Steven ; Foroud, Tatiana M. ; Frosch, Matthew P. ; Galasko, Douglas R. ; Gallins, Paul J. ; Ganguli, Mary ; Gearing, Marla ; Geschwind, Daniel H. ; Ghetti, Bernardino ; Gilbert, John ; Gilman, Sid ; Giordani, Bruno ; Glass, Jonathan D. ; Goate, Alison M. ; Graff-Radford, N. R. ; Green, Robert C. ; Growdon, John H. ; Hakonarson, Hakon ; Hamilton, Ronald L. ; Hardy, John ; Harrell, Lindy E. ; Head, Elizabeth ; Honig, Lawrence S. ; Huentelman, Matthew J. ; Hulette, Christine M. ; Hyman, Bradley T. ; Jarvik, Gail P. ; Jicha, Gregory A. ; Jin, Lee Way ; Johnson, Nancy ; Jun, Gyungah ; Kamboh, M. Ilyas ; Karlawish, Jason ; Karydas, Anna ; Kauwe, John S K ; Kaye, Jeffrey A. ; Kim, Ronald ; Koo, Edward H. ; Kowall, Neil W. ; Kramer, Patricia ; Kukull, Walter A. ; Lah, James J. ; Larson, Eric B. ; Levey, Allan I. ; Lieberman, Andrew P. ; Lopez, Oscar L. ; Lunetta, Kathryn L. ; Mack, Wendy J. ; Marson, Daniel C. ; Martin, Eden R ; Martiniuk, Frank ; Mash, Deborah C ; Masliah, Eliezer ; McCormick, Wayne C. ; McCurry, Susan M. ; McDavid, Andrew N. ; McKee, Ann C. ; Mesulam, Marsel ; Miller, Bruce L. ; Miller, Carol A. ; Miller, Joshua W. ; Montine, Thomas J. ; Morris, John C. ; Myers, Amanda J ; Naj, Adam C. ; Nowotny, Petra ; Parisi, Joseph E. ; Perl, Daniel P. ; Peskind, Elaine ; Petersen, Ronald C. ; Poon, Wayne W. ; Potter, Huntington ; Quinn, Joseph F. ; Raj, Ashok ; Rajbhandary, Ruchita A. ; Raskind, Murray ; Reiman, Eric M. ; Reisberg, Barry ; Reitz, Christiane ; Ringman, John M. ; Roberson, Erik D. ; Rogaeva, Ekaterina ; Rosenberg, Roger N. ; Sano, Mary ; Saykin, Andrew J. ; Schneider, Julie A. ; Schneider, Lon S. ; Seeley, William ; Shelanski, Michael L. ; Slifer, Michael A. ; Smith, Charles D. ; Sonnen, Joshua A. ; Spina, Salvatore ; George-Hyslop, Peter St ; Stern, Robert A. ; Tanzi, Rudolph E. ; Trojanowski, John Q. ; Troncoso, Juan C. ; Tsuang, Debby W. ; Van Deerlin, Vivianna M. ; Vardarajan, Badri Narayan ; Vinters, Harry V. ; Vonsattel, Jean Paul ; Wang, Li San ; Weintraub, Sandra ; Welsh-Bohmer, Kathleen A. ; Williamson, Jennifer ; Woltjer, Randall L. ; Younkin, Steven G. ; Ross, Owen A. ; Rademakers, Rosa ; Schellenberg, Gerard D. ; Miller, Bruce L. ; Mandelkow, Eckhard ; Geschwind, Daniel H. / Evidence for a role of the rare p.A152T variant in mapt in increasing the risk for FTD-spectrum and Alzheimer's diseases. In: Human Molecular Genetics. 2012 ; Vol. 21, No. 15. pp. 3500-3512.
@article{ee8917d1af3a4717964d1976a6320247,
title = "Evidence for a role of the rare p.A152T variant in mapt in increasing the risk for FTD-spectrum and Alzheimer's diseases",
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.",
author = "Giovanni Coppola and Subashchandrabose Chinnathambi and Lee, {Jason JiYong} and Dombroski, {Beth A.} and Baker, {Matt C.} and Soto-ortolaza, {Alexandra I.} and Lee, {Suzee E.} and Eric Klein and Huang, {Alden Y.} and Renee Sears and Lane, {Jessica R.} and Karydas, {Anna M.} and Kenet, {Robert O.} and Jacek Biernat and Wang, {Li San} and Cotman, {Carl W.} and Decarli, {Charles S.} and Levey, {Allan I.} and Ringman, {John M.} and Mendez, {Mario F.} and Chui, {Helena C.} and {Le ber}, Isabelle and Alexis Brice and Lupton, {Michelle K.} and Elisavet Preza and Simon Lovestone and John Powell and Neill Graff-radford and Petersen, {Ronald C.} and Boeve, {Bradley F.} and Lippa, {Carol F.} and Bigio, {Eileen H.} and Ian Mackenzie and Elizabeth Finger and Andrew Kertesz and Caselli, {Richard J.} and Marla Gearing and Juncos, {Jorge L.} and Bernardino Ghetti and Salvatore Spina and Bordelon, {Yvette M.} and Tourtellotte, {Wallace W.} and Frosch, {Matthew P.} and Vonsattel, {Jean Paul G} and Chris Zarow and Beach, {Thomas G.} and Albin, {Roger L.} and Lieberman, {Andrew P.} and Lee, {Virginia M.} and Trojanowski, {John Q.} and {Van deerlin}, {Vivianna M.} and Bird, {Thomas D.} and Galasko, {Douglas R.} and Eliezer Masliah and White, {Charles L.} and Troncoso, {Juan C.} and Didier Hannequin and Boxer, {Adam L.} and Geschwind, {Michael D.} and Satish Kumar and Mandelkow, {Eva Maria} and Wszolek, {Zbigniew K.} and Uitti, {Ryan J.} and Dickson, {Dennis W.} and Haines, {Jonathan L.} and Richard Mayeux and Pericak-Vance, {Margaret A} and Farrer, {Lindsay A.} and Apostolova, {Liana G.} and Arnold, {Steven E.} and Baldwin, {Clinton T.} and Robert Barber and Barmada, {Michael M.} and Thomas Beach and Beecham, {Gary W} and Duane Beekly and Bennett, {David A.} and Bigio, {Eileen H.} and Bird, {Thomas D.} and Deborah Blacker and Boeve, {Bradley F.} and Bowen, {James D.} and Adam Boxer and Burke, {James R.} and Jacqueline Buros and Buxbaum, {Joseph D.} and Cairns, {Nigel J.} and Cantwell, {Laura B.} and Chuanhai Cao and Carlson, {Chris S.} and Carney, {Regina M.} and Carrasquillo, {Minerva M.} and Carroll, {Steven L.} and Chui, {Helena C.} and Clark, {David G.} and Jason Corneveaux and Cotman, {Carl W.} and Crane, {Paul K.} and Carlos Cruchaga and Cummings, {Jeffrey L.} and {De Jager}, {Philip L.} and Charles DeCarli and DeKosky, {Steven T.} and Demirci, {F. Yesim} and Ramon Diaz-Arrastia and Malcolm Dick and Dickson, {Dennis W.} and Dombroski, {Beth A.} and Ranjan Duara and Ellis, {William G.} and Ertekin-Taner, {Nilufer N.} and Denis Evans and Faber, {Kelley M.} and Fallon, {Kenneth B.} and Farlow, {Martin R.} and Steven Ferris and Foroud, {Tatiana M.} and Frosch, {Matthew P.} and Galasko, {Douglas R.} and Gallins, {Paul J.} and Mary Ganguli and Marla Gearing and Geschwind, {Daniel H.} and Bernardino Ghetti and John Gilbert and Sid Gilman and Bruno Giordani and Glass, {Jonathan D.} and Goate, {Alison M.} and Graff-Radford, {N. R.} and Green, {Robert C.} and Growdon, {John H.} and Hakon Hakonarson and Hamilton, {Ronald L.} and John Hardy and Harrell, {Lindy E.} and Elizabeth Head and Honig, {Lawrence S.} and Huentelman, {Matthew J.} and Hulette, {Christine M.} and Hyman, {Bradley T.} and Jarvik, {Gail P.} and Jicha, {Gregory A.} and Jin, {Lee Way} and Nancy Johnson and Gyungah Jun and Kamboh, {M. Ilyas} and Jason Karlawish and Anna Karydas and Kauwe, {John S K} and Kaye, {Jeffrey A.} and Ronald Kim and Koo, {Edward H.} and Kowall, {Neil W.} and Patricia Kramer and Kukull, {Walter A.} and Lah, {James J.} and Larson, {Eric B.} and Levey, {Allan I.} and Lieberman, {Andrew P.} and Lopez, {Oscar L.} and Lunetta, {Kathryn L.} and Mack, {Wendy J.} and Marson, {Daniel C.} and Martin, {Eden R} and Frank Martiniuk and Mash, {Deborah C} and Eliezer Masliah and McCormick, {Wayne C.} and McCurry, {Susan M.} and McDavid, {Andrew N.} and McKee, {Ann C.} and Marsel Mesulam and Miller, {Bruce L.} and Miller, {Carol A.} and Miller, {Joshua W.} and Montine, {Thomas J.} and Morris, {John C.} and Myers, {Amanda J} and Naj, {Adam C.} and Petra Nowotny and Parisi, {Joseph E.} and Perl, {Daniel P.} and Elaine Peskind and Petersen, {Ronald C.} and Poon, {Wayne W.} and Huntington Potter and Quinn, {Joseph F.} and Ashok Raj and Rajbhandary, {Ruchita A.} and Murray Raskind and Reiman, {Eric M.} and Barry Reisberg and Christiane Reitz and Ringman, {John M.} and Roberson, {Erik D.} and Ekaterina Rogaeva and Rosenberg, {Roger N.} and Mary Sano and Saykin, {Andrew J.} and Schneider, {Julie A.} and Schneider, {Lon S.} and William Seeley and Shelanski, {Michael L.} and Slifer, {Michael A.} and Smith, {Charles D.} and Sonnen, {Joshua A.} and Salvatore Spina and George-Hyslop, {Peter St} and Stern, {Robert A.} and Tanzi, {Rudolph E.} and Trojanowski, {John Q.} and Troncoso, {Juan C.} and Tsuang, {Debby W.} and {Van Deerlin}, {Vivianna M.} and Vardarajan, {Badri Narayan} and Vinters, {Harry V.} and Vonsattel, {Jean Paul} and Wang, {Li San} and Sandra Weintraub and Welsh-Bohmer, {Kathleen A.} and Jennifer Williamson and Woltjer, {Randall L.} and Younkin, {Steven G.} and Ross, {Owen A.} and Rosa Rademakers and Schellenberg, {Gerard D.} and Miller, {Bruce L.} and Eckhard Mandelkow and Geschwind, {Daniel H.}",
year = "2012",
month = "1",
day = "1",
doi = "10.1093/hmg/dds161",
language = "English",
volume = "21",
pages = "3500--3512",
journal = "Human Molecular Genetics",
issn = "0964-6906",
publisher = "Oxford University Press",
number = "15",

}

TY - JOUR

T1 - Evidence for a role of the rare p.A152T variant in mapt in increasing the risk for FTD-spectrum and Alzheimer's diseases

AU - Coppola, Giovanni

AU - Chinnathambi, Subashchandrabose

AU - Lee, Jason JiYong

AU - Dombroski, Beth A.

AU - Baker, Matt C.

AU - Soto-ortolaza, Alexandra I.

AU - Lee, Suzee E.

AU - Klein, Eric

AU - Huang, Alden Y.

AU - Sears, Renee

AU - Lane, Jessica R.

AU - Karydas, Anna M.

AU - Kenet, Robert O.

AU - Biernat, Jacek

AU - Wang, Li San

AU - Cotman, Carl W.

AU - Decarli, Charles S.

AU - Levey, Allan I.

AU - Ringman, John M.

AU - Mendez, Mario F.

AU - Chui, Helena C.

AU - Le ber, Isabelle

AU - Brice, Alexis

AU - Lupton, Michelle K.

AU - Preza, Elisavet

AU - Lovestone, Simon

AU - Powell, John

AU - Graff-radford, Neill

AU - Petersen, Ronald C.

AU - Boeve, Bradley F.

AU - Lippa, Carol F.

AU - Bigio, Eileen H.

AU - Mackenzie, Ian

AU - Finger, Elizabeth

AU - Kertesz, Andrew

AU - Caselli, Richard J.

AU - Gearing, Marla

AU - Juncos, Jorge L.

AU - Ghetti, Bernardino

AU - Spina, Salvatore

AU - Bordelon, Yvette M.

AU - Tourtellotte, Wallace W.

AU - Frosch, Matthew P.

AU - Vonsattel, Jean Paul G

AU - Zarow, Chris

AU - Beach, Thomas G.

AU - Albin, Roger L.

AU - Lieberman, Andrew P.

AU - Lee, Virginia M.

AU - Trojanowski, John Q.

AU - Van deerlin, Vivianna M.

AU - Bird, Thomas D.

AU - Galasko, Douglas R.

AU - Masliah, Eliezer

AU - White, Charles L.

AU - Troncoso, Juan C.

AU - Hannequin, Didier

AU - Boxer, Adam L.

AU - Geschwind, Michael D.

AU - Kumar, Satish

AU - Mandelkow, Eva Maria

AU - Wszolek, Zbigniew K.

AU - Uitti, Ryan J.

AU - Dickson, Dennis W.

AU - Haines, Jonathan L.

AU - Mayeux, Richard

AU - Pericak-Vance, Margaret A

AU - Farrer, Lindsay A.

AU - Apostolova, Liana G.

AU - Arnold, Steven E.

AU - Baldwin, Clinton T.

AU - Barber, Robert

AU - Barmada, Michael M.

AU - Beach, Thomas

AU - Beecham, Gary W

AU - Beekly, Duane

AU - Bennett, David A.

AU - Bigio, Eileen H.

AU - Bird, Thomas D.

AU - Blacker, Deborah

AU - Boeve, Bradley F.

AU - Bowen, James D.

AU - Boxer, Adam

AU - Burke, James R.

AU - Buros, Jacqueline

AU - Buxbaum, Joseph D.

AU - Cairns, Nigel J.

AU - Cantwell, Laura B.

AU - Cao, Chuanhai

AU - Carlson, Chris S.

AU - Carney, Regina M.

AU - Carrasquillo, Minerva M.

AU - Carroll, Steven L.

AU - Chui, Helena C.

AU - Clark, David G.

AU - Corneveaux, Jason

AU - Cotman, Carl W.

AU - Crane, Paul K.

AU - Cruchaga, Carlos

AU - Cummings, Jeffrey L.

AU - De Jager, Philip L.

AU - DeCarli, Charles

AU - DeKosky, Steven T.

AU - Demirci, F. Yesim

AU - Diaz-Arrastia, Ramon

AU - Dick, Malcolm

AU - Dickson, Dennis W.

AU - Dombroski, Beth A.

AU - Duara, Ranjan

AU - Ellis, William G.

AU - Ertekin-Taner, Nilufer N.

AU - Evans, Denis

AU - Faber, Kelley M.

AU - Fallon, Kenneth B.

AU - Farlow, Martin R.

AU - Ferris, Steven

AU - Foroud, Tatiana M.

AU - Frosch, Matthew P.

AU - Galasko, Douglas R.

AU - Gallins, Paul J.

AU - Ganguli, Mary

AU - Gearing, Marla

AU - Geschwind, Daniel H.

AU - Ghetti, Bernardino

AU - Gilbert, John

AU - Gilman, Sid

AU - Giordani, Bruno

AU - Glass, Jonathan D.

AU - Goate, Alison M.

AU - Graff-Radford, N. R.

AU - Green, Robert C.

AU - Growdon, John H.

AU - Hakonarson, Hakon

AU - Hamilton, Ronald L.

AU - Hardy, John

AU - Harrell, Lindy E.

AU - Head, Elizabeth

AU - Honig, Lawrence S.

AU - Huentelman, Matthew J.

AU - Hulette, Christine M.

AU - Hyman, Bradley T.

AU - Jarvik, Gail P.

AU - Jicha, Gregory A.

AU - Jin, Lee Way

AU - Johnson, Nancy

AU - Jun, Gyungah

AU - Kamboh, M. Ilyas

AU - Karlawish, Jason

AU - Karydas, Anna

AU - Kauwe, John S K

AU - Kaye, Jeffrey A.

AU - Kim, Ronald

AU - Koo, Edward H.

AU - Kowall, Neil W.

AU - Kramer, Patricia

AU - Kukull, Walter A.

AU - Lah, James J.

AU - Larson, Eric B.

AU - Levey, Allan I.

AU - Lieberman, Andrew P.

AU - Lopez, Oscar L.

AU - Lunetta, Kathryn L.

AU - Mack, Wendy J.

AU - Marson, Daniel C.

AU - Martin, Eden R

AU - Martiniuk, Frank

AU - Mash, Deborah C

AU - Masliah, Eliezer

AU - McCormick, Wayne C.

AU - McCurry, Susan M.

AU - McDavid, Andrew N.

AU - McKee, Ann C.

AU - Mesulam, Marsel

AU - Miller, Bruce L.

AU - Miller, Carol A.

AU - Miller, Joshua W.

AU - Montine, Thomas J.

AU - Morris, John C.

AU - Myers, Amanda J

AU - Naj, Adam C.

AU - Nowotny, Petra

AU - Parisi, Joseph E.

AU - Perl, Daniel P.

AU - Peskind, Elaine

AU - Petersen, Ronald C.

AU - Poon, Wayne W.

AU - Potter, Huntington

AU - Quinn, Joseph F.

AU - Raj, Ashok

AU - Rajbhandary, Ruchita A.

AU - Raskind, Murray

AU - Reiman, Eric M.

AU - Reisberg, Barry

AU - Reitz, Christiane

AU - Ringman, John M.

AU - Roberson, Erik D.

AU - Rogaeva, Ekaterina

AU - Rosenberg, Roger N.

AU - Sano, Mary

AU - Saykin, Andrew J.

AU - Schneider, Julie A.

AU - Schneider, Lon S.

AU - Seeley, William

AU - Shelanski, Michael L.

AU - Slifer, Michael A.

AU - Smith, Charles D.

AU - Sonnen, Joshua A.

AU - Spina, Salvatore

AU - George-Hyslop, Peter St

AU - Stern, Robert A.

AU - Tanzi, Rudolph E.

AU - Trojanowski, John Q.

AU - Troncoso, Juan C.

AU - Tsuang, Debby W.

AU - Van Deerlin, Vivianna M.

AU - Vardarajan, Badri Narayan

AU - Vinters, Harry V.

AU - Vonsattel, Jean Paul

AU - Wang, Li San

AU - Weintraub, Sandra

AU - Welsh-Bohmer, Kathleen A.

AU - Williamson, Jennifer

AU - Woltjer, Randall L.

AU - Younkin, Steven G.

AU - Ross, Owen A.

AU - Rademakers, Rosa

AU - Schellenberg, Gerard D.

AU - Miller, Bruce L.

AU - Mandelkow, Eckhard

AU - Geschwind, Daniel H.

PY - 2012/1/1

Y1 - 2012/1/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84864505483&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84864505483&partnerID=8YFLogxK

U2 - 10.1093/hmg/dds161

DO - 10.1093/hmg/dds161

M3 - Article

VL - 21

SP - 3500

EP - 3512

JO - Human Molecular Genetics

JF - Human Molecular Genetics

SN - 0964-6906

IS - 15

M1 - dds161

ER -