EPHA2 is associated with age-related cortical cataract in mice and humans.
EPHA2 is associated with age-related cortical cataract in mice and humans.
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DOI：
10.1371/journal.pgen.1000584
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发表时间：
2009-07
期刊：
影响因子：
4.5
通讯作者：
Wang B
中科院分区：
文献类型：
--
作者：
Jun G;Guo H;Klein BE;Klein R;Wang JJ;Mitchell P;Miao H;Lee KE;Joshi T;Buck M;Chugha P;Bardenstein D;Klein AP;Bailey-Wilson JE;Gong X;Spector TD;Andrew T;Hammond CJ;Elston RC;Iyengar SK;Wang B
年龄相关性白内障是全世界失明的主要原因，皮质性白内障是第二常见的年龄相关性白内障类型。尽管很大一部分与年龄相关的白内障是可遗传的，但其遗传基础仍有待阐明。我们报告说，两个独立品系的小鼠中 Epha2 的纯合缺失导致了进行性皮质白内障。逆照显示一个月龄时皮质液泡发育；三个月左右出现可见白内障，六个月后发展为成熟白内障。 EPHA2蛋白在晶状体中的表达在空间和时间上受到调节。它在前部上皮细胞中含量较低，当细胞在赤道进入分化时上调，在皮质纤维细胞中强烈表达，但在细胞核中不存在。在白内障发病前，Epha2 的缺失导致 HSP25（人类 HSP27 的鼠同源物）的表达显着增加。过表达的 HSP25 处于磷酸化不足的形式，表明细胞应激过度和蛋白质错误折叠。在三个独立的全球白种人群体中测试了染色体 1p36 上的直系同源人类 EPHA2 基因与皮质白内障的等位基因关联。 EPHA2 中的常见变异被发现与皮质性白内障显着相关，其中 rs6678616 在荟萃分析中最为显着。此外，我们对连锁家族中 EPHA2 的外显子进行了测序，并在蛋白激酶结构域中发现了一个新的错义突变 Arg721Gln，该突变显着改变了 EPHA2 在细胞和生化检测中的功能。因此，来自人类和小鼠的综合证据表明，EPHA2 对于随着年龄的增长保持晶状体清晰度很重要。白内障是导致失明的主要原因。白内障可能在任何年龄形成，但发病率呈双峰分布——围产期或 50 岁以后。早期发病的形式遵循孟德尔遗传模式，并且很罕见。与年龄相关的白内障导致全球 1800 万例失明和 5900 万例视力下降。在三种类型的年龄相关性白内障中，已知皮质性白内障具有高度遗传性，尽管很少有基因与其病因相关。我们在这里报告 EPHA2 与皮质白内障相关。 EPHA2 在小鼠和人类皮质晶状体纤维细胞中表达，两个独立品系小鼠中 Epha2 的纯合缺失会导致白内障的发生，并随着年龄的增长而发展。常见和罕见的变异（包括 EPHA2 基因的错义突变）与三个不同白种人群体的皮质白内障相关。我们的研究确定了 EPHA2 是人类年龄相关性白内障的基因，并建立了 Epha2 敲除小鼠作为进行性皮质白内障的模型。
Age-related cataract is a major cause of blindness worldwide, and cortical cataract is the second most prevalent type of age-related cataract. Although a significant fraction of age-related cataract is heritable, the genetic basis remains to be elucidated. We report that homozygous deletion of Epha2 in two independent strains of mice developed progressive cortical cataract. Retroillumination revealed development of cortical vacuoles at one month of age; visible cataract appeared around three months, which progressed to mature cataract by six months. EPHA2 protein expression in the lens is spatially and temporally regulated. It is low in anterior epithelial cells, upregulated as the cells enter differentiation at the equator, strongly expressed in the cortical fiber cells, but absent in the nuclei. Deletion of Epha2 caused a significant increase in the expression of HSP25 (murine homologue of human HSP27) before the onset of cataract. The overexpressed HSP25 was in an underphosphorylated form, indicating excessive cellular stress and protein misfolding. The orthologous human EPHA2 gene on chromosome 1p36 was tested in three independent worldwide Caucasian populations for allelic association with cortical cataract. Common variants in EPHA2 were found that showed significant association with cortical cataract, and rs6678616 was the most significant in meta-analyses. In addition, we sequenced exons of EPHA2 in linked families and identified a new missense mutation, Arg721Gln, in the protein kinase domain that significantly alters EPHA2 functions in cellular and biochemical assays. Thus, converging evidence from humans and mice suggests that EPHA2 is important in maintaining lens clarity with age. Cataract is the leading cause of blindness. Cataract may form at any age, but the peak incidence is bimodal—in the perinatal period or later than 50 years of age. The early onset forms follow Mendelian inheritance patterns and are rare. Age-related cataract accounts for 18 million cases of blindness and 59 million cases of reduced vision worldwide. Among three types of age-related cataract, cortical cataract is known to be highly heritable, although few genes have been linked to its etiology. We report here that EPHA2 is associated with cortical cataract. EPHA2 is expressed in mouse and human cortical lens fiber cells, and homozygous deletion of Epha2 in two independent strains of mice led to development of cataract that progressed with age. Common and rare variants including a missense mutation in the EPHA2 gene were associated for cortical cataract in three different Caucasian populations. Our study identified EPHA2 as a gene for human age-related cataract and established Epha2 knockout mice as a model for progressive cortical cataract.
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影响因子：
4.2
作者：
Klein, BEK;Klein, R;Lee, KE
通讯作者：
Lee, KE
影响因子：
3.9
作者：
Foster, A;Resnikoff, S
通讯作者：
Resnikoff, S
影响因子：
16.2
作者：
Feldheim, DA;Vanderhaeghen, P;Flanagan, JG
通讯作者：
Flanagan, JG
DOI：
10.1073/pnas.0808987105
发表时间：
2008-10-28
影响因子：
11.1
作者：
Cooper, Margaret A.;Son, Alexander I.;Zhou, Renping
通讯作者：
Zhou, Renping
影响因子：
2.3
作者：
Frederikse, Peter H.;Donnelly, Robert;Partyka, Lukasz M.
通讯作者：
Partyka, Lukasz M.