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PMID |
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TITLE |
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Investigating the role of rare coding variability in Mendelian dementia genes (APP, PSEN1, PSEN2, GRN, MAPT, and PRNP) in late-onset Alzheimer's disease. |
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ABSTRACT |
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The overlapping clinical and neuropathologic features between late-onset apparently sporadic Alzheimer's disease (LOAD), familial Alzheimer's disease (FAD), and other neurodegenerative dementias (frontotemporal dementia, corticobasal degeneration, progressive supranuclear palsy, and Creutzfeldt-Jakob disease) raise the question of whether shared genetic risk factors may explain the similar phenotype among these disparate disorders. To investigate this intriguing hypothesis, we analyzed rare coding variability in 6 Mendelian dementia genes (APP, PSEN1, PSEN2, GRN, MAPT, and PRNP), in 141 LOAD patients and 179 elderly controls, neuropathologically proven, from the UK. In our cohort, 14 LOAD cases (10%) and 11 controls (6%) carry at least 1 rare variant in the genes studied. We report a novel variant in PSEN1 (p.I168T) and a rare variant in PSEN2 (p.A237V), absent in controls and both likely pathogenic. Our findings support previous studies, suggesting that (1) rare coding variability in PSEN1 and PSEN2 may influence the susceptibility for LOAD and (2) GRN, MAPT, and PRNP are not major contributors to LOAD. Thus, genetic screening is pivotal for the clinical differential diagnosis of these neurodegenerative dementias. |
Copyright © 2014 Elsevier Inc. All rights reserved. |
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DATE PUBLISHED |
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HISTORY |
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PUBSTATUS |
PUBSTATUSDATE |
received |
2014/04/20 |
revised |
2014/06/06 |
accepted |
2014/06/07 |
aheadofprint |
2014/06/16 |
entrez |
2014/08/09 06:00 |
pubmed |
2014/08/12 06:00 |
medline |
2015/11/10 06:00 |
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AUTHORS |
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NAME |
COLLECTIVENAME |
LASTNAME |
FORENAME |
INITIALS |
AFFILIATION |
AFFILIATIONINFO |
Sassi C |
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Sassi |
Celeste |
C |
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Department of Molecular Neuroscience, UCL Institute of Neurology, University College London, London, UK; Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA. Electronic address: celeste.sassi.10@ucl.ac.uk. |
Guerreiro R |
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Guerreiro |
Rita |
R |
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Department of Molecular Neuroscience, UCL Institute of Neurology, University College London, London, UK; Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA. |
Gibbs R |
|
Gibbs |
Raphael |
R |
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Department of Molecular Neuroscience, UCL Institute of Neurology, University College London, London, UK; Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA. |
Ding J |
|
Ding |
Jinhui |
J |
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Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA. |
Lupton MK |
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Lupton |
Michelle K |
MK |
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King's College London Institute of Psychiatry, London, UK. |
Troakes C |
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Troakes |
Claire |
C |
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King's College London Institute of Psychiatry, London, UK. |
Al-Sarraj S |
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Al-Sarraj |
Safa |
S |
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King's College London Institute of Psychiatry, London, UK. |
Niblock M |
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Niblock |
Michael |
M |
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King's College London Institute of Psychiatry, London, UK. |
Gallo JM |
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Gallo |
Jean-Marc |
JM |
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King's College London Institute of Psychiatry, London, UK. |
Adnan J |
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Adnan |
Jihad |
J |
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King's College London Institute of Psychiatry, London, UK. |
Killick R |
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Killick |
Richard |
R |
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King's College London Institute of Psychiatry, London, UK. |
Brown KS |
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Brown |
Kristelle S |
KS |
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Translation Cell Sciences-Human Genetics, School of Life Sciences, Queens Medical Centre, University of Nottingham, Nottingham, UK. |
Medway C |
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Medway |
Christopher |
C |
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Translation Cell Sciences-Human Genetics, School of Life Sciences, Queens Medical Centre, University of Nottingham, Nottingham, UK. |
Lord J |
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Lord |
Jenny |
J |
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Translation Cell Sciences-Human Genetics, School of Life Sciences, Queens Medical Centre, University of Nottingham, Nottingham, UK. |
Turton J |
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Turton |
James |
J |
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Translation Cell Sciences-Human Genetics, School of Life Sciences, Queens Medical Centre, University of Nottingham, Nottingham, UK. |
Bras J |
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Bras |
Jose |
J |
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Department of Molecular Neuroscience, UCL Institute of Neurology, University College London, London, UK. |
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Alzheimer's Research UK Consortium |
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Morgan K |
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Morgan |
Kevin |
K |
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Translation Cell Sciences-Human Genetics, School of Life Sciences, Queens Medical Centre, University of Nottingham, Nottingham, UK. |
Powell JF |
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Powell |
John F |
JF |
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King's College London Institute of Psychiatry, London, UK. |
Singleton A |
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Singleton |
Andrew |
A |
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Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA. |
Hardy J |
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Hardy |
John |
J |
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Department of Molecular Neuroscience, UCL Institute of Neurology, University College London, London, UK. |
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INVESTIGATORS |
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JOURNAL |
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VOLUME: 35 |
ISSUE: 12 |
TITLE: Neurobiology of aging |
ISOABBREVIATION: Neurobiol. Aging |
YEAR: 2014 |
MONTH: Dec |
DAY: |
MEDLINEDATE: |
SEASON: |
CITEDMEDIUM: Internet |
ISSN: 1558-1497 |
ISSNTYPE: Electronic |
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MEDLINE JOURNAL |
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MEDLINETA: Neurobiol Aging |
COUNTRY: United States |
ISSNLINKING: 0197-4580 |
NLMUNIQUEID: 8100437 |
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PUBLICATION TYPE |
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PUBLICATIONTYPE TEXT |
Journal Article |
Research Support, Non-U.S. Gov't |
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COMMENTS AND CORRECTIONS |
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REFTYPE |
REFSOURCE |
REFPMID |
NOTE |
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GRANTS |
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GRANTID |
AGENCY |
COUNTRY |
089698 |
Wellcome Trust |
United Kingdom |
089701 |
Wellcome Trust |
United Kingdom |
G1100695 |
Medical Research Council |
United Kingdom |
WT089698 |
Wellcome Trust |
United Kingdom |
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GENERAL NOTE |
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KEYWORDS |
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KEYWORD |
APP |
Alzheimer's disease |
Exome sequencing |
GRN |
MAPT |
Neurodegenerative dementia |
PRNP |
PSEN1 |
PSEN2 |
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MESH HEADINGS |
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DESCRIPTORNAME |
QUALIFIERNAME |
Aged |
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Aged, 80 and over |
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Alzheimer Disease |
genetics |
Amyloid beta-Protein Precursor |
genetics |
Cohort Studies |
genetics |
Dementia |
genetics |
Diagnosis, Differential |
genetics |
Female |
genetics |
Genetic Association Studies |
genetics |
Genetic Predisposition to Disease |
genetics |
Genetic Testing |
genetics |
Genetic Variation |
genetics |
Humans |
genetics |
Intercellular Signaling Peptides and Proteins |
genetics |
Male |
genetics |
Middle Aged |
genetics |
Presenilin-1 |
genetics |
Presenilin-2 |
genetics |
Prions |
genetics |
tau Proteins |
genetics |
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SUPPLEMENTARY MESH |
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GENE SYMBOLS |
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CHEMICALS |
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REGISTRYNUMBER |
NAMEOFSUBSTANCE |
0 |
APP protein, human |
0 |
Amyloid beta-Protein Precursor |
0 |
GRN protein, human |
0 |
Intercellular Signaling Peptides and Proteins |
0 |
MAPT protein, human |
0 |
PRNP protein, human |
0 |
PSEN1 protein, human |
0 |
PSEN2 protein, human |
0 |
Presenilin-1 |
0 |
Presenilin-2 |
0 |
Prions |
0 |
tau Proteins |
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OTHER ID's |
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OTHERID |
SOURCE |
PMC4236585 |
NLM |
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