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 language | English (US) |
|---|---|
| Pages (from-to) | 3500-3512 |
| Number of pages | 13 |
| Journal | Human molecular genetics |
| Volume | 21 |
| Issue number | 15 |
| DOIs | |
| State | Published - Aug 2012 |
ASJC Scopus subject areas
- Molecular Biology
- Genetics
- Genetics(clinical)
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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 Ji Yong; 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 R.; 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 V; Schellenberg, Gerard D.; Miller, Bruce L.; Mandelkow, Eckhard; Geschwind, Daniel H.
In: Human molecular genetics, Vol. 21, No. 15, 08.2012, p. 3500-3512.Research output: Contribution to journal › Article › peer-review
}
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 Ji Yong
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 R.
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 V
AU - Schellenberg, Gerard D.
AU - Miller, Bruce L.
AU - Mandelkow, Eckhard
AU - Geschwind, Daniel H.
PY - 2012/8
Y1 - 2012/8
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
C2 - 22556362
AN - SCOPUS:84864505483
VL - 21
SP - 3500
EP - 3512
JO - Human Molecular Genetics
JF - Human Molecular Genetics
SN - 0964-6906
IS - 15
ER -