δ-Catenin is genetically and biologically associated with cortical cataract and future Alzheimer-related structural and functional brain changes.
δ-Catenin is genetically and biologically associated with cortical cataract and future Alzheimer-related structural and functional brain changes.
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DOI：
10.1371/journal.pone.0043728
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Farrer LA
中科院分区：
文献类型：
--
作者：
Jun G;Moncaster JA;Koutras C;Seshadri S;Buros J;McKee AC;Levesque G;Wolf PA;St George-Hyslop P;Goldstein LE;Farrer LA
多种证据表明，年龄相关性白内障（ARC）和阿尔茨海默病（AD）的特定亚型在病因学上相关。为了确定ARC和AD的共同遗传因素，我们估计了1，249名在眼科检查后约10年进行脑部MRI扫描的Frauhal Eye研究成员中白内障亚型与AD相关脑部MRI特征的定量测量的共遗传性。发现皮质性白内障（CC）与AD的未来发展和几种MRI特征，特别是颞角体积（THV，ρ = 0.24，P<10−4）。一项使用187，657个单核苷酸多态性（SNP）进行CC和THV双变量结局的全基因组关联研究发现，CTNND 2 SNP rs 17183619、rs 13155993和rs 13170756与全基因组显著相关（P<2.6×10−7）。这些SNP也与CC的双变量结果和几个高度遗传的神经心理学测试的得分显著相关（5.7×10−9≤P<3.7×10−6）。CC（P = 0.0015）和CC-THV（P = 0.038）上rs 17183619和APP SNP rs 2096488之间存在统计学相互作用。 一种罕见的CTNND 2错义突变（G810 R）249碱基对从rs 17183619改变δ-连环蛋白定位和增加分泌的淀粉样蛋白β1-42在神经元细胞培养。从两名尸检证实的AD受试者和两名非AD对照者获得的透镜组织的免疫组织病理学分析显示，与对照组相比，AD受试者晶状体的上皮和皮质区域中δ-连环蛋白的表达升高。我们的研究结果表明，δ连环蛋白的遗传变异可能是中年时皮质透镜混浊和随后的MRI和认知变化的基础，这些变化预示着AD的发展。
Multiple lines of evidence suggest that specific subtypes of age-related cataract (ARC) and Alzheimer disease (AD) are related etiologically. To identify shared genetic factors for ARC and AD, we estimated co-heritability of quantitative measures of cataract subtypes with AD-related brain MRI traits among 1,249 members of the Framingham Eye Study who had a brain MRI scan approximately ten years after the eye exam. Cortical cataract (CC) was found to be co-heritable with future development of AD and with several MRI traits, especially temporal horn volume (THV, ρ = 0.24, P<10−4). A genome-wide association study using 187,657 single nucleotide polymorphisms (SNPs) for the bivariate outcome of CC and THV identified genome-wide significant association with CTNND2 SNPs rs17183619, rs13155993 and rs13170756 (P<2.6×10−7). These SNPs were also significantly associated with bivariate outcomes of CC and scores on several highly heritable neuropsychological tests (5.7×10−9≤P<3.7×10−6). Statistical interaction was demonstrated between rs17183619 and APP SNP rs2096488 on CC (P = 0.0015) and CC-THV (P = 0.038). A rare CTNND2 missense mutation (G810R) 249 base pairs from rs17183619 altered δ-catenin localization and increased secreted amyloid-β1–42 in neuronal cell culture. Immunohistopathological analysis of lens tissue obtained from two autopsy-confirmed AD subjects and two non-AD controls revealed elevated expression of δ-catenin in epithelial and cortical regions of lenses from AD subjects compared to controls. Our findings suggest that genetic variation in delta catenin may underlie both cortical lens opacities in mid-life and subsequent MRI and cognitive changes that presage the development of AD.
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影响因子：
--
作者：
Choi SH;Liu C;Dupuis J;Logue MW;Jun G
通讯作者：
Jun G
影响因子：
9.2
作者：
Israely, I;Costa, RM;Liu, X
通讯作者：
Liu, X
影响因子：
2.5
作者：
Dhaenens, CM;Van Brussel, E;Sablonnière, B
通讯作者：
Sablonnière, B
影响因子：
2
作者：
Frederikse, PH
通讯作者：
Frederikse, PH
影响因子：
2.3
作者：
FARMER, ME;WHITE, LR;FEINLEIB, M
通讯作者：
FEINLEIB, M