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Title | Evidence for a role of the rare p.A152T variant in MAPT in increasing the risk for FTD-spectrum and Alzheimer's diseases. |
Publication Type | Journal Article |
Year of Publication | 2012 |
Authors | Coppola G, Chinnathambi S, Lee JJiYong, Dombroski BA, Baker MC, Soto-Ortolaza AI, Lee SE, Klein E, Huang AY, Sears R, Lane JR, Karydas AM, Kenet RO, Biernat J, Wang L-S, 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 JPaul G, 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 E-M, Wszolek ZK, Uitti RJ, Dickson DW, Haines JL, Mayeux R, Pericak-Vance MA, Farrer LA, Ross OA, Rademakers R, Schellenberg GD, Miller BL, Mandelkow E, Geschwind DH |
Corporate Authors | Alzheimer's Disease Genetics Consortium |
Journal | Hum Mol Genet |
Volume | 21 |
Issue | 15 |
Pagination | 3500-12 |
Date Published | 2012 Aug 01 |
ISSN | 1460-2083 |
Keywords | Aged, Alzheimer Disease, Frontotemporal Dementia, Genetic Predisposition to Disease, Genetic Variation, Genotype, Haplotypes, Humans, Middle Aged, Risk, tau Proteins |
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. |
DOI | 10.1093/hmg/dds161 |
Alternate Journal | Hum. Mol. Genet. |
PubMed ID | 22556362 |
PubMed Central ID | PMC3392107 |
Grant List | R01 MH061675 / MH / NIMH NIH HHS / United States U01 HG006375 / HG / NHGRI NIH HHS / United States R01 NS078086 / NS / NINDS NIH HHS / United States R01 AG026938 / AG / NIA NIH HHS / United States UL1 TR000150 / TR / NCATS NIH HHS / United States R01 AG031278 / AG / NIA NIH HHS / United States P50-AG05142 / AG / NIA NIH HHS / United States P30 AG010133 / AG / NIA NIH HHS / United States U24 AG021886 / AG / NIA NIH HHS / United States P01 AG017586 / AG / NIA NIH HHS / United States U01 AG032984 / AG / NIA NIH HHS / United States R01 AG038791 / AG / NIA NIH HHS / United States P50NS072187 / NS / NINDS NIH HHS / United States / / Medical Research Council / United Kingdom U01 AG016976 / AG / NIA NIH HHS / United States UL1 RR025741 / RR / NCRR NIH HHS / United States R01 MH067257 / MH / NIMH NIH HHS / United States RC1AG035610 / AG / NIA NIH HHS / United States R01 MH060870 / MH / NIMH NIH HHS / United States P50 AG023501 / AG / NIA NIH HHS / United States R01 NS065782 / NS / NINDS NIH HHS / United States R01 MH059571 / MH / NIMH NIH HHS / United States R01 MH059565 / MH / NIMH NIH HHS / United States P01 AG019724 / AG / NIA NIH HHS / United States R37 AG11762 / AG / NIA NIH HHS / United States R01 MH059587 / MH / NIMH NIH HHS / United States R01 MH059586 / MH / NIMH NIH HHS / United States AG13854 / AG / NIA NIH HHS / United States P30 AG19610 / AG / NIA NIH HHS / United States R01 MH059566 / MH / NIMH NIH HHS / United States P30 AG019610 / AG / NIA NIH HHS / United States U24 AG21886 / AG / NIA NIH HHS / United States R01 MH059588 / MH / NIMH NIH HHS / United States P50 AG025688 / AG / NIA NIH HHS / United States 081864 / / Wellcome Trust / United Kingdom P50 AG-16570 / AG / NIA NIH HHS / United States R01 MH060879 / MH / NIMH NIH HHS / United States |