An ENU-induced mutation of Nrg1 causes dilated pupils and a reduction in muscarinic receptors in the sphincter pupillae.
An ENU-induced mutation of Nrg1 causes dilated pupils and a reduction in muscarinic receptors in the sphincter pupillae.
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ENU 诱导的 Nrg1 突变导致瞳孔放大和瞳孔括约肌中毒蕈碱受体减少
DOI：
10.1371/journal.pone.0025176
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发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Xue Z
中科院分区：
文献类型：
--
作者：
Chen B;Li K;Zhang F;Zhai G;Gong W;Qiang S;Xue Z
N-乙基-N-亚硝基脲（ENU）诱变是研究基因功能和建立人类疾病模型的有力工具。通过ENU诱变获得了大量具有多种表型的小鼠突变体。然而，在基因确认测试后，只有大约50%的异常表型被发现是可遗传的。用N-乙基-N-亚硝基脲（ENU）诱变策略诱导了具有散瞳表型的小鼠突变体Dp 1。Nrg 1的序列分析显示，在5′剪接供体位点，编码EGFβ结构域的外显子E59侧翼有一个G>A碱基取代。该突变影响但不消除Dp 1小鼠中EGFβ-型Nrg 1 mRNA的剪接，并通过激活其他隐蔽剪接位点产生几种不同的转录物。这些类型的蛋白质同种型是预期的，并且结果表明，在突变体中，效果是降低但不是消除高亲和力EGFβ型Nrg 1同种型。这部分地通过低亲和力α形式或无活性蛋白质的表达增加来补偿，表明突变导致亚型等位基因。有趣的是，遗传模型测试表明，Dp 1是一种突变，导致散大瞳孔表型，当杂合子时以非常低的遗传率遗传，而当纯合子时以完全的遗传率遗传。药理学和免疫组织化学测试显示Dp 1小鼠瞳孔括约肌中的毒蕈碱（M）受体减少，这是瞳孔扩大的主要原因。这项研究是第一次报告的Nrg 1突变与散瞳表型和M受体的减少。这一研究结果有助于建立更多的突变小鼠品系和人类遗传病模型，并可应用于其他生物。Dp 1小鼠是进一步阐明Nrg 1生物学功能的宝贵资源。
N-ethyl-N-nitrosourea (ENU)-induced mutagenesis is a powerful tool for the study of gene function and the generation of human disease models. A large number of mouse mutants obtained by ENU-induced mutagenesis with a variety of phenotypes have been recovered. However, after genetic confirmation testing, only approximately 50% of the abnormal phenotypes were found to be heritable. A mouse mutant, Dp1, with a dilated pupil phenotype was induced with an N-ethyl-N-nitrosourea (ENU) mutagenesis strategy. Sequence analysis for Nrg1 reveals a G>A base substitution that flanks exon E59, encoding for an EGFβ domain, in the 5′ splice donor site. The mutation affects but does not abolish the splicing of EGFβ-type Nrg1 mRNA in Dp1 mice and produces several different transcripts by activating other, cryptic splice sites. These types of protein isoforms are expected, and the result shows that, in the mutant, the effect is a decrease in but not an elimination of the high affinity EGFβ-type Nrg1 isoforms. This is partially compensated for by an increase in expression of the low affinity alpha forms or inactive proteins, suggesting that the mutation results in a hypomorphic allele. Interestingly, genetic model testing shows that Dp1 is a mutation that results in a dilated pupil phenotype that is inherited with very low penetrance when heterozygous and with complete penetrance when homozygous. Pharmacological and immunohistochemical tests show a reduction of muscarinic (M) receptors in the sphincter pupillae of Dp1 mice, which is a major cause of dilated pupils. This study is the first report of an Nrg1 mutation being associated with a dilated pupil phenotype and the reduction of M receptors. This report may help in establishing more mutant mouse lines and models of human genetic disease and can be applied to other organisms. Dp1 mice are a valuable resource for the further clarification of Nrg1 biological function.
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DOI：
10.1523/jneurosci.1815-08.2008
发表时间：
2008-07-02
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Chen YJ;Johnson MA;Lieberman MD;Goodchild RE;Schobel S;Lewandowski N;Rosoklija G;Liu RC;Gingrich JA;Small S;Moore H;Dwork AJ;Talmage DA;Role LW
通讯作者：
Role LW
影响因子：
56.9
作者：
Sandrock, AW;Dryer, SE;Fischbach, GD
通讯作者：
Fischbach, GD
DOI：
10.1073/pnas.97.17.9579
发表时间：
2000-08-15
影响因子：
11.1
作者：
Matsui, M;Motomura, D;Taketo, MM
通讯作者：
Taketo, MM
影响因子：
3.5
作者：
Steinthorsdottir, V;Stefansson, H;Gulcher, JR
通讯作者：
Gulcher, JR
影响因子：
3.5
作者：
Thaung, C;West, K;Cross, SH
通讯作者：
Cross, SH