Mutation of ATF6 causes autosomal recessive achromatopsia.
Mutation of ATF6 causes autosomal recessive achromatopsia.
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DOI：
10.1007/s00439-015-1571-4
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发表时间：
2015-09
期刊：
影响因子：
5.3
通讯作者：
Leal SM
中科院分区：
文献类型：
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作者：
Ansar M;Santos-Cortez RL;Saqib MA;Zulfiqar F;Lee K;Ashraf NM;Ullah E;Wang X;Sajid S;Khan FS;Amin-ud-Din M;University of Washington Center for Mendelian Genomics;Smith JD;Shendure J;Bamshad MJ;Nickerson DA;Hameed A;Riazuddin S;Ahmed ZM;Ahmad W;Leal SM
全色盲（ACHM）是一种早发性视网膜营养不良，其特征是畏光、眼球震颤、色盲和严重的视力下降。目前，五种基因CNGA 3、CNGB 3、GNAT 2、PDE 6C和PDE 6 H的突变与ACHM有关。我们对一个有血缘关系的巴基斯坦ACHM家族进行了纯合性定位和连锁分析，并将该基因座定位到染色体1q23.1-q24.3上的15.12 Mb区域，最大LOD评分为3.6。来自受影响家庭成员的DNA样本进行外显子组测序。在ATF 6基因内，鉴定了单碱基插入变体c.355_356dupG（p.Glu119Glyfs*8），其与家族内的ACHM表型完全分离。移码变异在公共变异数据库中不存在，在130个无关的巴基斯坦个体的外显子组中，以及在235个种族匹配的对照中。该变体被预测为导致缺乏DNA结合和跨膜结构域的截短蛋白，因此影响ATF 6作为在内质网（ER）应激期间启动未折叠蛋白反应的转录因子的功能。用抗-ATF 6抗体的免疫标记显示在整个小鼠神经元视网膜中定位，包括视网膜色素上皮、感光细胞、内核层、内丛状层和外丛状层，在视网膜神经节细胞中具有更突出的信号。与野生型蛋白质的细胞质表达相反，在异源细胞中，具有p.Glu119Glyfs*8变体的ATF 6蛋白质主要局限于细胞核。我们的研究结果表明，响应ER应激介导的ATF 6途径是必不可少的色觉在人类。本文的在线版本（doi：10.1007/s 00439 -015-1571-4）包含补充材料，可供授权用户使用。
Achromatopsia (ACHM) is an early-onset retinal dystrophy characterized by photophobia, nystagmus, color blindness and severely reduced visual acuity. Currently mutations in five genes CNGA3, CNGB3, GNAT2, PDE6C and PDE6H have been implicated in ACHM. We performed homozygosity mapping and linkage analysis in a consanguineous Pakistani ACHM family and mapped the locus to a 15.12-Mb region on chromosome 1q23.1–q24.3 with a maximum LOD score of 3.6. A DNA sample from an affected family member underwent exome sequencing. Within the ATF6 gene, a single-base insertion variant c.355_356dupG (p.Glu119Glyfs*8) was identified, which completely segregates with the ACHM phenotype within the family. The frameshift variant was absent in public variant databases, in 130 exomes from unrelated Pakistani individuals, and in 235 ethnically matched controls. The variant is predicted to result in a truncated protein that lacks the DNA binding and transmembrane domains and therefore affects the function of ATF6 as a transcription factor that initiates the unfolded protein response during endoplasmic reticulum (ER) stress. Immunolabeling with anti-ATF6 antibodies showed localization throughout the mouse neuronal retina, including retinal pigment epithelium, photoreceptor cells, inner nuclear layer, inner and outer plexiform layers, with a more prominent signal in retinal ganglion cells. In contrast to cytoplasmic expression of wild-type protein, in heterologous cells ATF6 protein with the p.Glu119Glyfs*8 variant is mainly confined to the nucleus. Our results imply that response to ER stress as mediated by the ATF6 pathway is essential for color vision in humans. The online version of this article (doi:10.1007/s00439-015-1571-4) contains supplementary material, which is available to authorized users.