Genetic Epidemiology, Translational Neurogenomics, Psychiatric Genetics and Statistical Genetics Laboratories investigate the pattern of disease in families, particularly identical and non-identical twins, to assess the relative importance of genes and environment in a variety of important health problems.
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PMID
22556362
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.
DATE PUBLISHED
2012 Aug 1
HISTORY
PUBSTATUS PUBSTATUSDATE
aheadofprint 2012/05/03
aheadofprint 2012/05/16
entrez 2012/05/05 06:00
pubmed 2012/05/05 06:00
medline 2013/06/26 06:00
AUTHORS
NAME COLLECTIVENAME LASTNAME FORENAME INITIALS AFFILIATION AFFILIATIONINFO
Coppola G Coppola Giovanni G Department of Neurology, University of California, Los Angeles, CA, USA.
Chinnathambi S Chinnathambi Subashchandrabose S
Lee JJ Lee Jason JiYong JJ
Dombroski BA Dombroski Beth A BA
Baker MC Baker Matt C MC
Soto-Ortolaza AI Soto-Ortolaza Alexandra I AI
Lee SE Lee Suzee E SE
Klein E Klein Eric E
Huang AY Huang Alden Y AY
Sears R Sears Renee R
Lane JR Lane Jessica R JR
Karydas AM Karydas Anna M AM
Kenet RO Kenet Robert O RO
Biernat J Biernat Jacek J
Wang LS Wang Li-San LS
Cotman CW Cotman Carl W CW
Decarli CS Decarli Charles S CS
Levey AI Levey Allan I AI
Ringman JM Ringman John M JM
Mendez MF Mendez Mario F MF
Chui HC Chui Helena C HC
Le Ber I Le Ber Isabelle I
Brice A Brice Alexis A
Lupton MK Lupton Michelle K MK
Preza E Preza Elisavet E
Lovestone S Lovestone Simon S
Powell J Powell John J
Graff-Radford N Graff-Radford Neill N
Petersen RC Petersen Ronald C RC
Boeve BF Boeve Bradley F BF
Lippa CF Lippa Carol F CF
Bigio EH Bigio Eileen H EH
Mackenzie I Mackenzie Ian I
Finger E Finger Elizabeth E
Kertesz A Kertesz Andrew A
Caselli RJ Caselli Richard J RJ
Gearing M Gearing Marla M
Juncos JL Juncos Jorge L JL
Ghetti B Ghetti Bernardino B
Spina S Spina Salvatore S
Bordelon YM Bordelon Yvette M YM
Tourtellotte WW Tourtellotte Wallace W WW
Frosch MP Frosch Matthew P MP
Vonsattel JP Vonsattel Jean Paul G JP
Zarow C Zarow Chris C
Beach TG Beach Thomas G TG
Albin RL Albin Roger L RL
Lieberman AP Lieberman Andrew P AP
Lee VM Lee Virginia M VM
Trojanowski JQ Trojanowski John Q JQ
Van Deerlin VM Van Deerlin Vivianna M VM
Bird TD Bird Thomas D TD
Galasko DR Galasko Douglas R DR
Masliah E Masliah Eliezer E
White CL White Charles L CL
Troncoso JC Troncoso Juan C JC
Hannequin D Hannequin Didier D
Boxer AL Boxer Adam L AL
Geschwind MD Geschwind Michael D MD
Kumar S Kumar Satish S
Mandelkow EM Mandelkow Eva-Maria EM
Wszolek ZK Wszolek Zbigniew K ZK
Uitti RJ Uitti Ryan J RJ
Dickson DW Dickson Dennis W DW
Haines JL Haines Jonathan L JL
Mayeux R Mayeux Richard R
Pericak-Vance MA Pericak-Vance Margaret A MA
Farrer LA Farrer Lindsay A LA
Alzheimer's Disease Genetics Consortium
Ross OA Ross Owen A OA
Rademakers R Rademakers Rosa R
Schellenberg GD Schellenberg Gerard D GD
Miller BL Miller Bruce L BL
Mandelkow E Mandelkow Eckhard E
Geschwind DH Geschwind Daniel H DH
INVESTIGATORS
JOURNAL
VOLUME: 21
ISSUE: 15
TITLE: Human molecular genetics
ISOABBREVIATION: Hum. Mol. Genet.
YEAR: 2012
MONTH: Aug
DAY: 1
MEDLINEDATE:
SEASON:
CITEDMEDIUM: Internet
ISSN: 1460-2083
ISSNTYPE: Electronic
MEDLINE JOURNAL
MEDLINETA: Hum Mol Genet
COUNTRY: England
ISSNLINKING: 0964-6906
NLMUNIQUEID: 9208958
PUBLICATION TYPE
PUBLICATIONTYPE TEXT
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
COMMENTS AND CORRECTIONS
REFTYPE REFSOURCE REFPMID NOTE
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GRANTS
GRANTID AGENCY COUNTRY
081864 Wellcome Trust United Kingdom
AG13854 NIA NIH HHS United States
P01 AG017586 NIA NIH HHS United States
P01 AG019724 NIA NIH HHS United States
P30 AG010133 NIA NIH HHS United States
P30 AG019610 NIA NIH HHS United States
P30 AG19610 NIA NIH HHS United States
P50 AG-16570 NIA NIH HHS United States
P50 AG023501 NIA NIH HHS United States
P50 AG025688 NIA NIH HHS United States
P50-AG05142 NIA NIH HHS United States
P50NS072187 NINDS NIH HHS United States
R01 AG026938 NIA NIH HHS United States
R01 AG031278 NIA NIH HHS United States
R01 AG038791 NIA NIH HHS United States
R01 AG038791 NIA NIH HHS United States
R01 NS065782 NINDS NIH HHS United States
R01 NS078086 NINDS NIH HHS United States
R01 NS078086 NINDS NIH HHS United States
R37 AG11762 NIA NIH HHS United States
RC1AG035610 NIA NIH HHS United States
U01 AG016976 NIA NIH HHS United States
U01 AG032984 NIA NIH HHS United States
U01 HG006375 NHGRI NIH HHS United States
U24 AG021886 NIA NIH HHS United States
U24 AG21886 NIA NIH HHS United States
UL1 RR025741 NCRR NIH HHS United States
UL1 TR000150 NCATS NIH HHS United States
Medical Research Council United Kingdom
GENERAL NOTE
KEYWORDS
MESH HEADINGS
DESCRIPTORNAME QUALIFIERNAME
Aged
Alzheimer Disease genetics
Frontotemporal Dementia genetics
Genetic Predisposition to Disease genetics
Genetic Variation genetics
Genotype genetics
Haplotypes genetics
Humans genetics
Middle Aged genetics
Risk genetics
tau Proteins genetics
SUPPLEMENTARY MESH
GENE SYMBOLS
CHEMICALS
REGISTRYNUMBER NAMEOFSUBSTANCE
0 MAPT protein, human
0 tau Proteins
OTHER ID's
OTHERID SOURCE
PMC3392107 NLM
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