Sassi, C;
Guerreiro, R;
Gibbs, R;
Ding, J;
Lupton, MK;
Troakes, C;
Al-Sarraj, S;
... Hardy, J; + view all
(2014)
Investigating the role of rare coding variability in Mendelian dementia genes (APP, PSEN1, PSEN2, GRN, MAPT, and PRNP) in late-onset Alzheimer's disease.
Neurobiology of Aging
, 35
(12)
2881.e1-2881.e6.
10.1016/j.neurobiolaging.2014.06.002.
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Abstract
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.
| Type: | Article |
|---|---|
| Title: | Investigating the role of rare coding variability in Mendelian dementia genes (APP, PSEN1, PSEN2, GRN, MAPT, and PRNP) in late-onset Alzheimer's disease |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1016/j.neurobiolaging.2014.06.002 |
| Publisher version: | http://dx.doi.org/10.1016/j.neurobiolaging.2014.06... |
| Language: | English |
| Additional information: | Copyright © 2014 Elsevier Inc. Article available under CC BY licence |
| Keywords: | APP, Alzheimer's disease, Exome sequencing, GRN, MAPT, Neurodegenerative dementia, PRNP, PSEN1, PSEN2, Aged, Aged, 80 and over, Alzheimer Disease, Amyloid beta-Protein Precursor, Cohort Studies, Dementia, Diagnosis, Differential, Female, Genetic Association Studies, Genetic Predisposition to Disease, Genetic Testing, Genetic Variation, Humans, Intercellular Signaling Peptides and Proteins, Male, Middle Aged, Presenilin-1, Presenilin-2, Prions, tau Proteins |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Neurodegenerative Diseases |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/1437467 |
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