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

卷:35

Article

Sassi, Celeste^1,2  Guerreiro, Rita^1,2  Gibbs, Raphael^1,2  Ding, Jinhui²  Lupton, Michelle K.³  Troakes, Claire³  Al-Sarraj, Safa³  Niblock, Michael³  Gallo, Jean-Marc³  Adnan, Jihad³  Killick, Richard³  Brown, Kristelle S.⁴  Medway, Christopher⁴  Lord, Jenny⁴  Turton, James⁴  Bras, Jose¹  Morgan, Kevin⁴  Powell, John F.³  Singleton, Andrew²  Hardy, John¹ 

[1] UCL, UCL Inst Neurol, Dept Mol Neurosci, London, England

[2] NIA, Neurogenet Lab, Bethesda, MD 20892 USA

[3] Kings Coll London, Inst Psychiat, London, England

[4] Univ Nottingham, Queens Med Ctr, Sch Life Sci, Nottingham NG7 2RD, England

关键词: Alzheimer's disease;    Neurodegenerative dementia;    APP;    PSEN1;    PSEN2;    MAPT;    GRN;    PRNP;    Exome sequencing;   

DOI  :  10.1016/j.neurobiolaging.2014.06.002

来源: Elsevier

【 摘 要 】

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. (C) 2014 Elsevier Inc. All rights reserved.

【 授权许可】

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