Allen Mariet, Lincoln Sarah J, Corda Morgane, Watzlawik Jens O, Carrasquillo Minerva M, Reddy Joseph S, Burgess Jeremy D, Nguyen Thuy, Malphrus Kimberly, Petersen Ronald C, Graff-Radford Neill R, Dickson Dennis W, Ertekin-Taner Nilüfer
Form the Department of Neuroscience (M.A., S.J.L., M.C., J.O.W., M.M.C., J.S.R., J.D.B., T.N., K.M., D.W.D., N.E.-T.), Department of Neurology (N.R.G.-R., N.E.-T.), Mayo Clinic, Jacksonville, FL; and Department of Neurology (R.C.P.), Mayo Clinic, Rochester, MN.
Neurol Genet. 2017 Jan 5;3(1):e126. doi: 10.1212/NXG.0000000000000126. eCollection 2017 Feb.
To investigate and characterize putative "loss-of-function" (LOF) adenosine triphosphate-binding cassette, subfamily A member 7 () mutations reported to associate with Alzheimer disease (AD) risk.
We genotyped 6 previously reported putative LOF variants in 1,465 participants with AD, 381 participants with other neuropathologies (non-AD), and 1,043 controls and assessed the overall mutational burden for association with different diagnosis groups. We measured brain ABCA7 protein and messenger RNA (mRNA) levels using Western blot and quantitative PCR, respectively, in 11 carriers of the 3 most common variants, and sequenced all 47 ABCA7 exons in these participants to screen for other coding variants.
At least one of the investigated variants was identified in 45 participants with late-onset Alzheimer disease, 12 participants with other neuropathologies, and 11 elderly controls. Association analysis revealed a significantly higher burden of these variants in participants with AD ( = 5.00E-04) and those with other neuropathologies ( = 8.60E-03) when compared with controls. Concurrent analysis of brain ABCA7 mRNA and protein revealed lower protein but not mRNA in p.L1403fs carriers, lower mRNA but not protein in p.E709fs carriers, and additional deleterious mutations in some c.5570+5G>C carriers.
Our results suggest that LOF may not be a common mechanism for these variants and expand the list of neurologic diseases enriched for them.
研究并表征据报道与阿尔茨海默病（AD）风险相关的假定“功能丧失”（LOF）三磷酸腺苷结合盒亚家族A成员7（ABCA7）突变。
我们对1465名AD患者、381名患有其他神经病理学疾病（非AD）的参与者和1043名对照者进行基因分型，检测6个先前报道的假定LOF变异，并评估与不同诊断组相关的总体突变负担。我们分别使用蛋白质免疫印迹法和定量聚合酶链反应，测量了11名携带3种最常见变异的携带者的脑ABCA7蛋白和信使核糖核酸（mRNA）水平，并对这些参与者的所有47个ABCA7外显子进行测序，以筛选其他编码变异。
在45名晚发性阿尔茨海默病患者、12名患有其他神经病理学疾病的参与者和11名老年对照者中鉴定出至少一种研究的变异。关联分析显示，与对照组相比，AD患者（P = 5.00E - 04）和患有其他神经病理学疾病的参与者（P = 8.60E - 03）中这些变异的负担显著更高。对脑ABCA7 mRNA和蛋白质的同步分析显示，p.L1403fs携带者中蛋白质水平较低但mRNA水平未降低，p.E709fs携带者中mRNA水平较低但蛋白质水平未降低，并且一些c.5570 + 5G>C携带者存在其他有害突变。
我们的结果表明，功能丧失可能不是这些变异的常见机制，并扩展了富含这些变异的神经系统疾病列表。
