Investigating the role of rare coding variability in Mendelian dementia genes (APP, PSEN1, PSEN2, GRN, MAPT, and PRNP) in late-onset Alzheimer's disease.
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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DOI：
10.1016/j.neurobiolaging.2014.06.002
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发表时间：
2014-12
影响因子：
4.2
通讯作者：
Hardy J
中科院分区：
文献类型：
--
作者：
Sassi C;Guerreiro R;Gibbs R;Ding J;Lupton MK;Troakes C;Al-Sarraj S;Niblock M;Gallo JM;Adnan J;Killick R;Brown KS;Medway C;Lord J;Turton J;Bras J;Alzheimer's Research UK Consortium;Morgan K;Powell JF;Singleton A;Hardy J
迟发性散发性阿尔茨海默病 (LOAD)、家族性阿尔茨海默病 (FAD) 和其他神经退行性痴呆（额颞叶痴呆、皮质基底节变性、进行性核上性麻痹和克雅氏病）之间重叠的临床和神经病理学特征提出了一个问题：共同的遗传风险因素是否可以解释这些不同疾病之间的相似表型。为了研究这个有趣的假设，我们分析了来自英国的 141 名 LOAD 患者和 179 名老年对照中 6 个孟德尔痴呆基因（APP、PSEN1、PSEN2、GRN、MAPT 和 PRNP）的罕见编码变异，这些基因均经过神经病理学证实。在我们的队列中，14 个 LOAD 病例 (10%) 和 11 个对照 (6%) 在所研究的基因中携带至少 1 个罕见变异。我们报告了 PSEN1 (p.I168T) 中的一种新变异和 PSEN2 (p.A237V) 中的一种罕见变异，这些变异在对照中不存在，并且都可能致病。我们的研究结果支持之前的研究，表明 (1) PSEN1 和 PSEN2 中罕见的编码变异可能会影响 LOAD 的敏感性，(2) GRN、MAPT 和 PRNP 不是 LOAD 的主要贡献者。因此，基因筛查对于这些神经退行性痴呆的临床鉴别诊断至关重要。我们使用外显子组测序来研究孟德尔痴呆基因（APP、PSEN1、PSEN2、GRN、MAPT 和 PRNP）的罕见编码变异，该队列由 141 名晚发散发性阿尔茨海默病病例和 179 名老年对照者组成，经英国尸检证实。我们报告了 PSEN1 (p.I168T) 的一种新突变和 PSEN2 (p.A237V) 的一种罕见变异，两者都可能致病。我们得出结论，PSEN1 和 PSEN2 含有散发性阿尔茨海默病的易感因素。相比之下，GRN、MAPT 和 PRNP 在晚发散发性阿尔茨海默病的发展中并不起主要作用。因此，遗传筛查对于散发性迟发性阿尔茨海默病和其他神经退行性痴呆（额颞叶痴呆、皮质基底节变性、进行性核上性麻痹和克雅氏病）的临床鉴别诊断至关重要。
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. We have used exome sequencing to investigate rare coding variability in Mendelian dementia genes (APP, PSEN1, PSEN2, GRN, MAPT, and PRNP) in a cohort composed of 141 late-onset sporadic Alzheimer's disease cases and 179 elderly controls, autopsy proven from the UK. We report a novel mutation in PSEN1 (p.I168T) and a rare variant in PSEN2 (p.A237V), both likely pathogenic. We conclude that PSEN1 and PSEN2 harbor susceptibility factors for sporadic Alzheimer's disease. By contrast, GRN, MAPT, and PRNP do not play a major role for the development of late-onset sporadic Alzheimer's disease. Genetic screening is therefore pivotal for a clinical differential diagnosis of sporadic late-onset Alzheimer's disease and other neurodegenerative dementias (frontotemporal dementia, corticobasal degeneration, progressive supranuclear palsy, and Creutzfeldt-Jakob disease).
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DOI：
10.1056/nejmoa1211851
发表时间：
2013-01-10
期刊：
The New England journal of medicine
影响因子：
--
作者：
Guerreiro R;Wojtas A;Bras J;Carrasquillo M;Rogaeva E;Majounie E;Cruchaga C;Sassi C;Kauwe JS;Younkin S;Hazrati L;Collinge J;Pocock J;Lashley T;Williams J;Lambert JC;Amouyel P;Goate A;Rademakers R;Morgan K;Powell J;St George-Hyslop P;Singleton A;Hardy J;Alzheimer Genetic Analysis Group
通讯作者：
Alzheimer Genetic Analysis Group
影响因子：
30.8
作者：
Harold, Denise;Abraham, Richard;Hollingworth, Paul;Sims, Rebecca;Gerrish, Amy;Hamshere, Marian L.;Pahwa, Jaspreet Singh;Moskvina, Valentina;Dowzell, Kimberley;Williams, Amy;Jones, Nicola;Thomas, Charlene;Stretton, Alexandra;Morgan, Angharad R.;Lovestone, Simon;Powell, John;Proitsi, Petroula;Lupton, Michelle K.;Brayne, Carol;Rubinsztein, David C.;Gill, Michael;Lawlor, Brian;Lynch, Aoibhinn;Morgan, Kevin;Brown, Kristelle S.;Passmore, Peter A.;Craig, David;McGuinness, Bernadette;Todd, Stephen;Holmes, Clive;Mann, David;Smith, A. David;Love, Seth;Kehoe, Patrick G.;Hardy, John;Mead, Simon;Fox, Nick;Rossor, Martin;Collinge, John;Maier, Wolfgang;Jessen, Frank;Schuermann, Britta;van den Bussche, Hendrik;Heuser, Isabella;Kornhuber, Johannes;Wiltfang, Jens;Dichgans, Martin;Froelich, Lutz;Hampel, Harald;Huell, Michael;Rujescu, Dan;Goate, Alison M.;Kauwe, John S. K.;Cruchaga, Carlos;Nowotny, Petra;Morris, John C.;Mayo, Kevin;Sleegers, Kristel;Bettens, Karolien;Engelborghs, Sebastiaan;De Deyn, Peter P.;Van Broeckhoven, Christine;Livingston, Gill;Bass, Nicholas J.;Gurling, Hugh;McQuillin, Andrew;Gwilliam, Rhian;Deloukas, Panagiotis;Al-Chalabi, Ammar;Shaw, Christopher E.;Tsolaki, Magda;Singleton, Andrew B.;Guerreiro, Rita;Muehleisen, Thomas W.;Noethen, Markus M.;Moebus, Susanne;Joeckel, Karl-Heinz;Klopp, Norman;Wichmann, H-Erich;Carrasquillo, Minerva M.;Pankratz, V. Shane;Younkin, Steven G.;Holmans, Peter A.;O'Donovan, Michael;Owen, Michael J.;Williams, Julie
通讯作者：
Williams, Julie
影响因子：
3.7
作者：
Cruchaga C;Haller G;Chakraverty S;Mayo K;Vallania FL;Mitra RD;Faber K;Williamson J;Bird T;Diaz-Arrastia R;Foroud TM;Boeve BF;Graff-Radford NR;St Jean P;Lawson M;Ehm MG;Mayeux R;Goate AM;NIA-LOAD/NCRAD Family Study Consortium
通讯作者：
NIA-LOAD/NCRAD Family Study Consortium
影响因子：
64.8
作者：
PALMER, MS;DRYDEN, AJ;COLLINGE, J
通讯作者：
COLLINGE, J
影响因子：
7
作者：
Biesecker, Leslie G.;Mullikin, James C.;Green, Eric D.
通讯作者：
Green, Eric D.