Evidence for a role of the rare p.A152T variant in MAPT in increasing the risk for FTD-spectrum and Alzheimers diseases

被引：185

作者：

Coppola, Giovanni ^{[2
]}

Chinnathambi, Subashchandrabose ^{[6
,7
]}

Lee, Jason JiYong

Dombroski, Beth A. ^{[8
]}

Baker, Matt C. ^{[9
,10
,11
]}

Soto-Ortolaza, Alexandra I. ^{[9
,10
,11
]}

Lee, Suzee E. ^{[3
]}

Klein, Eric

Huang, Alden Y.

Sears, Renee

Lane, Jessica R.

Karydas, Anna M. ^{[3
]}

Kenet, Robert O. ^{[12
]}

Biernat, Jacek ^{[6
,7
]}

Wang, Li-San ^{[8
]}

Cotman, Carl W. ^{[4
]}

DeCarli, Charles S. ^{[5
]}

Levey, Allan I. ^{[13
,14
,15
]}

Ringman, John M.

Mendez, Mario F.

Chui, Helena C. ^{[16
]}

Le Ber, Isabelle ^{[55
,56
]}

Brice, Alexis ^{[18
,55
]}

Lupton, Michelle K. ^{[19
]}

Preza, Elisavet ^{[19
]}

Lovestone, Simon ^{[19
]}

Powell, John ^{[19
]}

Graff-Radford, Neill ^{[9
,10
,11
]}

Petersen, Ronald C. ^{[20
]}

Boeve, Bradley F. ^{[20
]}

Lippa, Carol F. ^{[21
]}

Bigio, Eileen H. ^{[22
]}

Mackenzie, Ian ^{[23
]}

Finger, Elizabeth ^{[24
]}

Kertesz, Andrew ^{[24
]}

Caselli, Richard J. ^{[25
]}

Gearing, Marla ^{[13
,14
,15
]}

Juncos, Jorge L. ^{[13
,14
,15
]}

Ghetti, Bernardino ^{[26
]}

Spina, Salvatore ^{[26
]}

Bordelon, Yvette M.

Tourtellotte, Wallace W. ^{[27
]}

Frosch, Matthew P. ^{[28
,29
,30
]}

Vonsattel, Jean Paul G. ^{[31
,32
,33
]}

Zarow, Chris ^{[17
]}

Beach, Thomas G. ^{[34
]}

Albin, Roger L. ^{[35
,36
,37
]}

Lieberman, Andrew P. ^{[35
,36
,37
]}

Lee, Virginia M. ^{[8
]}

Trojanowski, John Q. ^{[8
]}

机构：

[1] Univ Calif Los Angeles, David Geffen Sch Med, Dept Neurol, Program Neurogenet, Los Angeles, CA 90095 USA

[2] Univ Calif Los Angeles, Dept Psychiat, Semel Inst Neurosci & Human Behav, Los Angeles, CA 90095 USA

[3] Univ Calif San Francisco, Dept Neurol, San Francisco, CA USA

[4] Univ Calif Irvine, Dept Neurol, Irvine, CA 92717 USA

[5] Univ Calif Davis, Dept Neurol, Davis, CA 95616 USA

[6] German Ctr Neurodegenerat Dis, DZNE, D-53175 Bonn, Germany

[7] CAESAR Res Ctr, D-53175 Bonn, Germany

[8] Univ Penn, Sch Med, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA

[9] Mayo Clin Florida, Dept Neurosci, Jacksonville, FL USA

[10] Mayo Clin Florida, Dept Neurol, Jacksonville, FL USA

[11] Mayo Clin Florida, Dept Pathol, Jacksonville, FL USA

[12] Weill Cornell Med Coll, New York Presbyterian Hosp, Dept Med, New York, NY USA

[13] Emory Univ, Sch Med, Dept Neurol, Atlanta, GA 30322 USA

[14] Emory Univ, Sch Med, Dept Pathol, Atlanta, GA 30322 USA

[15] Emory Univ, Sch Med, Dept Lab Med, Atlanta, GA 30322 USA

[16] Univ So Calif, Dept Neurol, Downey, CA USA

[17] Univ So Calif, Rancho Amigos Natl Rehabil Ctr, Downey, CA USA

[18] Hop La Pitie Salpetriere, AP HP, Dept Genet & Cytogenet, F-75013 Paris, France

[19] Kings Coll London, Inst Psychiat, London WC2R 2LS, England

[20] Mayo Clin Rochester, Dept Neurol, Rochester, MN USA

[21] Drexel Univ, Dept Neurol, Coll Med, Philadelphia, PA 19104 USA

[22] Northwestern Univ, Cognit Neurol & Alzheimer Dis Ctr, Feinberg Sch Med, Chicago, IL 60611 USA

[23] Univ British Columbia, Dept Pathol, Vancouver, BC, Canada

[24] Univ Western Ontario, Dept Clin Neurol Sci, London, ON, Canada

[25] Mayo Clin Scottsdale, Dept Neurol, Scottsdale, AZ USA

[26] Indiana Univ Sch Med, Dept Pathol & Lab Med, Indianapolis, IN USA

[27] Vet Affairs W Los Angeles Healthcare Ctr, Human Brain & Spinal Fluid Resource Ctr, Los Angeles, CA USA

[28] Massachusetts Gen Hosp, CS Kubik Lab Neuropathol, Boston, MA 02114 USA

[29] Massachusetts Gen Hosp, Mass Gen Inst Neurodegenerat Dis, Boston, MA 02114 USA

[30] Harvard Univ, Sch Med, Boston, MA USA

[31] Columbia Univ, Dept Neurol, New York, NY USA

[32] Columbia Univ, Dept Pathol, New York, NY USA

[33] Columbia Univ, Taub Inst Res Alzheimers Dis & Aging Brain, New York, NY USA

[34] Banner Sun Hlth Res Inst, Civin Lab Neuropathol, Sun City, AZ USA

[35] Univ Michigan, Dept Neurol, Ann Arbor, MI USA

[36] Univ Michigan, Dept Pathol, Ann Arbor, MI 48109 USA

[37] VA Ann Arbor Hlth Syst, Geriatr Res Educ & Clin Ctr, Ann Arbor, MI USA

[38] Univ Washington, Dept Med, Seattle, WA USA

[39] Univ Washington, Dept Neurol, Seattle, WA 98195 USA

[40] Univ Washington, Dept Med Genet, Seattle, WA 98195 USA

[41] Univ Calif San Diego, Dept Pathol, La Jolla, CA 92093 USA

[42] Univ Calif San Diego, Dept Neurosci, La Jolla, CA 92093 USA

[43] Univ Texas SW Med Ctr Dallas, Dept Pathol, Dallas, TX 75390 USA

[44] Johns Hopkins Univ Sch Med, Dept Neurol, Baltimore, MD USA

[45] CHU Charles Nicolle, CNR MAJ, INSERM, U614, Rouen, France

[46] CHU Charles Nicolle, Dept Neurol, Rouen, France

[47] Vanderbilt Univ, Dept Mol Physiol & Biophys, Vanderbilt Ctr Human Genet Res, Nashville, TN 37232 USA

[48] Univ Miami, John P Hussman Inst Human Genom, Miami, FL USA

[49] Univ Miami, Dr John T Macdonald Fdn, Dept Human Genet, Miami, FL USA

[50] Boston Univ, Dept Biostat, Boston, MA 02215 USA

来源：

HUMAN MOLECULAR GENETICS | 2012年 / 21卷 / 15期

基金：

英国医学研究理事会; 美国国家卫生研究院;

关键词：

COMMON VARIANTS; TAU-PROTEIN; FRONTOTEMPORAL DEMENTIA; AGGREGATION; ASSOCIATION; HAPLOTYPE; MUTATION; PHOSPHORYLATION; OLIGOMERS; UPSTREAM;

D O I：

10.1093/hmg/dds161

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Tau p.A152T significantly increases the risk for both FTD-s (n 2139, OR 3.0, CI: 1.65.6, P 0.0005) and Alzheimers disease (AD) (n 3345, OR 2.3, CI: 1.34.2, 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.

引用

页码：3500 / 3512

页数：13

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