Mutations in SCO2 Are Associated with Autosomal-Dominant High-Grade Myopia
Mutations in SCO2 Are Associated with Autosomal-Dominant High-Grade Myopia
复制标题
DOI：
10.1016/j.ajhg.2013.04.005
复制
发表时间：
2013-05-02
影响因子：
9.8
通讯作者：
Young, Terri L.
中科院分区：
文献类型：
--
作者：
Tran-Viet, Khanh-Nhat;Powell, Caldwell;Young, Terri L.
近视，或近视，是视网膜平面前散焦的图像质量的眼睛屈光不正。高度近视(屈光度大于-6.00)的人容易患上青光眼、视网膜脱离和近视性黄斑病变等眼部疾病。无综合征的高度近视具有高度的遗传性，到目前为止，已有多个基因位点的报道。我们对来自美国的一个11人的欧洲血统家庭的4个个体进行了外显子组测序。受影响的人的平均屈光度相当于-22.00球。在位于染色体22q13.33的SCO2中发现了与疾病相关的过早终止密码子突变c.157C>；T(p.Gln53*)。随后的分析在三个高度近视无关个体(c.341G>；A、c.418G>；A和c.776C>；T)中发现了另外三个突变。为了确定发育小鼠模型中差异基因的表达，我们通过在一只眼睛上应用-15.00D透镜来诱导近视。近视小鼠视网膜中SCO2的信使RNA水平显著下调。小鼠眼睛的免疫组织化学证实SCO2蛋白定位于视网膜、视网膜色素上皮和巩膜。SCO2编码一种铜稳态蛋白，影响线粒体细胞色素C氧化酶的活性。铜缺乏与光感受器丧失和近视与巩膜壁弹性增加有关。据报道，视网膜变薄与SCO2的变种有关。在诱导近视动物的支持下，人类突变鉴定提供了近视发展的生物学见解。
Myopia, or near-sightedness, is an ocular refractive error of unfocused image quality in front of the retinal plane. Individuals with high-grade myopia (dioptric power greater than -6.00) are predisposed to ocular morbidities such as glaucoma, retinal detachment, and myopic maculopathy. Nonsyndromic, high-grade myopia is highly heritable, and to date multiple gene loci have been reported. We performed exome sequencing in 4 individuals from an 11-member family of European descent from the United States. Affected individuals had a mean dioptric spherical equivalent of -22.00 sphere. A premature stop codon mutation c.157C>T (p.Gln53*) cosegregating with disease was discovered within SCO2 that maps to chromosome 22q13.33. Subsequent analyses identified three additional mutations in three highly myopic unrelated individuals (c.341G>A, c.418G>A, and c.776C>T). To determine differential gene expression in a developmental mouse model, we induced myopia by applying a -15.00D lens over one eye. Messenger RNA levels of SCO2 were significantly downregulated in myopic mouse retinae. Immunohistochemistry in mouse eyes confirmed SCO2 protein localization in retina, retinal pigment epithelium, and sclera. SCO2 encodes for a copper homeostasis protein influential in mitochondrial cytochrome c oxidase activity. Copper deficiencies have been linked with photoreceptor loss and myopia with increased scleral wall elasticity. Retinal thinning has been reported with an SCO2 variant. Human mutation identification with support from an induced myopic animal provides biological insights of myopic development.